Lectins with Anti-HIV Activity: A Review
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Ouafae Akkouh
2015-01-01
Full Text Available Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin lectin, concanavalin A, Galanthus nivalis (snowdrop agglutinin-related lectins, Musa acuminata (banana lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus. The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed.
DEFF Research Database (Denmark)
Aly, Youssef L.; Pedersen, Erik Bjerreg.; La Colla, Paolo
2007-01-01
The synthesis and the anti-HIV-1 activity of a series of 2-arylthio-6-benzyl-2,3-dihydro-1H-pyrimidin-4-ones (aryl S-DABOs) are reported. These compounds were synthesized via a coupling reaction of the corresponding 6-benzyl-2-thiouracils with aryl iodides in the presence of neocuproine hydrate...
Faroux-Corlay, B; Clary, L; Gadras, C; Hammache, D; Greiner, J; Santaella, C; Aubertin, A M; Vierling, P; Fantini, J
2000-07-24
Galactosylceramide (GalCer) is an alternative receptor allowing HIV-1 entry into CD4(-)/GalCer(+) cells. This glycosphingolipid recognizes the V3 loop of HIV gp120, which plays a key role in the fusion of the HIV envelope and cellular membrane. To inhibit HIV uptake and infection, we designed and synthesized analogs of GalCer. These amphiphiles and bolaamphiphiles consist of single and double hydrocarbon and/or fluorocarbon chain beta-linked to galactose and galactosamine. They derive from serine (GalSer), cysteine (GalCys), and ethanolamine (GalAE). The anti-HIV activity and cytotoxicity of these galactolipids were evaluated in vitro on CEM-SS (a CD4(+) cell line), HT-29, a CD4(-) cell line expressing high levels of GalCer receptor, and/or HT29 genetically modified to express CD4. GalSer and GalAE derivatives, tested in aqueous medium or as part of liposome preparation, showed moderate anti-HIV-1 activities (IC50 in the 20-220 microM range), whereas none of the GalCys derivatives was found to be active. Moreover, only some of these anti-HIV active analogs inhibited the binding of [3H]suramin (a polysulfonyl compound which displays a high affinity for the V3 loop) to SPC3, a synthetic peptide which contains the conserved GPGRAF region of the V3 loop. Our results most likely indicate that the neutralization of the virion through masking of this conserved V3 loop region is not the only mechanism involved in the HIV-1 antiviral activity of our GalCer analogs.
Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model.
Directory of Open Access Journals (Sweden)
Silvana Pasetto
Full Text Available HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM-bl, HeLa, PBMC, and H9 cell cultures using 0.01-100 µM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic, H9 and PBMC cells plus HIV-1 MN (X4 tropic, and the dual tropic (X4R5 HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited ≥90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV-1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research.
DEFF Research Database (Denmark)
Aly, Youssef L.; Pedersen, Erik Bjerreg.; La Colla, Paolo
2007-01-01
Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse...... transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding...
Directory of Open Access Journals (Sweden)
Mimi Ghosh
2010-06-01
Full Text Available We investigated the impact of antimicrobials in cervicovaginal lavage (CVL from HIV(+ and HIV(- women on target cell infection with HIV. Since female reproductive tract (FRT secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+ and (- women inhibit HIV infection.CVL from 32 HIV(+ healthy women with high CD4 counts and 15 healthy HIV(- women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti-HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and anti-gp160 HIV IgG antibodies were measured by ELISA. When CXCR4 and CCR5 tropic HIV-1 were incubated with CVL from HIV(+ women prior to addition to TZM-bl cells, anti-HIV activity in CVL ranged from none to 100% inhibition depending on the viral strains used. CVL from HIV(- controls showed comparable anti-HIV activity. Analysis of CH077.c (clone of an R5-tropic, mucosally-transmitted founder virus viral inhibition by CVL was comparable to laboratory strains. Measurement of CVL for antimicrobials HBD2, trappin-2/elafin, SLPI and MIP3alpha indicated that each was present in CVL from HIV(+ and HIV(- women. HBD2 and MIP3alpha correlated with anti-HIV activity as did anti-gp160 HIV IgG antibodies in CVL from HIV(+ women.These findings indicate that CVL from healthy HIV(+ and HIV(- women contain innate and adaptive defense mechanisms that inhibit HIV infection. Our data suggest that innate endogenous antimicrobials and HIV-specific IgG in the FRT can act in concert to contribute toward the anti-HIV activity of the CVL and may play a role in inhibition of HIV transmission to women.
New findings on the d(TGGGAG) sequence: Surprising anti-HIV-1 activity.
Romanucci, Valeria; Zarrelli, Armando; Liekens, Sandra; Noppen, Sam; Pannecouque, Christophe; Di Fabio, Giovanni
2018-02-10
The biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations. The anti-HIV assays have been designed favouring the limited kinetics involved in the tetramolecular G4-association based on the d(TGGGAG) sequence. Aiming to determine the stoichiometry of G-quadruplex structures in the same experimental conditions of the anti-HIV assays, a native gel electrophoresis was performed. The gel confirmed the G-quadruplex formation for almost all sample solutions while showing the formation of high order G4 structures for the more concentrated ODNs solutions. The most significant result is the discovery of a potent anti-HIV activity of the G-quadruplex formed by the natural d(TGGGAG) sequence (IC 50 = 14 nM) that, until now, has been reported to be completely inactive against HIV infection. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
Energy Technology Data Exchange (ETDEWEB)
Kim, Seyeon; Hong, Joon Hee [Chosun University, Gwangju (Korea, Republic of)
2016-04-15
The first synthesis of novel 5',5'-difluoro-30-hydroxy apiose nucleoside cyclomonophosphonic acid analogs was performed as potent anti-retroviral agents. Phosphonation was performed by direct displacement of a triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding(α, α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside cyclomonophosphonic acid analogs. The synthesized nucleoside analogs were subjected to anti-viral screening against the human immunodeficiency virus-1 (HIV-1). Cytosine analogs show significant anti-HIV activity.
Synthesis and Antimicrobial Activities of Some New Pyrazoles ...
African Journals Online (AJOL)
NICO
29 antimalarial,30 antimicrobial,31,32 antiviral,33,34 hypoglycaemic,35 anti-HIV activity,36 insecticidal,37 and anti- fungal38 activities. In view of these reports and in continuation of our previous work39 we describe here a facile synthesis of.
Sulfated Polysaccharides in Marine Sponges: Extraction Methods and Anti-HIV Activity
Directory of Open Access Journals (Sweden)
Ana I. S. Esteves
2011-01-01
Full Text Available The extraction, fractionation and HIV-1 inhibition potential of polysaccharides extracted from three species of marine sponges, Erylus discophorus, Cliona celata and Stelletta sp., collected in the Northeastern Atlantic, is presented in this work. The anti-HIV activity of 23 polysaccharide pellets and three crude extracts was tested. Crude extracts prepared from Erylus discophorus specimens were all highly active against HIV-1 (90 to 95% inhibition. Cliona celata pellets showed low polysaccharide content (bellow 38.5% and almost no anti-HIV activity (<10% inhibition. Stelletta sp. pellets, although quite rich in polysaccharide (up to 97.3%, showed only modest bioactivity (<36% HIV-1 inhibition. Erylus discophorus pellets were among the richest in terms of polysaccharide content (up to 98% and the most active against HIV-1 (up to 95% inhibition. Chromatographic fractionation of the polysaccharide pellet obtained from a specimen of Erylus discophorus (B161 yielded only modestly active fractions. However, we could infer that the active molecule is most probably a high molecular weight sulfated polysaccharide (>2000 kDa, whose mechanism is possibly preventing viral attachment and entry (fusion inhibitor.
Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.
Lu, Zhenyu; Harper, Mary Kay; Pond, Christopher D; Barrows, Louis R; Ireland, Chris M; Van Wagoner, Ryan M
2012-08-24
As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 μM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 μM.
Mechanism of anti-HIV activity of succinylated human serum albumin
Kuipers, ME; Berg, HVD; Swart, PJ; Laman, Jon; Meijer, DKF; Kopelman, MHGM; Huisman, H
1999-01-01
In the present study, we described the interaction of succinylated human serum albumin (Suc-HSA), a negatively charged anti-HIV-1 active protein, with HIV-1 gp120 and in detail with the third variable domain of gp120 (V3 loop). To this end, different assay formats were tested in which gp120- and
International Nuclear Information System (INIS)
Uryu, Toshiyuki
1998-01-01
We have been synthesizing sulfated polysaccharides and oligosaccharides with highly anti-HIV (human immunodeficiency virus) activities. It has been known that sulfated polysaccharides such as dextran sulfate and pentosan polysulfate have biological activities such as anticoagulant activity and recently anti-HIV activity. Curdlan sulfate having 1,3-β-linked glucan backbone had high anti-HIV activity but low anticoagulant activity. Phase I/II test for the curdlan sulfate as an AIDS (acquired immunodeficiency syndrome) drug was carried out in the United States. In this study, regioselectivity sulfatec curdlan sulfates were prepared in order to study effects of sulfate groups and conformation of curdlan sulfates. In addition, action mechanisms of curdlan sulfate as anti-AIDS drug and of heparin as an anticoagulant were examined by means of NMR spectroscopy. 1. Structure dependence of anti-HIV and anticoagulant activities of sulfated polysaccharides. Curdlan with M n 9000 was regioselectively sulfated on its hydroxyl groups at 6, 4, and 2 positions. Those were a curdlan sulfate 62S in which 100% of 6-OH, and about 50% of 2-OH was sulfated, a curdlan sulfate 42S in which 4- and 2-OH's were sulfated, and a curdlan sulfate in which 6, 4, and 2-OH's were partially sulfated. All curdlan sulfates had very high anti-HIV activities exhibited by the drug concentration of 50% inhibition of infection, i.e., EC 50 of 0.04 - 0.25 μg/mL. However, there was almost no difference in the activity among the samples. Therefore, it was revealed that the degree of sulfation and putative conformation of the curdlan sulfates but not the position of sulfate groups have large effects on the anti-HIV activity. On the other hand, the anticoagulant activity increased with increasing molecular weight of the curdlan sulfates. As a result, it is assumed that the size of reaction sites of the virus protein reacting with curdlan sulfate is different from that of the proteins related to anticoagulant
Energy Technology Data Exchange (ETDEWEB)
Li, Hui-Guang [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Huang, Philip L. [American Biosciences, Boston, MA 02114 (United States); Zhang, Dawei; Sun, Yongtao [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Chen, Hao-Chia [Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892 (United States); Zhang, John [Department of Chemistry, New York University, New York, NY 10003 (United States); Huang, Paul L. [Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114 (United States); Kong, Xiang-Peng, E-mail: xiangpeng.kong@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Lee-Huang, Sylvia, E-mail: sylvia.lee-huang@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)
2010-01-01
We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.
Patel, Mickey V.; Ghosh, Mimi; Fahey, John V.; Ochsenbauer, Christina; Rossoll, Richard M.; Wira, Charles R.
2015-01-01
Problem Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions changes across the menstrual cycle is unknown. Method of Study Using a menstrual cup, vaginal secretions from premenopausal women were recovered at the proliferative (d6–8), mid-cycle (d13–15) and secretory (d21–23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line. Results CCL20, RANTES, elafin, HBD2, SDF-1α and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women, and in consecutive cycles from the same woman. Conclusion The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and inter-individual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life. PMID:24806967
Patel, Mickey V; Ghosh, Mimi; Fahey, John V; Ochsenbauer, Christina; Rossoll, Richard M; Wira, Charles R
2014-07-01
Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions change across the menstrual cycle is unknown. Using a menstrual cup, vaginal secretions from pre-menopausal women were recovered at the proliferative (d6-8), mid-cycle (d13-15), and secretory (d21-23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line. CCL20, RANTES, elafin, HBD2, SDF-1α, and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women and in consecutive cycles from the same woman. The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and interindividual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life. © 2014 John Wiley & Sons Ltd.
Agrahari, Vivek; Meng, Jianing; Ezoulin, Miezan Jm; Youm, Ibrahima; Dim, Daniel C; Molteni, Agostino; Hung, Wei-Ting; Christenson, Lane K; Youan, Bi-Botti C
2016-11-01
To develop a seminal enzyme bioresponsive, mucoadhesive nanofibers (NFs) as safe and effective nanocarriers for the prevention of HIV vaginal transmission. A novel thiolated hyaluronic acid (HA-SH) polymer was synthesized to fabricate tenofovir (TFV)-loaded electrospun NFs (HA-SH-NFs) and characterized in vitro/in vivo. A triggered drug release (87% w/w) from the engineered HA-SH-NFs (mean diameter ∼75 nm) occured within 1 h under the influence of seminal hyaluronidase enzyme. HA-SH-NFs were noncytotoxic, induced no damage on the C57BL/6 mice genital-tract and other organs. No significant CD45 cell-infiltration and changes in cytokines level in cervicovaginal tissues were observed. HA-SH-NFs significantly enhanced both TFV retention and bioavailability in vaginal tissue compared with the 1% TFV-gel. The anti-HIV activity of TFV (on pseudotyped virus followed by luciferase assay) was not adversely affected by the electrospinning process. HA-SH-NFs developed in this study could potentially serve as a safe nanotemplate for topical intravaginal delivery of HIV/AIDS microbicides.
Ali, Mohamed A; Ismail, Rusli; Choon, Tan S; Yoon, Yeong K; Wei, Ang C; Pandian, Suresh; Samy, Jeyabalan G; De Clercq, Eric; Pannecouque, Christophe
2011-01-01
A series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized by the reaction of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-indanone with hydroxylamine hydrochloride. The title compounds were tested for their in vitro anti-HIV activity. Among the compounds, (4g) showed a promising anti-HIV activity in the in vitro testing against IIIB and ROD strains. The IC50 of both IIIB and ROD were found to be 9.05 microM and > 125 microM, respectively.
Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV-1.
Gudmundsson, Kristjan S; Boggs, Sharon D; Catalano, John G; Svolto, Angilique; Spaltenstein, Andrew; Thomson, Michael; Wheelan, Pat; Jenkinson, Stephen
2009-11-15
Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.
Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides
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Li Yun-Yao
2006-10-01
Full Text Available Abstract Background Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP, a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. Methods The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring β-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP, the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. Results The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate, cellulose sulfate, carrageenan, CAP (in soluble form and polystyrene sulfonate, respectively, was considerably (range ≈ 4 to ≈ 73-fold diminished in the presence of SP (33.3%. Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. Conclusion The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors.
Dalod, Marc; Dupuis, Marion; Deschemin, Jean-Christophe; Sicard, Didier; Salmon, Dominique; Delfraissy, Jean-Francois; Venet, Alain; Sinet, Martine; Guillet, Jean-Gerard
1999-01-01
The ex vivo antiviral CD8+ repertoires of 34 human immunodeficiency virus (HIV)-seropositive patients with various CD4+ T-cell counts and virus loads were analyzed by gamma interferon enzyme-linked immunospot assay, using peptides derived from HIV type 1 and Epstein-Barr virus (EBV). Most patients recognized many HIV peptides, with markedly high frequencies, in association with all the HLA class I molecules tested. We found no correlation between the intensity of anti-HIV CD8+ responses and the CD4+ counts or virus load. In contrast, the polyclonality of anti-HIV CD8+ responses was positively correlated with the CD4+ counts. The anti-EBV responses were significantly less intense than the anti-HIV responses and were positively correlated with the CD4+ counts. Longitudinal follow-up of several patients revealed the remarkable stability of the anti-HIV and anti-EBV CD8+ responses in two patients with stable CD4+ counts, while both antiviral responses decreased in two patients with obvious progression toward disease. Last, highly active antiretroviral therapy induced marked decreases in the number of anti-HIV CD8+ T cells, while the anti-EBV responses increased. These findings emphasize the magnitude of the ex vivo HIV-specific CD8+ responses at all stages of HIV infection and suggest that the CD8+ hyperlymphocytosis commonly observed in HIV infection is driven mainly by virus replication, through intense, continuous activation of HIV-specific CD8+ T cells until ultimate progression toward disease. Nevertheless, highly polyclonal anti-HIV CD8+ responses may be associated with a better clinical status. Our data also suggest that a decrease of anti-EBV CD8+ responses may occur with depletion of CD4+ T cells, but this could be restored by highly active antiretroviral treatment. PMID:10438796
Heyman, Heino Martin; Senejoux, François; Seibert, Isabell; Klimkait, Thomas; Maharaj, Vinesh Jaichand; Meyer, Jacobus Johannes Marion
2015-06-01
South Africa being home to more than 35% of the world's Helichrysum species (c.a. 244) of which many are used in traditional medicine, is seen potentially as a significant resource in the search of new anti-HIV chemical entities. It was established that five of the 30 Helichrysum species selected for this study had significant anti-HIV activity ranging between 12 and 21 μg/mL (IC50) by using an in-house developed DeCIPhR method on a full virus model. Subsequent toxicity tests also revealed little or no toxicity for these active extracts. With the use of NMR-based metabolomics, the search for common chemical characteristics within the plant extract was conducted, which resulted in specific chemical shift areas identified that could be linked to the anti-HIV activity of the extracts. The NMR chemical shifts associated with the activity were identified to be 2.56-3.08 ppm, 5.24-6.28 ppm, 6.44-7.04 ppm and 7.24-8.04 ppm. This activity profile was then used to guide the fractionation process by narrowing down and focusing the fractionation and purification processes to speed up the putative identification of five compounds with anti-HIV activity in the most active species, Helichrysum populifolium. The anti-HIV compounds identified for the first time from H. populifolium were three dicaffeoylquinic acid derivatives, i.e. 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid as well as two tricaffeoylquinic acid derivatives i.e. 1,3,5-tricaffeoylquinic acid and either 5-malonyl-1,3,4-tricaffeoylquinic or 3-malonyl-1,4,5-tricaffeoylquinic acid, with the latter being identified for the first time in the genus. Copyright © 2015 Elsevier B.V. All rights reserved.
Flazinamide, a novel β-carboline compound with anti-HIV actions
International Nuclear Information System (INIS)
Wang Yunhua; Tang Jianguo; Wang Ruirui; Yang Liumeng; Dong Zejun; Du Li; Shen Xu; Liu Jikai; Zheng Yongtang
2007-01-01
A β-carboline compound, flazin isolated from Suillus granulatus has been shown weak anti-HIV-1 activity. Based on the structure of flazin, flazinamide [1-(5'- hydromethyl-2'-furyl)-β-carboline-3-carboxamide] was synthesized and its anti-HIV activities were evaluated in the present study. The cytotoxicity of flazinamide was about 4.1-fold lower than that of flazin. Flazinamide potently reduced syncytium formation induced by HIV-1IIIB with EC50 value of 0.38 μM, the EC50 of flazinamide was about 6.2-fold lower than that of flazin. Flazinamide also inhibited HIV-2ROD and HIV-2CBL-20 infection with EC50 values of 0.57 and 0.89 μM, respectively. Flazinamide reduced p24 antigen expression in HIV-1IIIB acute infected C8166 and in clinical isolated strain HIV-1KM018 infected PBMC, with EC50 values of 1.45 and 0.77 μM, respectively. Flazinamide did not suppress HIV-1 replication in chronically infected H9 cells. Flazinamide blocked the fusion between normal cells and HIV-1 or HIV-2 chronically infected cells. It weakly inhibited activities of recombinant HIV-1 reverse transcriptase, protease or integrase at higher concentrations. In conclusion, the conversion of the carboxyl group in 3 position of flazin markedly enhanced the anti-viral activity (TI value increased from 12.1 to 312.2) and flazinamide might interfere in the early stage of HIV life cycle
DEFF Research Database (Denmark)
Pedersen, Erik Bjerregaard; Nielsen, Jakob Toudahl; Nielsen, Claus
2011-01-01
Two G-quadruplex forming sequences, 50-TGGGAG and the 17-mer sequence T30177, which exhibit anti-HIV-1 activity on cell lines, were modified using either locked nucleic acids (LNA) or via insertions of (R)-1-O-(pyren-1-ylmethyl)glycerol (intercalating nucleic acid, INA) or (R)-1-O-[4-(1......-pyrenylethynyl)phenylmethyl]glycerol (twisted intercalating nucleic acid, TINA). Incorporation of LNA or INA/TINA monomers provide as much as 8-fold improvement of anti-HIV-1 activity. We demonstrate for the first time a detailed analysis of the effect the incorporation of INA/TINA monomers in quadruplex forming...
A Survey of Plants with Anti-HIV Active Compounds and their Modes ...
African Journals Online (AJOL)
Background: Several limitations of current antiretroviral therapy (ART) programmes will continue to push patients towards the use of plants to manage HIV/AIDS. However, evidence about the use of anti-HIV plants is anecdotal. Objectives: Search the literature for research articles that document plants with anti-HIV ...
Directory of Open Access Journals (Sweden)
Marla J Keller
2011-01-01
Full Text Available Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001 and fit a sigmoid E(max pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development
Design, Synthesis, Antinociceptive and Anti-Inflammatory Activities of Novel Piroxicam Analogues
Directory of Open Access Journals (Sweden)
Eliezer J. Barreiro
2012-11-01
Full Text Available In this paper we report the design, synthesis, antinociceptive and anti-inflammatory activities of a series of benzothiazine N-acylhydrazones 14a–h, planned by structural modification of piroxicam (1, a non steroidal anti-inflammatory drug. Among the synthesized analogues, compounds 14f (LASSBio-1637 and 14g (LASSBio-1639 were identified as novel antinociceptive and anti-inflammatory prototypes, active by oral administration, acting by a mechanism of action that seems to be different from that of piroxicam, since they were inactive as an inhibitor of cyclooxygenase (COX-1 and COX-2 at concentrations of 10 mM.
Design, synthesis, antinociceptive and anti-inflammatory activities of novel piroxicam analogues.
de Miranda, Amanda Silva; Bispo Júnior, Walfrido; da Silva, Yolanda Karla Cupertino; Alexandre-Moreira, Magna Suzana; Castro, Rosane de Paula; Sabino, José Ricardo; Lião, Luciano Morais; Lima, Lídia Moreira; Barreiro, Eliezer J
2012-11-28
In this paper we report the design, synthesis, antinociceptive and anti-inflammatory activities of a series of benzothiazine N-acylhydrazones 14a–h, planned by structural modification of piroxicam (1), a non steroidal anti-inflammatory drug. Among the synthesized analogues, compounds 14f (LASSBio-1637) and 14g (LASSBio-1639) were identified as novel antinociceptive and anti-inflammatory prototypes, active by oral administration, acting by a mechanism of action that seems to be different from that of piroxicam, since they were inactive as an inhibitor of cyclooxygenase (COX-1 and COX-2) at concentrations of 10 mM.
7,8-secolignans from Schisandra neglecta and their anti-HIV-1 activities
Energy Technology Data Exchange (ETDEWEB)
Gao, Xuemei; Mu, Huaixue; Hu, Qiufen, E-mail: huqiufena@yahoo.com.cn [Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities (China); Wang, Ruirui; Yang, Liumeng; Zheng, Yongtang [Kunming Institute of Zoology, Chinese Academy of Sciences (China); Sun, Handong; Xiao, Weilie, E-mail: xwl@mail.kib.ac.cn [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China)
2012-10-15
Four new 7,8-secolignans (neglectahenols A-D), together with two known 7,8-secolignans, were isolated from leaves and stems of Schisandra neglecta. The structures were elucidated by spectroscopic methods, including extensive one and two dimension NMR (nuclear magnetic resonance) techniques. 7,8-Secolignans and neglectahenols A-D were also tested for their anti-HIV-1 (human immunodeficiency virus type 1) activities, and all of them showed modest activities. (author)
Picomolar dichotomous activity of gnidimacrin against HIV-1.
Directory of Open Access Journals (Sweden)
Li Huang
Full Text Available Highly active antiretroviral therapy (HAART has offered a promising approach for controlling HIV-1 replication in infected individuals. However, with HARRT, HIV-1 is suppressed rather than eradicated due to persistence of HIV-1 in latent viral reservoirs. Thus, purging the virus from latent reservoirs is an important strategy toward eradicating HIV-1 infection. In this study, we discovered that the daphnane diterpene gnidimacrin, which was previously reported to have potent anti-cancer cell activity, activated HIV-1 replication and killed persistently-infected cells at picomolar concentrations. In addition to its potential to purge HIV-1 from latently infected cells, gnidimacrin potently inhibited a panel of HIV-1 R5 virus infection of peripheral blood mononuclear cells (PBMCs at an average concentration lower than 10 pM. In contrast, gnidimacrin only partially inhibited HIV-1 ×4 virus infection of PBMCs. The strong anti-HIV-1 R5 virus activity of gnidimacrin was correlated with its effect on down-regulation of the HIV-1 coreceptor CCR5. The anti-R5 virus activity of gnidimacrin was completely abrogated by a selective protein kinase C beta inhibitor enzastaurin, which suggests that protein kinase C beta plays a key role in the potent anti-HIV-1 activity of gnidimacrin in PBMCs. In summary, these results suggest that gnidimacrin could activate latent HIV-1, specifically kill HIV-1 persistently infected cells, and inhibit R5 viruses at picomolar concentrations.
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Xiao-Liang ZHANG
2016-07-01
Full Text Available Northern pig-tailed macaques (NPMs, Macaca leonina are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5α. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection.
Rotili, Dante; Tarantino, Domenico; Artico, Marino; Nawrozkij, Maxim B; Gonzalez-Ortega, Emmanuel; Clotet, Bonaventura; Samuele, Alberta; Esté, José A; Maga, Giovanni; Mai, Antonello
2011-04-28
Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.
Quarter Century of Anti-HIV CAR T Cells.
Wagner, Thor A
2018-04-01
A therapy that might cure HIV is a very important goal for the 30-40 million people living with HIV. Chimeric antigen receptor T cells have recently had remarkable success against certain leukemias, and there are reasons to believe they could be successful for HIV. This manuscript summarizes the published research on HIV CAR T cells and reviews the current anti-HIV chimeric antigen receptor strategies. Research on anti-HIV chimeric antigen receptor T cells has been going on for at least the last 25 years. First- and second-generation anti-HIV chimeric antigen receptors have been developed. First-generation anti-HIV chimeric antigen receptors were studied in clinical trials more than 15 years ago, but did not have meaningful clinical efficacy. There are some reasons to be optimistic about second-generation anti-HIV chimeric antigen receptor T cells, but they have not yet been tested in vivo.
Nanomedicine in the development of anti-HIV microbicides.
das Neves, José; Nunes, Rute; Rodrigues, Francisca; Sarmento, Bruno
2016-08-01
Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure prophylaxis of HIV sexual transmission. The prospects of having an effective product available are expected to be fulfilled in the near future as driven by recent and forthcoming results of clinical trials. Different dosage forms and delivery strategies have been proposed and tested for multiple microbicide drug candidates presently at different stages of the development pipeline. One particularly interesting approach comprises the application of nanomedicine principles to the development of novel anti-HIV microbicides, but its implications to efficacy and safety are not yet fully understood. Nanotechnology-based systems, either presenting inherent anti-HIV activity or acting as drug nanocarriers, may significantly influence features such as drug solubility, stability of active payloads, drug release, interactions between active moieties and virus/cells, intracellular drug delivery, drug targeting, safety, antiviral activity, mucoadhesive behavior, drug distribution and tissue penetration, and pharmacokinetics. The present manuscript provides a comprehensive and holistic overview of these topics as relevant to the development of vaginal and rectal microbicides. In particular, recent advances pertaining inherently active microbicide nanosystems and microbicide drug nanocarriers are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.
Broad anti-HIV activity of the Oscillatoria agardhii agglutinin homologue lectin family.
Férir, Geoffrey; Huskens, Dana; Noppen, Sam; Koharudin, Leonardus M I; Gronenborn, Angela M; Schols, Dominique
2014-10-01
Oscillatoria agardhii agglutinin homologue (OAAH) proteins belong to a recently discovered lectin family. The founding member OAA and a designed hybrid OAAH (OPA) recognize similar but unique carbohydrate structures of Man-9, compared with other antiviral carbohydrate-binding agents (CBAs). These two newly described CBAs were evaluated for their inactivating properties on HIV replication and transmission and for their potential as microbicides. Various cellular assays were used to determine antiviral activity against wild-type and certain CBA-resistant HIV-1 strains: (i) free HIV virion infection in human T lymphoma cell lines and PBMCs; (ii) syncytium formation assay using persistently HIV-infected T cells and non-infected CD4+ T cells; (iii) DC-SIGN-mediated viral capture; and (iv) transmission to uninfected CD4+ T cells. OAA and OPA were also evaluated for their mitogenic properties and potential synergistic effects using other CBAs. OAA and OPA inhibit HIV replication, syncytium formation between HIV-1-infected and uninfected T cells, DC-SIGN-mediated HIV-1 capture and transmission to CD4+ target T cells, thereby rendering a variety of HIV-1 and HIV-2 clinical isolates non-infectious, independent of their coreceptor use. Both CBAs competitively inhibit the binding of the Manα(1-2)Man-specific 2G12 monoclonal antibody (mAb) as shown by flow cytometry and surface plasmon resonance analysis. The HIV-1 NL4.3(2G12res), NL4.3(MVNres) and IIIB(GRFTres) strains were equally inhibited as the wild-type HIV-1 strains by these CBAs. Combination studies indicate that OAA and OPA act synergistically with Hippeastrum hybrid agglutinin, 2G12 mAb and griffithsin (GRFT), with the exception of OPA/GRFT. OAA and OPA are unique CBAs with broad-spectrum anti-HIV activity; however, further optimization will be necessary for microbicidal application. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights
Sepúlveda-Crespo, Daniel; Lorente, Raquel; Leal, Manuel; Gómez, Rafael; De la Mata, Francisco J; Jiménez, José Luis; Muñoz-Fernández, M Ángeles
2014-04-01
Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides. © 2014.
Estimation of Anti-HIV Activity of HEPT Analogues Using MLR, ANN, and SVM Techniques
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Basheerulla Shaik
2013-01-01
value than those of MLR and SVM techniques. Rm2= metrics and ridge regression analysis indicated that the proposed four-variable model MATS5e, RDF080u, T(O⋯O, and MATS5m as correlating descriptors is the best for estimating the anti-HIV activity (log 1/C present set of compounds.
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands.
Sancineto, Luca; Iraci, Nunzio; Barreca, Maria Letizia; Massari, Serena; Manfroni, Giuseppe; Corazza, Gianmarco; Cecchetti, Violetta; Marcello, Alessandro; Daelemans, Dirk; Pannecouque, Christophe; Tabarrini, Oriana
2014-09-01
It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT-RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives. Copyright © 2014 Elsevier Ltd. All rights reserved.
Synthesis, structure analysis, anti-bacterial and in vitro anti-cancer ...
Indian Academy of Sciences (India)
DOI 10.1007/s12039-015-0824-z. Synthesis, structure analysis, anti-bacterial and in vitro anti-cancer activity of new Schiff base and its copper complex derived from sulfamethoxazole. I RAMA∗ and R SELVAMEENA. PG and Research Department of Chemistry, Seethalakshmi Ramaswami College,. Tiruchirappalli 620 002 ...
Regulated production and anti-HIV type 1 activities of cytidine deaminases APOBEC3B, 3F, and 3G.
Rose, Kristine M; Marin, Mariana; Kozak, Susan L; Kabat, David
2005-07-01
APOBEC3G and 3F (A3G and A3F) cytidine deaminases incorporate into retroviral cores where they lethally hypermutate nascent DNA reverse transcripts. As substantiated here, the viral infectivity factor (Vif) encoded by human immunodeficiency virus type-1 (HIV-1) binds A3G and A3F and induces their degradation, thereby precluding their incorporation into viral progeny. Previous evidence suggested that A3G is expressed in H9 and other nonpermissive cells that contain this antiviral defense but not in several permissive cells, and that overexpression of A3G or A3F makes permissive cells nonpermissive. Using a broader panel of cell lines, we confirmed a correlation between A3G and cellular abilities to inactivate HIV-1(Deltavif). However, there was a quantitative discrepancy because several cells with weak antiviral activities had similar amounts of wild-type A3G mRNA and protein compared to H9 cells. Antiviral activity of H9 cells was also attenuated in some conditions. These quantitative discrepancies could not be explained by the presence of A3F or other A3G paralogs in some of the cell lines. Thus, A3A, A3B, and A3C had weak but significant anti-HIV-1 activities and did not dominantly interfere with A3G or A3F antiviral functions. Control of A3G synthesis by the protein kinase C/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway was also similar in permissive and nonpermissive cells. A3G in highly permissive cells is degraded by Vif, suggesting that it is not in a sequestered site, and is specifically incorporated in low amounts into HIV-1(Deltavif). Although A3G and/or A3F inactivate HIV-1(Deltavif) and are neutralized by Vif, the antiviral properties of cell lines are also influenced by other cellular and viral factors.
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Hao-Bing Yu
2014-12-01
Full Text Available Five new alkaloids of aaptamine family, compounds (1–5 and three known derivatives (6–8, have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.
Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.
Huang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, Xinyong
2015-12-01
The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.
DEFF Research Database (Denmark)
Kankala, Shravankumar; Kankala, Ranjith Kumar; Gundepaka, Prasad
2013-01-01
Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized....
Prospects for Foamy Viral Vector Anti-HIV Gene Therapy
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Arun K. Nalla
2016-03-01
Full Text Available Stem cell gene therapy approaches for Human Immunodeficiency Virus (HIV infection have been explored in clinical trials and several anti-HIV genes delivered by retroviral vectors were shown to block HIV replication. However, gammaretroviral and lentiviral based retroviral vectors have limitations for delivery of anti-HIV genes into hematopoietic stem cells (HSC. Foamy virus vectors have several advantages including efficient delivery of transgenes into HSC in large animal models, and a potentially safer integration profile. This review focuses on novel anti-HIV transgenes and the potential of foamy virus vectors for HSC gene therapy of HIV.
Novel anti-HIV peptides containing multiple copies of artificially designed heptad repeat motifs
International Nuclear Information System (INIS)
Shi Weiguo; Qi Zhi; Pan Chungen; Xue Na; Debnath, Asim K.; Qie Jiankun; Jiang Shibo; Liu Keliang
2008-01-01
The peptidic anti-HIV drug T20 (Fuzeon) and its analog C34 share a common heptad repeat (HR) sequence, but they have different functional domains, i.e., pocket- and lipid-binding domains (PBD and LBD, respectively). We hypothesize that novel anti-HIV peptides may be designed by using artificial sequences containing multiple copies of HR motifs plus zero, one or two functional domains. Surprisingly, we found that the peptides containing only the non-natural HR sequences could significantly inhibit HIV-1 infection, while addition of PBD and/or LBD to the peptides resulted in significant improvement of anti-HIV-1 activity. These results suggest that these artificial HR sequences, which may serve as structural domains, could be used as templates for the design of novel antiviral peptides against HIV and other viruses with class I fusion proteins
International Nuclear Information System (INIS)
Nair, M.P.N.; Pottathil, R.; Heimer, E.P.; Schwartz, S.A.
1988-01-01
Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by [ 3 H]thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3 + lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3 - lymphocytes. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection
Anti-glomerular basement membrane glomerulonephritis in an HIV positive patient: case report
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Eduardo José Bellotto Monteiro
Full Text Available We report on a case of a patient with HIV infection, diagnosed 18 months prior to the development of an anti-glomerular basement membrane (anti-GBM rapidly progressive glomerulonephritis; this is probably the first report of such an association. A 30-year-old white man presented with elevation of serum creatinine (1.3 - 13.5 mg/dL within one month. At admission, the urinalysis showed proteinuria of 7.2 g/L and 8,000,000 erythrocytes/mL. Renal biopsy corresponded to a crescentic diffuse proliferative glomerulonephritis mediated by anti-GBM, and serum testing for anti-GBM antibodies was positive; antinuclear antibodies (ANA and anti-neutrophilic cytoplasmic antibodies (ANCA were also positive. The patient underwent hemodyalisis and was treated with plasmapheresis, cyclophosphamide and prednisone. The association described here is not casual, as crescentic glomerulonephritis is not common in HIV-positive patients, anti-GBM glomerulonephritis is rare and anti-GBM antibodies are frequently observed in HIV-positive subjects when compared to the overall population. Based on the current case and on the elevated frequency of the positivity for such antibodies in this group of patients, it is advisable to be aware of the eventual association between these two conditions and to promote an active search for anti-GBM antibodies and early diagnosis of eventual urinary abnormalities in HIV-positive subjects, considering the severity of anti-GBM glomerulonephritis.
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Paolo Monini
Full Text Available Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus entry complex favoring R5 or X4 virus entry and productive infection of dendritic cells (DCs via an integrin-mediated pathway. These Tat effects do not require Tat-transactivation activity and are blocked by anti-integrin antibodies (Abs. Productive DC infection promoted by Tat is associated with a highly efficient virus transmission to T cells. In the Tat/Env complex the cysteine-rich region of Tat engages the Env V3 loop, whereas the Tat RGD sequence remains free and directs the virus to integrins present on DCs. V2 loop deletion, which unshields the CCR5 binding region of Env, increases Tat/Env complex stability. Of note, binding of Tat to Env abolishes neutralization of Env entry or infection of DCs by anti-HIV sera lacking anti-Tat Abs, which are seldom present in natural infection. This is reversed, and neutralization further enhanced, by HIV sera containing anti-Tat Abs such as those from asymptomatic or Tat-vaccinated patients, or by sera from the Tat/Env vaccinated monkeys. Thus, both anti-Tat and anti-Env Abs are required for efficient HIV neutralization. These data suggest that the Tat/Env interaction increases HIV acquisition and spreading, as a mechanism evolved by the virus to escape anti-Env neutralizing Abs. This may explain the low effectiveness of Env-based vaccines, which are also unlikely to elicit Abs against new Env epitopes exposed by the Tat/Env interaction. As Tat also binds Envs from different clades, new vaccine strategies should exploit the Tat/Env interaction for both preventative and therapeutic interventions.
Anti-HIV-1 activities of the extracts from the medicinal plant Linum grandiflorum Desf
DEFF Research Database (Denmark)
Mohammed, Magdy M. D.; Christensen, Lars Porskjær; Ibrahim, Nabaweya A.
2009-01-01
As part of our screening of anti-AIDS agents from natural sources e.g. Ixora undulata, Paulownia tomentosa, Fortunella margarita, Aegle marmelos and Erythrina abyssinica, the different organic and aqueous extracts of Linum grandiflorum leaves and seeds were evaluated in vitro by the microculture...... tetrazolium (MTT) assay. The activity of the tested extracts against multiplication of HIV-1 wild type IIIB, N119, A17, and EFVR in acutely infected cells was based on inhibition of virus-induced cytopathicity in MT-4 cells. Results revealed that both the MeOH and the CHCl3 extracts of L. grandiflorum have...... significant inhibitory effects against HIV-1 induced infection with MT-4 cells. The MeOH extract of the leaves is more potent than other extracts against MT-4 cell cultures infected with the wild type HIV-1, strain IIIB with an ED50 of 46 ± 6 µM, while the CHCl3 extract of the seeds is more potent than other...
A Survey of Plants with Anti-HIV Active Compounds and their Modes ...
African Journals Online (AJOL)
Administrator
proteins, alkaloids, and biflavonoids inhibit various ... several plant families and species contain anti-HIV .... articles reviewed, only about a third were included .... membranes against free .... Pedersen, B.K. Low plasma level of adiponectin.
Anti-HIV Antibody Responses and the HIV Reservoir Size during Antiretroviral Therapy.
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Sulggi A Lee
Full Text Available A major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir". We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART.We evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR; integrated DNA (Alu PCR; unspliced RNA (rtPCR, multiply-spliced RNA (TILDA, residual plasma HIV RNA (single copy PCR, and replication-competent virus (outgrowth assay. We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR. Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.Among 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years, the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004 and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003. However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.Our findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.
Seropositivity of HBsAg, anti-HCV and anti-HIV in preoperative patients
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Berrin Karaayak Uzun
2014-12-01
Full Text Available Objective: The infections caused by human immunodeficiency virus (HIV, hepatitis B (HBV and C (HCV viruses pose a serious occupational risk for the healthcare workers especially those in emergency services, laboratories and surgery wards. Vaccination and establishment of the strict biosafety procedures are the main principles to prevent blood-borne infections in healthcare workers. Additionally, serological screening of the preoperative patients could decrease the risk for exposure. In this study, we aimed to determine the seroprevalence of HBsAg, anti-HCV, anti-HIV 1/2 in preoperative patients. Methods: Hospital automation records were evaluated retrospectively for 4.367 patients who were scheduled for surgery and scanned for anti-HIV 1/2, HBsAg and anti-HCV as preoperative procedures in the preparation period of operation between January 2012 and December 2012. Results: HBsAg positivity rate was found in 7.7% (n=336, anti-HCV positivity rate was found in 2.3% (n=101. A two (0.05% of five patients were positive for anti-HIV 1/2 was found positive verification test and the other three samples were accepted as false positive test results. Conclusion: All healthcare workers must be trained about occupational diseases and vaccinated against Hepatitis B. Universal precautions must be strictly followed particularly in the operating room. In addition, all patients should be considered as potential carriers regarded as a carrier of the potential for infection. J Clin Exp Invest 2013; 4 (4: 449-452
Zhang, Da-Wei; Zhao, Ming-Ming; Chen, Juan; Li, Chao; Guo, Shun-Xing
2013-05-01
A total of 52 endophytic fungi were isolated from roots and stems of Tibetan medicinal plant Phlomis younghusbandii Mukerjee. These fungal isolates were molecularly identified based on ITS sequnces and 28S sequences distributed to 12 genera, including Phoma, Chaetosphaeronema, Fusarium and Leptosphaeria, etc. Among them, the dominant genus was Phoma. Extracts of all strains were evaluated for anti-HIV-1 integrase activity by using soluable integrase expressed in E. coli BL21 (DE3). The results showed that seven samples from five fungal endophytes PHY-24, PHY-38, PHY-40, PHY-51, PHY-53, which belonged to genus Chaetosphaeronema, inhibited strand transfer reaction catalyzed by HIV-1 integrase with IC50 values, of 6.60, 5.20, 2.86, 7.86, 4.47, 4.56 and 3.23 microg x mL(-1) respectively. In conclusion, the endophytic fungi of Phlomis younghusbandii Mukerjee are valuable for further screening anti-HIV-1 integrase agents.
Design, Green Synthesis, and Anti-Inflammatory Activity of Schiff Base of 1,3,4-oxadiazole Analogues
Czech Academy of Sciences Publication Activity Database
Sahoo, B. M.; Dinda, S. C.; Kumar, B. V. V. R.; Panda, J.; Brahmkshatriya, Pathik
2014-01-01
Roč. 11, č. 1 (2014), s. 82-89 ISSN 1570-1808 Institutional support: RVO:61388963 Keywords : anti-inflammatory activity * design * green synthesis * oxadiazole * schiff base * spectroscopic studies Subject RIV: CC - Organic Chemistry Impact factor: 0.770, year: 2014
Afantitis, Antreas; Melagraki, Georgia; Sarimveis, Haralambos; Koutentis, Panayiotis A; Markopoulos, John; Igglessi-Markopoulou, Olga
2006-08-01
A quantitative-structure activity relationship was obtained by applying Multiple Linear Regression Analysis to a series of 80 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives with significant anti-HIV activity. For the selection of the best among 37 different descriptors, the Elimination Selection Stepwise Regression Method (ES-SWR) was utilized. The resulting QSAR model (R (2) (CV) = 0.8160; S (PRESS) = 0.5680) proved to be very accurate both in training and predictive stages.
Vermeire, Kurt; Lisco, Andrea; Grivel, Jean-Charles; Scarbrough, Emily; Dey, Kaka; Duffy, Noah; Margolis, Leonid; Bell, Thomas W; Schols, Dominique
2007-08-15
A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs.
Molecular Mechanisms in Activation of Latent HIV-1
H. Rafati (Haleh)
2014-01-01
markdownabstract__Abstract__ Finding a cure for the human immunodeficiency virus type 1 (HIV-1) is extremely challenging. Development of highly active anti-retroviral therapy (HAART), transformed HIV-1 infection from an acute syndrome into chronic disease. Although using HAART results in
Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Lavecchia, Antonio; Marinelli, Luciana; Novellino, Ettore; Palmisano, Lucia; Andreotti, Mauro; Amici, Roberta; Galluzzo, Clementina Maria; Nencioni, Lucia; Palamara, Anna Teresa; Pommier, Yves; Marchand, Christophe
2008-01-01
The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3′-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-crosslinking experiments. PMID:16539381
Fluorine Substituted 1,2,4-Triazinones as Potential Anti-HIV-1 and CDK2 Inhibitors
Directory of Open Access Journals (Sweden)
Mohammed S. I. Makki
2014-01-01
Full Text Available Fluorine substituted 1,2,4-triazinones have been synthesized via alkylation, amination, and/or oxidation of 6-(2-amino-5-fluorophenyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H-one 1 and 4-fluoro-N-(4-fluoro-2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-ylphenylbenzamide 5 as possible anti-HIV-1 and CDK2 inhibitors. Alkylation on positions 2 and 4 in 1,2,4-triazinone gave compounds 6–8. Further modification was performed by selective alkylation and amination on position 3 to form compounds 9–15. However oxidation of 5 yielded compounds 16–18. Structures of the target compounds have been established by spectral analysis data. Five compounds (5, 11, 14, 16, and 17 have shown very good anti-HIV activity in MT-4 cells. Similarly, five compounds (1, 3, and 14–16 have exhibited very significant CDK2 inhibition activity. Compounds 14 and 16 were found to have dual anti-HIV and anticancer activities.
Accuracy of different thresholds for the anti-HIV avidity index
Directory of Open Access Journals (Sweden)
Claudio Galli
2008-03-01
Full Text Available Surveillance programs for human immunodeficiency virus (HIV infection are based on the reporting of newly diagnosed cases. In order to guarantee a more accurate estimate of the trends and behaviours of infected people, simple and reliable methods aimed at identifying recent (< 6 months HIV infections are needed. We evaluated the accuracy of the avidity index (AI of anti-HIV antibodies on 357 serum samples obtained from 127 subjects for whom an estimated date of seroconversion was calculated on the basis of the interval between the last negative and first positive anti-HIV test result.The ROC curve analysis performed at different thresholds of the AI showed that a cutoff of 0.80 (93.0% sensitivity and 98.5% specificity yields the best overall accuracy (95.8% and should be employed for surveillance purposes, whereas the application of the anti-HIV AI on individual cases is not recommended.
Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities
Ikeda, Terumasa; Ong, Eugene Boon Beng; Watanabe, Nobumoto; Sakaguchi, Nobuo; Maeda, Kazuhiko; Koito, Atsushi
2016-01-01
APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV-1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C-terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1.
Use of Anti-HIV Immunotoxins as Probes of the Biology of HIV-Infected Cells
Directory of Open Access Journals (Sweden)
SETH H Pincus
1994-01-01
Full Text Available OBJECTIVE: Anti-human immunodeficiency virus (HIV immunotoxins are potential treatments for HIV infection. but they may also be used as probes to study the relationship between HIV and the cell it infects. Data from the present study indicate the complexity of this relationship.
DEFF Research Database (Denmark)
Loksha, Yasser M.; Pedersen, Erik B.
2018-01-01
Because MC1220 is a promising microbicide with anti-HIV-1 activity, the possibility for asymmetric synthesis of its potential precursors is explored. Here, we investigate asymmetric reduction of the vinyl double bond of 6-(1-arylvinyl)pyrimidine derivatives to their corresponding ethylidene analo...... analogues. Catalysts with ligands bearing trivalent phosphorus ligating the soft metals rhodium(I), ruthenium(II), or iridium(I) are used for asymmetric reduction of the vinyl derivatives 5a-e. The enantioselective reduction reaches 92% ee and about 71% conversion for reduction of the 6...
Batraville, Laurie-Anne; Richard, Jonathan; Veillette, Maxime; Labbé, Annie-Claude; Alary, Michel; Guédou, Fernand; Kaufmann, Daniel E; Poudrier, Johanne; Finzi, Andrés; Roger, Michel
2014-11-01
Characterization of the immune correlates of protection against HIV infection is crucial for the development of preventive strategies. This study examined HIV-1 envelope (Env) glycoproteins, specifically immunoglobulin G (IgG), in systemic and mucosal compartments of female Beninese commercial sex workers (CSWs). Samples of 23 HIV-1-positive and 20 highly exposed HIV-1-seronegative (HESN) CSWs were studied. HIV-1 Env-specific IgG detection in sera and cervicovaginal lavages (CVLs) from the study population was done by cell-based ELISA. The HIV neutralizing activity was evaluated with a neutralization assay. The HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) response of the cohort was measured with a FACS-based assay evaluating the ADCC-mediated elimination of gp120-coated target cells. No anti-HIV-1 Env-specific IgG neutralizing or ADCC activities were detected in samples from HESN CSWs. Samples from HIV-1-infected CSWs presented ADCC activity in both sera and CVLs. Anti-Env IgG from sera and CVLs from HIV-1-infected CSWs preferentially recognized Env in its CD4-bound conformation. HIV-1-infected CSWs have ADCC-mediating IgG that preferentially recognizes Env in its CD4-bound conformation at the mucosal site.
Directory of Open Access Journals (Sweden)
Gaurav ALANG
2011-04-01
Full Text Available In the present study, six new derivatives of PYridazinone were synthesized and evaluate their anti-bacterial activity. The experimental work involves the synthesis of benzoyl propionic acid (a, then 6-phenyl-2,3,4,5-tetrahydro pyridazin-3-one (b which was then condensed with various, aldehydes to form respective derivatives, AH the synthesized compounds were identified by IR, 1HNMR and antimicrobial activity was performed on the compounds synthesized against Staphylococcus aureus (MTCC 737, Staphylococcus epidermidis (MTCC 3615, Pseudomonas aeruginosa (MTCC 424 and Escherichia coli (MTCC 1687
Directory of Open Access Journals (Sweden)
Min Qiu
Full Text Available Some secondary metabolites from plants show to have potent inhibitory activities against microbial pathogens, such as human immunodeficiency virus (HIV, herpes simplex virus (HSV, Treponema pallidum, Neisseria gonorrhoeae, etc. Here we report that lignosulfonic acid (LSA, a polymeric lignin derivative, exhibits potent and broad activity against HIV-1 isolates of diverse subtypes including two North America strains and a number of Chinese clinical isolates values ranging from 21.4 to 633 nM. Distinct from other polyanions, LSA functions as an entry inhibitor with multiple targets on viral gp120 as well as on host receptor CD4 and co-receptors CCR5/CXCR4. LSA blocks viral entry as determined by time-of-drug addiction and cell-cell fusion assays. Moreover, LSA inhibits CD4-gp120 interaction by blocking the binding of antibodies specific for CD4-binding sites (CD4bs and for the V3 loop of gp120. Similarly, LSA interacts with CCR5 and CXCR4 via its inhibition of specific anti-CCR5 and anti-CXCR4 antibodies, respectively. Interestingly, the combination of LSA with AZT and Nevirapine exhibits synergism in viral inhibition. For the purpose of microbicide development, LSA displays low in vitro cytotoxicity to human genital tract epithelial cells, does not stimulate NF-κB activation and has no significant up-regulation of IL-1α/β and IL-8 as compared with N-9. Lastly, LSA shows no adverse effect on the epithelial integrity and the junctional protein expression. Taken together, our findings suggest that LSA can be a potential candidate for tropical microbicide.
Development of an anti-HIV vaccine eliciting broadly neutralizing antibodies.
Ahmed, Yousuf; Tian, Meijuan; Gao, Yong
2017-09-12
The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV-1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response.
Murugan, Ravichandran N; Jacob, Binu; Ahn, Mija; Hwang, Eunha; Sohn, Hoik; Park, Hyo-Nam; Lee, Eunjung; Seo, Ji-Hyung; Cheong, Chaejoon; Nam, Ky-Youb; Hyun, Jae-Kyung; Jeong, Ki-Woong; Kim, Yangmee; Shin, Song Yub; Bang, Jeong Kyu
2013-01-01
Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability. In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(π)- and N(τ)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes. The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics.
Contribution of the anti HIV/AIDS community conversation programs ...
African Journals Online (AJOL)
Background: HIV/AIDS has now been around for about three and half decades since first diagnosed in 1981. If we wish to curb the spread of HIV/AIDS effectively and sustainably, we need to design strategies that help mobilizing communities at large. Anti-HIV/AIDS Community Conversation (CC) Programs are part of ...
Antiviral activity of Justicia gendarussa Burm.f. leaves against HIV ...
African Journals Online (AJOL)
Backgrounds: Justicia gendarussa Burm.f. has been known to have anti-HIV activity. This study was conducted to evaluate the effect of incubation time on the antiviral activity of the J. gendarussa leaves extract on HIV-infected MT-4 cells in vitro. Molecular docking test was also conducted to determine the interaction of ...
Koharudin, Leonardus M I; Kollipara, Sireesha; Aiken, Christopher; Gronenborn, Angela M
2012-09-28
Oscillatoria agardhii agglutinin homolog (OAAH) proteins belong to a recently discovered lectin family. All members contain a sequence repeat of ~66 amino acids, with the number of repeats varying among different family members. Apart from data for the founding member OAA, neither three-dimensional structures, information about carbohydrate binding specificities, nor antiviral activity data have been available up to now for any other members of the OAAH family. To elucidate the structural basis for the antiviral mechanism of OAAHs, we determined the crystal structures of Pseudomonas fluorescens and Myxococcus xanthus lectins. Both proteins exhibit the same fold, resembling the founding family member, OAA, with minor differences in loop conformations. Carbohydrate binding studies by NMR and x-ray structures of glycan-lectin complexes reveal that the number of sugar binding sites corresponds to the number of sequence repeats in each protein. As for OAA, tight and specific binding to α3,α6-mannopentaose was observed. All the OAAH proteins described here exhibit potent anti-HIV activity at comparable levels. Altogether, our results provide structural details of the protein-carbohydrate interaction for this novel lectin family and insights into the molecular basis of their HIV inactivation properties.
Eleje, George Uchenna; Edokwe, Emeka Stephen; Ikechebelu, Joseph Ifeanyichukwu; Onubogu, Chinyere Ukamaka; Ugochukwu, Ebele Francesca; Okam, Princeston Chukwuemeka; Ibekwe, Adaobi Maryann
2018-01-01
To determine mother-to-child transmission (MTCT) rate and associated risk factors of human immune-deficiency virus (HIV) among HIV-infected pregnant women with term premature rupture of membranes (PROM) in comparison with those without PROM at term. All optimally managed HIV-positive pregnant women of Nnamdi Azikiwe University Teaching Hospital, on highly active anti-retroviral therapy (HAART) who had PROM at term were enrolled. Maternal HIV-1 viral load was not assessed. Follow up was for a minimum of 18 months for evidence of HIV infection. Of the 121 women with PROM at term, 46 (38.0%) were HIV sero-positive, 22/46 (47.8%) of which had their babies followed up till 18 months. The mean latency period was 10.5 ± 5.3 h in PROM group. Apart from duration of PROM (OR = 0.01; 95%CI = 0.00-0.13; p 0.05). Of the 22 (47.8%) babies followed-up in the PROM group and 13 in non-PROM group, none tested positive to HIV, given an MTCT rate of 0%. MTCT rate was 0% following term PROM and in women without PROM. Since maternal HIV-1 viral load was not assessed, we need to be critical while interpreting the findings.
Anti-HIV and immunomodulation activities of cacao mass lignin-carbohydrate complex.
Sakagami, Hiroshi; Kawano, Michiyo; Thet, May Maw; Hashimoto, Ken; Satoh, Kazue; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Haishima, Yuji; Maeda, Yuuichi; Sakurai, Koji
2011-01-01
Recently, a prominent antiviral and macrophage stimulatory activity of cacao lignin-carbohydrate complex (LCC) has been reported. However, the solubility and sterility of LCC have not been considered yet. In the present study, complete solubilisation and sterilisation was achieved by autoclaving under mild alkaline conditions and the previously reported biological activities were re-examined. LCCs were obtained by 1% NaOH extraction and acid precipitation, and a repeated extraction-precipitation cycle. Nitric oxide (NO) and cytokine productions were assayed by the Griess method and ELISA, respectively. Inducible NO synthase (iNOS) expression was determined by Western blot analysis. Superoxide anion, hydroxyl radical and nitric oxide radical-scavenging activity was determined by ESR spectroscopy. Cacao mass LCC showed reproducibly higher anti-HIV activity than cacao husk LCC. Cacao mass LCC, up to 62.5 μg/ml, did not stimulate mouse macrophage-like cells (RAW264.7 and J774.1) to produce NO, nor did it induce iNOS protein, in contrast to lipopolysaccharide (LPS). Cacao mass LCC and LPS synergistically stimulated iNOS protein expression, suggesting a different point of action. Cacao mass LCC induced tumour necrosis factor-α production markedly less than LPS, and did not induce interleukin-1β, interferon-α or interferon-γ. ESR spectroscopy showed that cacao mass LCC, but not LPS, scavenged NO produced from NOC-7. This study demonstrated several new biological activities of LCCs distinct from LPS and further confirmed the promising antiviral and immunomodulating activities of LCCs.
Synthesis and Study of Analgesic and Anti-inflammatory Activities of Amide Derivatives of Ibuprofen.
Ahmadi, Abbas; Khalili, Mohsen; Olama, Zahra; Karami, Shirin; Nahri-Niknafs, Babak
2017-01-01
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide and represent a mainstay in the therapy of acute and chronic pain and inflammation. The traditional NSAIDs like ibuprofen (I) contain free carboxylic acid group which can produce gastrointestinal (GI) damage for long-term use. In order to obtain the novel NSAIDs with less side effects; carboxylic acid moiety has been modified into various amide groups which is the most active area of research in this family. In this research, synthesis of various pharmacological heterocyclic amides of ibuprofen is described. All the new compounds were tested for their analgesic and anti-inflammatory activities in mice and compared with standard (Ibuprofen) and control (saline) groups. The results revealed that all the synthesized compounds (III-VI) exhibited more analgesic and anti-inflammatory activities in tail immersion (as a model of acute thermal pain), formalin (as a model of acute chemical and chronic pain) and paw edema (as a model of acute inflammation) tests when compared with standard and control animals. These pharmacological activities were significant for VI compared to other new compounds (III-V) which may be concern to more effective role of morpholin for the reduction of pain and inflammation compared to other used heterocyclic amines. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica
DEFF Research Database (Denmark)
Valsaraj, R; Pushpangadan, P; Smitt, U W
1997-01-01
A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....
Therapeutic genes for anti-HIV/AIDS gene therapy.
Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca
2013-01-01
The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.
Shaikh, Anas Ejaz; Satardekar, Kshitij Vasant; Khan, Rummana Rehman; Tarte, Nanda Amit; Barve, Siddhivinayak Satyasandha
2018-03-01
Hydro-alcoholic (2:8 v/v) extract of the pulp of Phoenix dactylifera fruit pulp obtained using Soxhlet extraction (70 °C, 6 h) was found to contain alkaloids, sterols, tannins, flavonoids, cardiac glycosides, proteins, and carbohydrates. An aqueous solution (20% v/v) of the extract led to the synthesis of silver nanoparticles (AgNPs) from 0.01 M AgNO3 solution as confirmed by the surface plasmon resonance at 445 nm determined using UV-visible spectroscopy after 24 h. The synthesized AgNPs were found to be mostly spherical and complexed with phytochemicals from the extract. The size of AgNPs ranged from 12.2-140.2 nm with mean diameter of 47.0 nm as characterized by scanning electron microscopy (SEM). The elemental composition of the AgNPs complexed with the phytochemicals was found to be 80.49% silver (Ag), 15.21% carbon (C), and 4.30% oxygen (O) on a weight basis by energy-dispersive spectroscopy (EDS). Using the α,α-diphenyl-β-picrylhydrazyl (DPPH) assay, an anti-oxidant activity of 89.15% for 1 µg L-1 ultrasonically homogenized ethanolic solution of complexed AgNPs was obtained (equivalent to 0.20 mg mL-1 gallic acid solution), while methanolic solution of plant extract possessed an EC50 value of 3.45% (v/v) (equivalent to 0.11 mg mL-1 gallic acid solution). The plant-nanosilver broth was also found to possess effective anti-microbial activity against Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538, and Candida albicans ATCC 10231 as assessed by the disc diffusion assay. However, the plant extract showed negligible anti-microbial activity.
Ahmed, Nafees; Brahmbhatt, Keyur G; Khan, Shabana I; Jacob, Melissa; Tekwani, Babu L; Sabde, Sudeep; Mitra, Debashis; Singh, Inder P; Khan, Ikhlas A; Bhutani, Kamlesh K
2013-04-01
Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC(50) 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC(50) 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC(50) 2.39 and 2.78 μM and IC(90) 11.27 and 12.76 μM, respectively. Three analogues 12c, 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC(50) Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity. © 2012 John Wiley & Sons A/S.
Lin, J; Opoku, A R; Geheeb-Keller, M; Hutchings, A D; Terblanche, S E; Jäger, A K; van Staden, J
1999-12-15
Aqueous and methanolic extracts from different parts of nine traditional Zulu medicinal plants, of the Vitaceae from KwaZulu-Natal, South Africa were evaluated for therapeutic potential as anti-inflammatory and anti-microbial agents. Of the twenty-nine crude extracts assayed for prostaglandin synthesis inhibitors, only five methanolic extracts of Cyphostemma natalitium-root, Rhoicissus digitata-leaf, R. rhomboidea-root, R. tomentosa-leaf/stem and R. tridentata-root showed significant inhibition of cyclo-oxygenase (COX-1). The extracts of R. digitata-leaf and of R. rhomboidea-root exhibited the highest inhibition of prostaglandin synthesis with 53 and 56%, respectively. The results suggest that Rhoicissus digitata leaves and of Rhoicissus rhomboidea roots may have the potential to be used as anti-inflammatory agents. All the screened plant extracts showed some degrees of anti-microbial activity against gram-positive and gram-negative microorganisms. The methanolic extracts of C. natalitium-stem and root, R. rhomboidea-root, and R. tomentosa-leaf/stem, showed different anti-microbial activities against almost all micro-organisms tested. Generally, these plant extracts inhibited the gram-positive micro-organisms more than the gram-negative ones. Several plant extracts inhibited the growth of Candida albicans while only one plant extract showed inhibitory activity against Saccharomyces cerevisiae. All the plant extracts which demonstrated good anti-inflammatory activities also showed better inhibitory activity against Candida albicans.
Cloaked similarity between HIV-1 and SARS-CoV suggests an anti-SARS strategy
Directory of Open Access Journals (Sweden)
Kliger Yossef
2003-09-01
Full Text Available Abstract Background Severe acute respiratory syndrome (SARS is a febrile respiratory illness. The disease has been etiologically linked to a novel coronavirus that has been named the SARS-associated coronavirus (SARS-CoV, whose genome was recently sequenced. Since it is a member of the Coronaviridae, its spike protein (S2 is believed to play a central role in viral entry by facilitating fusion between the viral and host cell membranes. The protein responsible for viral-induced membrane fusion of HIV-1 (gp41 differs in length, and has no sequence homology with S2. Results Sequence analysis reveals that the two viral proteins share the sequence motifs that construct their active conformation. These include (1 an N-terminal leucine/isoleucine zipper-like sequence, and (2 a C-terminal heptad repeat located upstream of (3 an aromatic residue-rich region juxtaposed to the (4 transmembrane segment. Conclusions This study points to a similar mode of action for the two viral proteins, suggesting that anti-viral strategy that targets the viral-induced membrane fusion step can be adopted from HIV-1 to SARS-CoV. Recently the FDA approved Enfuvirtide, a synthetic peptide corresponding to the C-terminal heptad repeat of HIV-1 gp41, as an anti-AIDS agent. Enfuvirtide and C34, another anti HIV-1 peptide, exert their inhibitory activity by binding to a leucine/isoleucine zipper-like sequence in gp41, thus inhibiting a conformational change of gp41 required for its activation. We suggest that peptides corresponding to the C-terminal heptad repeat of the S2 protein may serve as inhibitors for SARS-CoV entry.
González-Díaz, Humberto; Herrera-Ibatá, Diana María; Duardo-Sánchez, Aliuska; Munteanu, Cristian R; Orbegozo-Medina, Ricardo Alfredo; Pazos, Alejandro
2014-03-24
This work is aimed at describing the workflow for a methodology that combines chemoinformatics and pharmacoepidemiology methods and at reporting the first predictive model developed with this methodology. The new model is able to predict complex networks of AIDS prevalence in the US counties, taking into consideration the social determinants and activity/structure of anti-HIV drugs in preclinical assays. We trained different Artificial Neural Networks (ANNs) using as input information indices of social networks and molecular graphs. We used a Shannon information index based on the Gini coefficient to quantify the effect of income inequality in the social network. We obtained the data on AIDS prevalence and the Gini coefficient from the AIDSVu database of Emory University. We also used the Balaban information indices to quantify changes in the chemical structure of anti-HIV drugs. We obtained the data on anti-HIV drug activity and structure (SMILE codes) from the ChEMBL database. Last, we used Box-Jenkins moving average operators to quantify information about the deviations of drugs with respect to data subsets of reference (targets, organisms, experimental parameters, protocols). The best model found was a Linear Neural Network (LNN) with values of Accuracy, Specificity, and Sensitivity above 0.76 and AUROC > 0.80 in training and external validation series. This model generates a complex network of AIDS prevalence in the US at county level with respect to the preclinical activity of anti-HIV drugs in preclinical assays. To train/validate the model and predict the complex network we needed to analyze 43,249 data points including values of AIDS prevalence in 2,310 counties in the US vs ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4,856 protocols, and 10 possible experimental measures.
Anti-tuberculosis therapy-induced hepatotoxicity among Ethiopian HIV-positive and negative patients.
Directory of Open Access Journals (Sweden)
Getnet Yimer
2008-03-01
Full Text Available To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH in HIV positive and HIV negative tuberculosis (TB patients in Ethiopia.In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3% of the patients and 8 out of the 197 (4.1% developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg.Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002, concomitant drug intake (p = 0.008, and decrease in CD4 count (p = 0.001. Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk.
Synthesis and Anti-HIV-1 Evaluation of New Sonogashira-Modified Emivirine (MKC-442) Analogues
DEFF Research Database (Denmark)
Danel, Krzystof; Jørgensen, Per Trolle; La Colla, Paolo
2009-01-01
The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV-1. The C C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with hig......The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV-1. The C C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents...... with higher activity against HIV-1-resistant mutants. The syntheses involved Pd-catalyzed C,C-coupling reactions, addition of disulfides, and click chemistry on the terminal C C bond as well as addition of bromine to the so formed internal C C bonds. Sonogashira coupling were performed with silyl...
Anti-proliferative therapy for HIV cure: a compound interest approach.
Reeves, Daniel B; Duke, Elizabeth R; Hughes, Sean M; Prlic, Martin; Hladik, Florian; Schiffer, Joshua T
2017-06-21
In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4 + T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone.
Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation
International Nuclear Information System (INIS)
Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei; Qu, Xiying; Wang, Xiaohui; Zeng, Hanxian; Chen, Huabiao; Zhu, Huanzhang
2014-01-01
Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alone or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies
Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation
Energy Technology Data Exchange (ETDEWEB)
Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei; Qu, Xiying; Wang, Xiaohui; Zeng, Hanxian [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China); Chen, Huabiao [Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139 (United States); Zhu, Huanzhang, E-mail: hzzhu@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China)
2014-07-18
Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alone or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies.
Pontikis, R; Benhida, R; Aubertin, A M; Grierson, D S; Monneret, C
1997-06-06
A series of 33 N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1, HEPT) were synthesized and evaluated for their anti-HIV-1 activity. In particular, the influence of substitution of the terminal hydroxy group of the acyclic structure of HEPT and the structural rigidity of this side chain were investigated. Halo (7, 8), azido (9), and amino (10-15) derivatives were synthesized from HEPT via the p-tosylate derivative 6. Acylation of the primary amine 15 afforded the amido analogs 16-20. The diaryl derivatives 26-29 were prepared by reaction of HEPT, or of the 6-(2-pyridylthio) analog 23, with diaryl disulfides in the presence of tri-n-butylphosphine. Compounds 39-41, in which the N-1 side chain is rigidified by incorporation of an E-configured double bond, were obtained by palladium(0)-catalyzed coupling of several different 6-(arylthio)uracil derivatives (37, 38) with allyl acetates 33. Compounds 13, 40a,c,d,f, and 41, incorporating an aromatic ring at the end of the acyclic side chain, were found to be more potent than the known diphenyl-substituted HEPT analog BPT (2), two of them, 40c,d, being 10-fold more active.
Directory of Open Access Journals (Sweden)
Valdiléa G Veloso
2008-10-01
Full Text Available OBJECTIVE: To assess rates of offering and uptake of HIV testing and their predictors among women who attended prenatal care. METHODS: A population-based cross-sectional study was conducted among postpartum women (N=2,234 who attended at least one prenatal care visit in 12 cities. Independent and probabilistic samples were selected in the cities studied. Sociodemographic data, information about prenatal care and access to HIV prevention interventions during the current pregnancy were collected. Bivariate and multivariate analyses were carried out to assess independent effects of the covariates on offering and uptake of HIV testing. Data collection took place between November 1999 and April 2000. RESULTS: Overall, 77.5% of the women reported undergoing HIV testing during the current pregnancy. Offering of HIV testing was positively associated with: previous knowledge about prevention of mother-to-child transmission of HIV; higher number of prenatal care visits; higher level of education and being white. HIV testing acceptance rate was 92.5%. CONCLUSIONS: The study results indicate that dissemination of information about prevention of mother-to-child transmission among women may contribute to increasing HIV testing coverage during pregnancy. Non-white women with lower level of education should be prioritized. Strategies to increase attendance of vulnerable women to prenatal care and to raise awareness among health care workers are of utmost importance.OBJETIVO: Estimar las tasas de oferta y realización de la prueba anti-HIV y sus predictivos entre mujeres que recibieron atención prenatal. MÉTODOS: Se realizó un estudio transversal, de base poblacional, con 2.234 puérperas en 12 ciudades de Brasil. Las muestras probabilísticas fueron seleccionadas independientemente por ciudad, entre puérperas que asistieron a por lo menos una visita prenatal. Se colectaron datos sociodemográficos, informaciones sobre cuidado prenatal y acceso a
Medical UV exposures and HIV activation
International Nuclear Information System (INIS)
Zmudzka, B.Z.; Miller, S.A.; Jacobs, M.E.; Beer, J.Z.
1996-01-01
This paper presents the first attempt to evaluate the potential of clinical UV exposures to induce the human immunodeficiency (HIV) promoter and, thus, to upregulate HIV growth in those skin cells that are directly affected by the exposure. Using the data for HIV promoter activation in vitro, we computed UVB and psoralen plus UVA (PUVA) doses that produce 50% of the maximal promoter activation (AD 50 ). Then, using (a) literature data for UV transmittance in the human skin, (b) a composite action spectrum for HIV promoter and pyrimidine dimer induction by UVB and (c) an action spectrum for DNA synthesis inhibition by PUVA, we estimated the distribution of medical UVB and PUVA doses in the skin. This allowed us to estimate how deep into the skin the HIV-activating doses might penetrate in an initial and an advanced stge of UVB and PUVA therapy. Such analysis was done for normal type II skin and for single exposures. For UVB we found that, when the incident dose on the surface of the skin is 500 J/m 2 (290-320 nm) (initial stage of the therapy), the dose producing 50% of the maximal HIV promoter activation (AD 50 UVB ) is limited to the stratum corneum. For PUVA we found that, when the incident UVA doses are 25 or 100 kJ/m 2 (320-400 nm) (an initial and an advanced stage of therapy, respectively), and the 8-methoxypsoralen concentration in the blood is 0.1 μg/mL (the desired level), the combined doses to the mid epidermis (and some areas of the upper dermis) are well below the 50% HIV promoter-activating PUVA dose (AD 50 PUVA ). These results suggest that the probability of HIV activation in the epidermis by direct mechanisms is higher for UVB than for PUVA treatment. However, complexities of the UV-inducible HIV activation and immunomodulatory phenomena are such that our results by themselves should not be taken as an indication that UVB therapy carries a high risk than PUVA therapy when administered to HIV-infected patients. (Author)
Frequency of class I anti-HLA alloantibodies in patients infected by HIV-1
Directory of Open Access Journals (Sweden)
Elza Regina Manzolli Leite
2010-02-01
Full Text Available The aim of this study was to evaluate the presence of class I anti-HLA alloantibodies in patients infected by HIV-1 and relate it with the different clinical courses of the disease. Blood samples were collected in EDTA tubes from 145 individuals. HIV-1 infection was confirmed by ELISA test. The presence of class I anti-HLA alloantibodies and HLA allele's were determined. Clinical evolution was set as fast (3 years. Class I anti-HLA alloantibodies presence was lower in healthy individuals than in those infected by HIV-1 (4.2% against 32.4%. However, an equal distribution of these alloantibodies was found among the individuals infected, independent on the clinical evolution. Thus, class I anti-HLA alloantibodies was not a determinant factor for patient worsening.O objetivo deste estudo foi avaliar a presença de aloanticorpos anti-HLA classe I em pacientes infectados pelo HIV-1 e relacioná-la aos diferentes cursos clínicos da doença. Amostras de sangue de 145 indivíduos HIV positivo foram coletadas em tubos com EDTA. A infecção pelo HIV-1 foi confirmada por teste ELISA e a presença de aloanticorpos anti-HLA classe I determinada em seguida. A evolução clínica foi definida como rápida (3 anos. A presença de aloanticorpos anti-HLA classe I foi menor em indivíduos saudáveis em relação aos infectados pelo HIV-1 (4,2% contra 32,4%. Porém, a distribuição destes aloanticorpos entre os indivíduos infectados foi igual, independente da evolução clínica. Deste modo, a presença de aloanticorpos anti-HLA classe I não é um fator determinante na piora clínica do paciente.
Rutenber, E E; McPhee, F; Kaplan, A P; Gallion, S L; Hogan, J C; Craik, C S; Stroud, R M
1996-09-01
The essential role of HIV-1 protease (HIV-1 PR) in the viral life cycle makes it an attractive target for the development of substrate-based inhibitors that may find efficacy as anti-AIDS drugs. However, resistance has arisen to potent peptidomimetic drugs necessitating the further development of novel chemical backbones for diversity based chemistry focused on probing the active site for inhibitor interactions and binding modes that evade protease resistance. AQ148 is a potent inhibitor of HIV-1 PR and represents a new class of transition state analogues incorporating an aminimide peptide isostere. A 3-D crystallographic structure of AQ148, a tetrapeptide isostere, has been determined in complex with its target HIV-1 PR to a resolution of 2.5 A and used to evaluate the specific structural determinants of AQ148 potency and to correlate structure-activity relationships within the class of related compounds. AQ148 is a competitive inhibitor of HIV-1 PR with a Ki value of 137 nM. Twenty-nine derivatives have been synthesized and chemical modifications have been made at the P1, P2, P1', and P2' sites. The atomic resolution structure of AQ148 bound to HIV-1 PR reveals both an inhibitor binding mode that closely resembles that of other peptidomimetic inhibitors and specific protein/inhibitor interactions that correlate with structure-activity relationships. The structure provides the basis for the design, synthesis and evaluation of the next generation of hydroxyethyl aminimide inhibitors. The aminimide peptide isostere is a scaffold with favorable biological properties well suited to both the combinatorial methods of peptidomimesis and the rational design of potent and specific substrate-based analogues.
Hamza, O.J.M.; Matee, M.I.N.; Simon, E.N.; Kikwilu, E.N.; Moshi, M.J.; Mugusi, F.; Mikx, F.H.M.; Verweij, P.E.; Ven, A.J.A.M. van der
2006-01-01
ABSTRACT: BACKGROUND: The aim of the study was to compare the prevalence and types of HIV-related oral lesions between children and adult Tanzanian patients on HAART with those not on HAART and to relate the occurrence of the lesions with anti-HIV drug regimen, clinical stage of HIV disease and CD4+
Adherence to anti-retroviral drugs in pregnant and lactating HIV ...
African Journals Online (AJOL)
Background: Anti-retroviral drugs reduce morbidity and mortality due to HIV and prevent transmission from mother to child. But compliance on anti-retroviral treatment is an essential element for the success of therapeutic goals. Objective: To assess the level of compliance of anti-retroviral treatment in pregnant and lactating ...
Bashyal, Bharat P; Wellensiek, Brian P; Ramakrishnan, Rajesh; Faeth, Stanley H; Ahmad, Nafees; Gunatilaka, A A Leslie
2014-11-01
Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3-5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM, respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. Copyright © 2014 Elsevier Ltd. All rights reserved.
Anti-retroviral therapy-induced status epilepticus in "pseudo-HIV serodeconversion".
Etgen, Thorleif; Eberl, Bernhard; Freudenberger, Thomas
2010-01-01
Diligence in the interpretation of results is essential as information gained from the psychiatric patient's history might often be restricted. Nonobservance of established guidelines may lead to a wrong diagnosis, induce a false therapy and result in life-threatening situations. Communication errors between hospitals and doctors and uncritical acceptance of prior diagnoses add substantially to this problem. We present a patient with alcohol-related dementia who received anti-retroviral therapy that promoted a non-convulsive status epilepticus. HIV serodeconversion was considered after our laboratory result yielded a HIV-negative status. Critical review of previous diagnostic investigations revealed several errors in the diagnosis of HIV infection leading to a "pseudo-serodeconversion." Finally, anti-retroviral therapy could be discontinued. Copyright © 2010 Elsevier Inc. All rights reserved.
Gómara, María José; Pérez-Pomeda, Ignacio; Gatell, José María; Sánchez-Merino, Victor; Yuste, Eloisa; Haro, Isabel
2017-02-01
The work reports the design and synthesis of a chimeric peptide that is composed of the peptide sequences of two entry inhibitors which target different sites of HIV-1 gp41. The chimeric peptide offers the advantage of targeting two gp41 regions simultaneously: the fusion peptide and the loop both of which are membrane active and participate in the membrane fusion process. We therefore use lipid raft-like liposomes as a tool to specifically direct the chimeric inhibitor peptide to the membrane domains where the HIV-1 envelope protein is located. Moreover, the liposomes that mimic the viral membrane composition protect the chimeric peptide against proteolytic digestion thereby increasing the stability of the peptide. The described liposome preparations are suitable nanosystems for managing hydrophobic entry-inhibitor peptides as putative therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.
A Novel Method for Determining the Inhibitory Potential of Anti-HIV Drugs
Shen, Lin; Rabi, S. Alireza; Siliciano, Robert F.
2009-01-01
In the absence of a cure, most HIV-1-infected individuals will require life-long treatment. It is therefore essential to optimize highly active antiretroviral therapy. Recent research has shown that the slope parameter or Hill coefficient, which describes the steepness of a dose-response curve, is a critical missing dimension in the evaluation of antiviral drug activity. Based on this finding, the instantaneous inhibitory potential (IIP) has been derived as a new measure of antiviral drug activity. IIP incorporates the slope parameter and thus is a more accurate pharmacodynamic measure of antiviral activity than current measures such as IC50 and inhibitory quotient. However, it remains important to determine how to use IIP to predict the in vivo efficacy of anti-HIV-1 drugs. This article discusses recent advances in in vitro measures of antiviral activity and the therapeutic implications of the dose-response curve slope and IIP. PMID:19837466
Mai, Antonello; Artico, Marino; Rotili, Dante; Tarantino, Domenico; Clotet-Codina, Imma; Armand-Ugón, Mercedes; Ragno, Rino; Simeoni, Silvia; Sbardella, Gianluca; Nawrozkij, Maxim B; Samuele, Alberta; Maga, Giovanni; Esté, José A
2007-11-01
Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.
Testing of viscous anti-HIV microbicides using Lactobacillus
Moncla, B.J.; Pryke, K.; Rohan, L. C.; Yang, H.
2011-01-01
The development of topical microbicides for intravaginal use to prevent HIV infection requires that the drugs and formulated products be nontoxic to the endogenous vaginal Lactobacillus. In 30 min exposure tests we found dapivirine, tenofovir and UC781 (reverse transcriptase inhibitor anti-HIV drugs) as pure drugs or formulated as film or gel products were not deleterious to Lactobacillus species; however, PSC-RANTES (a synthetic CCR5 antagonist) killed 2 strains of Lactobacillus jensenii. To...
Homeostatic properties of Lactobacillus jensenii engineered as a live vaginal anti-HIV microbicide.
Yamamoto, Hidemi S; Xu, Qiang; Fichorova, Raina N
2013-01-08
Vaginal probiotics are investigated as a binary strategy for prevention of bacterial vaginosis and HIV. We applied an innovative experimental model using primary and immortalized human cervical and vaginal epithelial cells to assess the functional properties of Lactobacillus jensenii, a predominant constituent of the healthy vaginal microbiome, engineered to express the HIV-1 entry inhibitor modified cyanovirin-N (mCV-N). In this model bacteria colonize the epithelial cells over a period of 24-72 h. Staurosporine and the Toll-like receptor 2/6 ligand macrophage-activating lipopeptide-2 (MALP-2) serve as positive controls for apoptosis and proinflammatory activation, respectively. In 24-hour intervals, the colonized epithelium is assessed microscopically, supernatants are collected for measurement of soluble immunoinflammatory mediators and production of CV-N, and cells are lysed for assessment of: 1) apoptosis by cleaved versus total caspase-3 assay; 2) NF-κB activation by a luciferase reporter assay; or 3) epithelia-associated colony forming units (CFU) in Brucella agar. Wild type (WT) L. jensenii 1153 consistently colonized cervical and vaginal cells in the absence of epithelial damage and apoptosis. The bioengineered derivatives expressing mCV-N or control plasmids showed the same stable colonization pattern, which was reproducible between technologists and bacterial batches (CFU coefficient of variation <10% within and between experiments and epithelial cell types). MALP-2 activated NF-κB and caused fold-increased levels of proinflammatory mediators with clinically established significance in the cervicovaginal environment (IL-1α, IL-1β, IL-6, TNF-α, IL-8, RANTES, MIP-3α, and ICAM-1), measured by a multiplex electrochemiluminescence assay. At the same time levels of protective anti-inflammatory mediators interleukin 1 receptor antagonist (IL-1RA) and secretory leukocyte protease inhibitor (SLPI), both measured by ELISA, remained constant (IL-1RA) or
Saison, J; Ferry, T; Demaret, J; Maucort Boulch, D; Venet, F; Perpoint, T; Ader, F; Icard, V; Chidiac, C; Monneret, G
2014-06-01
The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort. © 2014 British Society for Immunology.
Mohanta, Yugal Kishore; Biswas, Kunal; Panda, Sujogya Kumar; Bandyopadhyay, Jaya; De, Debashis; Jayabalan, Rasu; Bastia, Akshaya Kumar; Mohanta, Tapan Kumar
2017-12-01
Bio- synthesis of silver nanoparticles (AgNPs) was made by using the aqueous leaf extract of Ardisia solanacea. Rapid formation of AgNPs was observed from silver nitrate upon treatment with the aqueous extract of A. solanacea leaf. The formation and stability of the AgNPs in the colloidal solution were monitored by UV-visible spectrophotometer. The mean particle diameter of AgNPs was calculated from the DLS with an average size ∼4 nm and ∼65 nm. ATR-FTIR spectroscopy confirmed the presence of alcohols, aldehydes, flavonoids, phenols and nitro compounds in the leaf which act as the stabilizing agent. Antimicrobial activity of the synthesized AgNPs was performed using agar well diffusion and broth dilution method against the Gram-positive and Gram-negative bacteria. Further, robust anti-oxidative potential was evaluated by DPPH assay. The highest antimicrobial activity of synthesized AgNPs was found against Pseudomonas aeruginosa (28.2 ± 0.52 mm) whereas moderate activity was found against Bacillus subtilis (16.1 ± 0.76), Candida kruseii (13.0 ± 1.0), and Trichophyton mentagrophytes (12.6 ± 1.52). Moreover, the potential wound healing activity was observed against the BJ-5Ta normal fibroblast cell line. Current research revealed that A. solanacea was found to be a suitable source for the green synthesis of silver nanoparticles.
Synthesis, Analgesic, Anti-inflammatory and Antimicrobial Activities ...
African Journals Online (AJOL)
Purpose: Microbial infections often produce pain and inflammation. Chemotherapeutic, analgesic and anti-inflammatory drugs are prescribed simultaneously in normal practice. The compound possessing all three activities is not common.The purpose of the present study was to examine whether molecular modification ...
Sebitloane, Hannah M; Moodley, Jagidesa; Sartorius, Benn
2017-02-01
To explore potential relationships between HIV and highly active anti-retroviral therapy (HAART), and hypertensive disorders of pregnancy (HDP). A retrospective secondary analysis of maternal-deaths data from the 2011-2013 Saving Mothers Report from South Africa. The incidence of HIV infection amongst individuals who died owing to HDP was determined and comparisons were made based on HIV status and the use of HAART. Among 4452 maternal deaths recorded in the Saving Mothers report, a lower risk of a maternal deaths being due to HDP was observed among women who had HIV infections compared with women who did not have HIV (relative risk [RR] 0.57, 95% confidence interval [CI] 0.51-0.64). Further, reduced odds of death being due to HDP were recorded among women with AIDS not undergoing HAART compared with women with HIV who did not require treatment (RR 0.42, 95% CI 0.3-0.58). Notably, among all women with AIDS, a greater risk of death due to HDP was demonstrated among those who received HAART compared with those who did not (RR 1.15, 95% CI 1.02-1.29). HIV and AIDS were associated with a decreased risk of HDP being the primary cause of death; the use of HAART increased this risk. © 2016 International Federation of Gynecology and Obstetrics.
International Nuclear Information System (INIS)
Kamata, Masakazu; Kim, Patrick Y.; Ng, Hwee L.; Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O.; Chen, Irvin S.Y.
2015-01-01
Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8 + T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8 + T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8 + T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24 Gag in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8 + T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8 + T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8 + T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8 + T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8 + T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8 + T cells from HIV-1 infection suppresses its cytopathic effect
Cohen, Yehuda Z; Lorenzi, Julio C C; Seaman, Michael S; Nogueira, Lilian; Schoofs, Till; Krassnig, Lisa; Butler, Allison; Millard, Katrina; Fitzsimons, Tomas; Daniell, Xiaoju; Dizon, Juan P; Shimeliovich, Irina; Montefiori, David C; Caskey, Marina; Nussenzweig, Michel C
2018-03-01
HIV-1 epidemic. Antibodies with exceptional neutralizing activity against HIV-1 may provide several advantages to traditional HIV drugs, including an improved side-effect profile, a reduced dosing frequency, and immune enhancement. The activity of these antibodies has been established in vitro by utilizing HIV-1 Env-pseudotyped viruses derived from circulating viruses but produced in 293T cells by pairing Env proteins with a backbone vector. We tested PBMC-produced circulating viruses against five anti-HIV-1 antibodies currently in clinical development. We found that the activity of these antibodies against PBMC isolates is significantly less than that against 293T Env-pseudotyped viruses. This decline varied among the antibodies tested, with some demonstrating moderate reductions in activity and others showing an almost 100-fold reduction. As the development of these antibodies progresses, it will be critical to determine how the results of different in vitro tests correspond to performance in the clinic. Copyright © 2018 Cohen et al.
The anti-HIV-1 effect of scutellarin
International Nuclear Information System (INIS)
Zhang Gaohong; Wang Qian; Chen Jijun; Zhang Xuemei; Tam, S.-C.; Zheng Yongtang
2005-01-01
Scutellarin was purified from the plant Erigeron breviscapus (Vant.) Hand.-Mazz. The activity against 3 strains of human immunodeficiency virus (HIV) was determined in vitro in this study. These were laboratory-derived virus (HIV-1 IIIB ), drug-resistant virus (HIV-1 74V ), and low-passage clinical isolated virus (HIV-1 KM018 ). From syncytia inhibition study, the EC 50 of scutellarin against HIV-1 IIIB direct infection in C8166 cells was 26 μM with a therapeutic index of 36. When the mode of infection changed from acute infection to cell-to-cell infection, this compound became even more potent and the EC 50 reduced to 15 μM. This suggested that cell fusion might be affected by this compound. By comparing the inhibitory effects on p24 antigen, scutellarin was also found to be active against HIV-1 74V (EC 50 253 μM) and HIV-1 KM018 (EC 50 136 μM) infection with significant difference in potency. The mechanism of its action was also explored in this study. At a concentration of 433 μM, scutellarin inhibited 48% of the cell free recombinant HIV-1 RT activity. It also caused 82% inhibition of HIV-1 particle attachment and 45% inhibition of fusion at the concentrations of 54 μM. In summary, scutellarin was found to inhibit several strains of HIV-1 replication with different potencies. It appeared to inhibit HIV-1 RT activity, HIV-1 particle attachment and cell fusion. These are essential activities for viral transmission and replication
Photo-translocation of anti-HIV-1 drugs into TZM-bl cells
CSIR Research Space (South Africa)
Khanyile, T
2013-04-01
Full Text Available Targeted drug delivery into HIV-1 infected cells offers a reduction in toxicity and side effect. Using a femtosecond (fs) laser of different beam shapes anti-HIV-1 drugs are efficiently delivered into TZM-bl cells....
Mantri, Chinmay K; Mantri, Jyoti V; Pandhare, Jui; Dash, Chandravanu
2014-01-01
Methamphetamine is the second most frequently used illicit drug in the United States. Methamphetamine abuse is associated with increased risk of HIV-1 acquisition, higher viral loads, and enhanced HIV-1 pathogenesis. Although a direct link between methamphetamine abuse and HIV-1 pathogenesis remains to be established in patients, methamphetamine has been shown to increase HIV-1 replication in macrophages, dendritic cells, and cells of HIV transgenic mice. Intriguingly, the effects of methamphetamine on HIV-1 replication in human CD4(+) T cells that serve as the primary targets of infection in vivo are not clearly understood. Therefore, we examined HIV-1 replication in primary CD4(+) T cells in the presence of methamphetamine in a dose-dependent manner. Our results demonstrate that methamphetamine had a minimal effect on HIV-1 replication at concentrations of 1 to 50 μmol/L. However, at concentrations >100 μmol/L, it inhibited HIV-1 replication in a dose-dependent manner. We also discovered that methamphetamine up-regulated the cellular anti-HIV-1 microRNAs (miR-125b, miR-150, and miR-28-5p) in CD4(+) T cells. Knockdown experiments illustrated that up-regulation of the anti-HIV miRNAs inhibited HIV-1 replication. These results are contrary to the paradigm that methamphetamine accentuates HIV-1 pathogenesis by increasing HIV-1 replication. Therefore, our findings underline the complex interaction between drug use and HIV-1 and necessitate comprehensive understanding of the effects of methamphetamine on HIV-1 pathogenesis. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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Kamata, Masakazu, E-mail: masa3k@ucla.edu [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Kim, Patrick Y. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ng, Hwee L. [Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O' Connor, Sean [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Yang, Otto O. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States); AIDS Healthcare Foundation, Los Angeles, CA (United States); Chen, Irvin S.Y. [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States)
2015-07-31
Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8{sup +} T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8{sup +} T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8{sup +} T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24{sup Gag} in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8{sup +} T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8{sup +} T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8{sup +} T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8{sup +} T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection suppresses its cytopathic effect.
Frye, Victoria; Paige, Mark Q; Gordon, Steven; Matthews, David; Musgrave, Geneva; Kornegay, Mark; Greene, Emily; Phelan, Jo C; Koblin, Beryl A; Taylor-Akutagawa, Vaughn
2017-08-01
HIV/AIDS stigma and homophobia are associated with significant negative health and social outcomes among people living with HIV/AIDS (PLWHA) and those at risk of infection. Interventions to decrease HIV stigma have focused on providing information and education, changing attitudes and values, and increasing contact with people living with HIV/AIDS (PLWHA), activities that act to reduce stereotyped beliefs and prejudice, as well as acts of discrimination. Most anti-homophobia interventions have focused on bullying reduction and have been implemented at the secondary and post-secondary education levels. Few interventions address HIV stigma and homophobia and operate at the community level. Project CHHANGE, Challenge HIV Stigma and Homophobia and Gain Empowerment, was a community-level, multi-component anti-HIV/AIDS stigma and homophobia intervention designed to reduce HIV stigma and homophobia thus increasing access to HIV prevention and treatment access. The theory-based intervention included three primary components: workshops and trainings with local residents, businesses and community-based organizations (CBO); space-based events at a CBO-partner drop-in storefront and "pop-up" street-based events and outreach; and a bus shelter ad campaign. This paper describes the intervention design process, resultant intervention and the study team's experiences working with the community. We conclude that CHHANGE was feasible and acceptable to the community. Promoting the labeling of gay and/or HIV-related "space" as a non-stigmatized, community resource, as well as providing opportunities for residents to have contact with targeted groups and to understand how HIV stigma and homophobia relate to HIV/AIDS prevalence in their neighborhood may be crucial components of successful anti-stigma and discrimination programming. Copyright © 2017. Published by Elsevier Ltd.
Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan
2015-01-01
The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host-pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration.
Weak anti-HIV CD8+ T-cell effector activity in HIV primary infection
Dalod, Marc; Dupuis, Marion; Deschemin, Jean-Christophe; Goujard, Cécile; Deveau, Christiane; Meyer, Laurence; Ngo, Nicole; Rouzioux, Christine; Guillet, Jean-Gérard; Delfraissy, Jean-François; Sinet, Martine; Venet, Alain
1999-01-01
HIV-specific CD8+ T cells play a major role in the control of virus during HIV primary infection (PI) but do not completely prevent viral replication. We used IFN-γ enzyme-linked immunospot assay and intracellular staining to characterize the ex vivo CD8+ T-cell responses to a large variety of HIV epitopic peptides in 24 subjects with early HIV PI. We observed HIV-specific responses in 71% of subjects. Gag and Nef peptides were more frequently recognized than Env and Pol peptides. The number of peptides recognized was low (median 2, range 0–6). In contrast, a much broader response was observed in 30 asymptomatic subjects with chronic infection: all were responders with a median of 5 peptides recognized (range 1–13). The frequency of HIV-specific CD8+ T cells among PBMC for a given peptide was of the same order of magnitude in both groups. The proportion of HIV-specific CD8+CD28– terminally differentiated T cells was much lower in PI than at the chronic stage of infection. The weakness of the immune response during HIV PI could partially account for the failure to control HIV. These findings have potential importance for defining immunotherapeutic strategies and establishing the goals for effective vaccination. J. Clin. Invest. 104:1431–1439 (1999). PMID:10562305
Bashyal, Bharat P.; Wellensiek, Brian P.; Ramakrishnan, Rajesh; Faeth, Stanley H.; Ahmad, Nafees; Leslie Gunatilaka, A. A.
2014-01-01
Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, alterto...
Birse, Kenzie D M; Cole, Amy L; Hirbod, Taha; McKinnon, Lyle; Ball, Terry B; Westmacott, Garrett R; Kimani, Joshua; Plummer, Frank; Cole, Alexander M; Burgener, Adam; Broliden, Kristina
2015-01-01
Cationic proteins found in cervicovaginal secretions (CVS) are known to contribute to the early antiviral immune response against HIV-infection in vitro. We here aimed to define additional antiviral factors that are over-expressed in CVS from female sex workers at high risk of infection. CVS were collected from Kenyan HIV-seronegative (n = 34) and HIV-seropositive (n = 12) female sex workers, and were compared with those from HIV-seronegative low-risk women (n = 12). The highly exposed seronegative (HESN) sex workers were further divided into those with less (n = 22) or more (n = 12) than three years of documented sex work. Cationic protein-depleted CVS were assessed for HIV-neutralizing activity by a PBMC-based HIV-neutralizing assay, and then characterized by proteomics. HIV neutralizing activity was detected in all unprocessed CVS, however only CVS from the female sex worker groups maintained its HIV neutralizing activity after cationic protein-depletion. Differentially abundant proteins were identified in the cationic protein-depleted secretions including 26, 42, and 11 in the HESN>3 yr, HESNHIV-positive groups, respectively. Gene ontology placed these proteins into functional categories including proteolysis, oxidation-reduction, and epidermal development. The proteins identified in this study include proteins previously associated with the HESN phenotype in other cohorts as well as novel proteins not yet associated with anti-HIV activities. While cationic proteins appear to contribute to the majority of the intrinsic HIV neutralizing activity in the CVS of low-risk women, a broader range of non-cationic proteins were associated with HIV neutralizing activity in HESN and HIV-positive female sex workers. These results indicate that novel protein factors found in CVS of women with high-risk sexual practices may have inherent antiviral activity, or are involved in other aspects of anti-HIV host defense, and warrant further exploration into their mode of action.
Potential use of rapamycin in HIV infection
DEFF Research Database (Denmark)
Donia, Marco; McCubrey, James A; Bendtzen, Klaus
2010-01-01
The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies...... indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1...... replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood...
Thyroid hormone synthesis and anti-thyroid drugs
Indian Academy of Sciences (India)
The inhibition of thyroid hormone synthesis is required for the treatment of hyperthyroidism and this can be achieved by one or more anti-thyroid drugs. The most widely used anti-thyroid drug methimazole (MMI) inhibits the production of thyroid hormones by irreversibly inactivating the enzyme TPO. Our studies show that the ...
Mthethwa, Ningy S; Oyedeji, Bola A O; Obi, Larry C; Aiyegoro, Olayinka A
2014-12-18
Medicinal plants represent an important opportunity to rural communities in Africa, as a source of affordable medicine and as a source of income. Increased patient awareness about safe usage is important as well as more training with regards to traditional medicine. The aim of this study was to evaluate the ethnomedicinal prowess of some indigenous South African plants commonly used in Eastern Cape Province of South Africa for the treatment of skin and respiratory tract infections, HIV and their toxicity potential. Cassine transvaalensis, Vangueria infausta, Croton gratissimus and Vitex ferruginea were tested for antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis using Kirby-Bauer disk diffusion and minimum inhibition concentration (MIC). Cytotoxic and anti-HIV-1 activities of plants were tested using MTT Assay (3- (Dimethylthiozole-2-yl-2,5-diphenyltetrazolium bromide)) and anti- HIV-1iib assay. In search of bioactive lead compounds, Cassine transvaalensis which was found to be the most active plant extract against the two Staphylocoous bacteria was subjected to various chromatographic. Thin layer chromatography, Column chromatography and Nuclear Magnetic Resonance (NMR), (1H-1H, 13C-13C, in DMSO_d6, Bruker 600 MHz) were used to isolate and characterize 3-Oxo-28-hydroxylbetuli-20(29)-ene and 3,28-dihydroxylbetuli-20(29)-ene bioactive compounds from C. transvaalensis. The four plants studied exhibited bioactive properties against the test isolates. The zones of inhibition ranged between 16 mm to 31 mm for multi-drug resistant staphylococci species. MIC values varied between 0.6 and 0.02 μg/ml. C. gratissimus and C. transvaalensis exhibited the abilities to inhibit HIV-1iib. Two bioactive compounds were isolated from C. transvaalensis. Data from this study reveals the use of these plant by traditional healers in the Eastern Cape. Furthermore, C. transvaalensis and C. gratissimus were found to be more active as against HIV-1iib
Monocyte activation in HIV/HCV coinfection correlates with cognitive impairment.
Directory of Open Access Journals (Sweden)
Hans Rempel
Full Text Available Coinfection with human immunodeficiency virus (HIV and hepatitis C virus (HCV challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS. Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects' GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be
Differential effect of CLK SR Kinases on HIV-1 gene expression: potential novel targets for therapy
Directory of Open Access Journals (Sweden)
Dobson Wendy
2011-06-01
Full Text Available Abstract Background RNA processing plays a critical role in the replication of HIV-1, regulated in part through the action of host SR proteins. To explore the impact of modulating SR protein activity on virus replication, the effect of increasing or inhibiting the activity of the Cdc2-like kinase (CLK family of SR protein kinases on HIV-1 expression and RNA processing was examined. Results Despite their high homology, increasing individual CLK expression had distinct effects on HIV-1, CLK1 enhancing Gag production while CLK2 inhibited the virus. Parallel studies on the anti-HIV-1 activity of CLK inhibitors revealed a similar discrepant effect on HIV-1 expression. TG003, an inhibitor of CLK1, 2 and 4, had no effect on viral Gag synthesis while chlorhexidine, a CLK2, 3 and 4 inhibitor, blocked virus production. Chlorhexidine treatment altered viral RNA processing, decreasing levels of unspliced and single spliced viral RNAs, and reduced Rev accumulation. Subsequent experiments in the context of HIV-1 replication in PBMCs confirmed the capacity of chlorhexidine to suppress virus replication. Conclusions Together, these findings establish that HIV-1 RNA processing can be targeted to suppress virus replication as demonstrated by manipulating individual CLK function and identified chlorhexidine as a lead compound in the development of novel anti-viral therapies.
Stereoselective total synthesis of the potent anti-asthmatic compound CMI-977 (LDP-977)
Energy Technology Data Exchange (ETDEWEB)
Dias, Luiz Carlos; Farina, Lui Strambi; Ferreira, Marco Antonio Barbosa, E-mail: ldias@iqm.unicamp.br [Universidade de Campinas (UNICAMP), SP (Brazil). Instituto de Quimica
2013-02-15
A short and efficient stereoselective total synthesis of CMI-977 (LDP-977), a potent and orally active anti-asthmatic compound, was developed. The key steps involve a highly diastereoselective Mukaiyama oxidative cyclization, which provides the trans-THF (tetrahydrofuran) unit and a Seyferth-Gilbert homologation to construct the triple bond in the target molecule. The synthesis of the key chiral building block was performed using Jacobsen hydrolytic kinetic resolution. (author)
Stereoselective total synthesis of the potent anti-asthmatic compound CMI-977 (LDP-977)
International Nuclear Information System (INIS)
Dias, Luiz Carlos; Farina, Lui Strambi; Ferreira, Marco Antonio Barbosa
2013-01-01
A short and efficient stereoselective total synthesis of CMI-977 (LDP-977), a potent and orally active anti-asthmatic compound, was developed. The key steps involve a highly diastereoselective Mukaiyama oxidative cyclization, which provides the trans-THF (tetrahydrofuran) unit and a Seyferth-Gilbert homologation to construct the triple bond in the target molecule. The synthesis of the key chiral building block was performed using Jacobsen hydrolytic kinetic resolution. (author)
AtriplaR/anti-TB combination in TB/HIV patients. Drug in focus
Directory of Open Access Journals (Sweden)
Semvua Hadija H
2011-11-01
Full Text Available Abstract Background Co-administration of anti-tuberculosis and antiretroviral therapy is often inevitable in high-burden countries where tuberculosis is the most common opportunistic infection associated with HIV/AIDS. Concurrent use of rifampicin and several antiretroviral drugs is complicated by pharmacokinetic drug-drug interaction. Method Pubmed and Google search following the key words tuberculosis, HIV, emtricitabine, tenofovir efavirenz, interaction were used to find relevant information on each drug of the fixed dose combination AtriplaR Results Information on generic name, trade name, pharmacokinetic parameter, metabolism and the pharmacokinetic interaction with Anti-TB drugs of emtricitabine, tenofovir, and efavirenz was obtained. Conclusion Fixed dose combination of emtricitabine/tenofovir/efavirenz (ATRIPLAR which has been approved by Food and Drug Administration shows promising results as far as safety and efficacy is concerned in TB/HIV co-infection patients, hence can be considered effective and safe antiretroviral drug in TB/HIV management for adult and children above 3 years of age.
Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain.
Roy, Upal; Drozd, Vadym; Durygin, Andriy; Rodriguez, Jesse; Barber, Paul; Atluri, Venkata; Liu, Xiaohua; Voss, Thomas G; Saxena, Surendra; Nair, Madhavan
2018-01-25
Human Immunodeficiency Virus Type 1 (HIV-1) remains one of the leading causes of death worldwide. Present combination antiretroviral therapy has substantially improved HIV-1 related pathology. However, delivery of therapeutic agents to the HIV reservoir organ like Central nervous system (CNS) remains a major challenge primarily due to the ineffective transmigration of drugs through Blood Brain Barrier (BBB). The recent advent of nanomedicine-based drug delivery has stimulated the development of innovative systems for drug delivery. In this regard, particular focus has been given to nanodiamond due to its natural biocompatibility and non-toxic nature-making it a more efficient drug carrier than other carbon-based materials. Considering its potential and importance, we have characterized unmodified and surface-modified (-COOH and -NH 2 ) nanodiamond for its capacity to load the anti-HIV-1 drug efavirenz and cytotoxicity, in vitro. Overall, our study has established that unmodified nanodiamond conjugated drug formulation has significantly higher drug loading capacity than surface-modified nanodiamond with minimum toxicity. Further, this nanodrug formulation was characterized by its drug dissolution profile, transmigration through the BBB, and its therapeutic efficacy. The present biological characterizations provide a foundation for further study of in-vivo pharmacokinetics and pharmacodynamics of nanodiamond-based anti-HIV drugs.
G-Quadruplex Forming Oligonucleotides as Anti-HIV Agents.
Musumeci, Domenica; Riccardi, Claudia; Montesarchio, Daniela
2015-09-22
Though a variety of different non-canonical nucleic acids conformations have been recognized, G-quadruplex structures are probably the structural motifs most commonly found within known oligonucleotide-based aptamers. This could be ascribed to several factors, as their large conformational diversity, marked responsiveness of their folding/unfolding processes to external stimuli, high structural compactness and chemo-enzymatic and thermodynamic stability. A number of G-quadruplex-forming oligonucleotides having relevant in vitro anti-HIV activity have been discovered in the last two decades through either SELEX or rational design approaches. Improved aptamers have been obtained by chemical modifications of natural oligonucleotides, as terminal conjugations with large hydrophobic groups, replacement of phosphodiester linkages with phosphorothioate bonds or other surrogates, insertion of base-modified monomers, etc. In turn, detailed structural studies have elucidated the peculiar architectures adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. An overview of the state-of-the-art knowledge of the relevance of putative G-quadruplex forming sequences within the viral genome and of the most studied G-quadruplex-forming aptamers, selectively targeting HIV proteins, is here presented.
Directory of Open Access Journals (Sweden)
Grinsztejn Beatriz
2010-12-01
Full Text Available Abstract Background Concomitant infections may influence HIV progression by causing chronic activation leading to decline in T-cell function. In the Americas, visceral (AVL and tegumentary leishmaniasis (ATL have emerged as important opportunistic infections in HIV-AIDS patients and both of those diseases have been implicated as potentially important co-factors in disease progression. We investigated whether leishmaniasis increases lymphocyte activation in HIV-1 co-infected patients. This might contribute to impaired cellular immune function. Methods To address this issue we analyzed CD4+ T absolute counts and the proportion of CD8+ T cells expressing CD38 in Leishmania/HIV co-infected patients that recovered after anti-leishmanial therapy. Results We found that, despite clinical remission of leishmaniasis, AVL co-infected patients presented a more severe immunossupression as suggested by CD4+ T cell counts under 200 cells/mm3, differing from ATL/HIV-AIDS cases that tends to show higher lymphocytes levels (over 350 cells/mm3. Furthermore, five out of nine, AVL/HIV-AIDS presented low CD4+ T cell counts in spite of low or undetectable viral load. Expression of CD38 on CD8+ T lymphocytes was significantly higher in AVL or ATL/HIV-AIDS cases compared to HIV/AIDS patients without leishmaniasis or healthy subjects. Conclusions Leishmania infection can increase the degree of immune system activation in individuals concomitantly infected with HIV. In addition, AVL/HIV-AIDS patients can present low CD4+ T cell counts and higher proportion of activated T lymphocytes even when HIV viral load is suppressed under HAART. This fact can cause a misinterpretation of these laboratorial markers in co-infected patients.
Zeng, Li-Yan; Liu, Teng; Yang, Jie; Yang, Yueli; Cai, Chun; Liu, Shuwen
2017-07-10
A facile and versatile "on-water" protocol for the synthesis of pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/H 2 O was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists.
HIV enhancing activity of semen impairs the antiviral efficacy of microbicides
Zirafi, Onofrio; Kim, Kyeong-Ae; Roan, Nadia R.; Kluge, Silvia F.; Müller, Janis A.; Jiang, Shibo; Mayer, Benjamin; Greene, Warner C.; Kirchhoff, Frank; Münch, Jan
2015-01-01
Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. Here, we report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was Maraviroc. This HIV entry inhibitor targets the host cell CCR5 coreceptor and was highly active against both untreated and semen-exposed HIV. These data help explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission. PMID:25391483
Directory of Open Access Journals (Sweden)
Ryan B Craig
Full Text Available BACKGROUND: Anti-HIV immunoconjugates targeted to the HIV envelope protein may be used to eradicate the latent reservoir of HIV infection using activate-and-purge protocols. Previous studies have identified the two target epitopes most effective for the delivery of cytotoxic immunoconjugates the CD4-binding site of gp120, and the hairpin loop of gp41. Here we construct and test tetravalent double variable domain immunoglobulin molecules (DVD-Igs that bind to both epitopes. METHODS: Synthetic genes that encode DVD-Igs utilizing V-domains derived from human anti-gp120 and anti-gp41 Abs were designed and expressed in 293F cells. A series of constructs tested different inter-V-linker domains and orientations of the two V domains. Antibodies were tested for binding to recombinant Ag and native Env expressed on infected cells, for neutralization of infectious HIV, and for their ability to deliver cytotoxic immunoconjugates to infected cells. FINDINGS: The outer V-domain was the major determinant of binding and functional activity of the DVD-Ig. Function of the inner V-domain and bifunctional binding required at least 15 AA in the inter-V-domain linker. A molecular model showing the spatial orientation of the two epitopes is consistent with this observation. Linkers that incorporated helical domains (A[EAAAK](nA resulted in more effective DVD-Igs than those based solely on flexible domains ([GGGGS](n. In general, the DVD-Igs outperformed the less effective parental antibody and equaled the activity of the more effective. The ability of the DVD-Igs to deliver cytotoxic immunoconjugates in the absence of soluble CD4 was improved over that of either parent. CONCLUSIONS: DVD-Igs can be designed that bind to both gp120 and gp41 on the HIV envelope. DVD-Igs are effective in delivering cytotoxic immunoconjugates. The optimal design of these DVD-Igs, in which both domains are fully functional, has not yet been achieved.
Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides
Directory of Open Access Journals (Sweden)
Li Yun-Yao
2002-11-01
Full Text Available Abstract Background Cellulose acetate phthalate (CAP in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH Methods Enzyme linked immunosorbent assays (ELISA were used to (1 study HIV-1 IIIB and BaL binding to micronized CAP; (2 detect virus disintegration; and (3 measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the β-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. Results 1 HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2 The interaction between HIV-1 and micronized CAP led to: (a gp41 six-helix bundle formation; (b virus disintegration and shedding of envelope glycoproteins; and (c rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate, in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. Conclusions Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect.
Sero-prevalance of anti-R7V antibody in HIV infected patients in the ...
African Journals Online (AJOL)
The seroprevalence of Anti-R7V antibody was therefore investigated in HIV patients attending clinic within the Federal Capital Territory (FCT) and compared with HIV negative patients. Correlation between the presence of the antibody and the clinical status of patients was also investigated. The HIV positive patients were ...
Swart, P J; Beljaars, E; Smit, C; Pasma, A; Schuitemaker, H; Meijer, D K
1996-01-01
Charge modification by succinylation or cis-aconitylation of the terminal epsilon NH2 functions of the amino acid lysine in human serum albumin, resulted in polyanionic compounds with an anti-HIV-1 activity in the low nanomolar concentration range. After iv injections in rats of the negatively
Banarouei, Nasimossadat; Davood, Asghar; Shafaroodi, Hamed; Saeedi, Ghazaleh; Shafiee, Abbas
2018-04-23
N-aryl derivatives of phthalimide and 4-nitro phthalimide have demonstrated cyclooxygenase inhibitory activity. Also they possess an excellent analgesic and anti-inflammatory activity. In this work, a new series of N-arylmethylideneamino derivatives of phthalimide and 4-nitro phthalimide were designed and synthesized. The designed compounds were synthesized by condensation of the appropriate aldehyde and N-aminophthalimide in ethanol at room temperature at PH around 3. Their analgesic and anti-inflammatory activity were evaluated by acetic acid-induced pain test and carrageenan-induced paw edema test in mice and rats, respectively. The details of the synthesis and chemical characterization of the analogs are described. In vivo screening showed compounds 3a, 3b, 3f and 3h were the most potent analgesic compounds. In addition compounds 3a, 3c, 3d, 3e and 3j indicated comparable anti-inflammatory activity to indomethacin as reference drug. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Berkhout, Ben; van Wamel, Jeroen L. B.; Beljaars, Leonie; Meijer, Dirk K. F.; Visser, Servaas; Floris, René
2002-01-01
In a search for natural proteins with anti-HIV activity, we screened a large set of purified proteins from bovine milk and peptide fragments thereof. Because several charged proteins and peptides are known to inhibit the process of virus entry, we selected proteins with an unusual charge composition
Berkhout, B; van Wamel, JLB; Beljaars, L; Meijer, DKF; Visser, Servaas; Floris, R
In a search for natural proteins with anti-HIV activity, we screened a large set of purified proteins from bovine milk and peptide fragments thereof. Because several charged proteins and peptides are known to inhibit the process of virus entry, we selected proteins with an unusual charge composition
Li, Jingfen; Yin, Yong; Wang, Lisheng; Liang, Pengyun; Li, Menghua; Liu, Xu; Wu, Lichuan; Yang, Hua
2016-11-23
In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.
Evaluation of HBsAg and anti-HBc assays in saliva and dried blood spot samples according HIV status.
Flores, Geane Lopes; Cruz, Helena Medina; Potsch, Denise Vigo; May, Silvia Beatriz; Brandão-Mello, Carlos Eduardo; Pires, Marcia Maria Amendola; Pilotto, Jose Henrique; Lewis-Ximenez, Lia Laura; Lampe, Elisabeth; Villar, Livia Melo
2017-09-01
Influence of HIV status in HBV markers detection in saliva and dried blood spots (DBS) was not well established. This study aims to evaluate the performance of optimized commercial immunoassay for identifying HBsAg and anti-HBc in saliva and DBS according HIV status. A sum of 535 individuals grouped as HIV + , HBV + , HIV/HBV + and HIV/HBV- were recruited where 347 and 188 were included for HBsAg and anti-HBc evaluation, respectively. Serum, DBS collected in Whatman 903 paper and saliva obtained using salivette device were analyzed using EIA. Increased sample volume and ROC curve analysis for cut off determination were used for DBS and saliva testing. HBsAg detection in saliva and DBS exhibited sensitivities of 80.9% and 85.6% and specificities of 86.8% and 96.3%. Sensitivity of anti-HBc in saliva and DBS were 82.4% and 76.9% and specificities in saliva and DBS were 96.9% and 91.7%. Low sensitivities were observed for HBsAg (62%) and anti-HBc (47%) detection in saliva of HIV/HBV+ individuals. OD values were also lower for HBsAg detection in DBS and saliva of HIV/HBV+ individuals compared to their serum samples. Statistical significance was found for sensitivities in HBsAg detection between saliva and DBS demonstrating high sensitivity for DBS specimens. In conclusion, HIV status or antiretroviral treatment appears to interfere in the performance of HBsAg and anti-HBc detection in DBS and saliva samples using the adapted commercial EIA. Copyright © 2017 Elsevier B.V. All rights reserved.
Abdulhaqq, S A; Zorrilla, C; Kang, G; Yin, X; Tamayo, V; Seaton, K E; Joseph, J; Garced, S; Tomaras, G D; Linn, K A; Foulkes, A S; Azzoni, L; VerMilyea, M; Coutifaris, C; Kossenkov, A V; Showe, L; Kraiselburd, E N; Li, Q; Montaner, L J
2016-07-01
Sex workers practicing in high HIV endemic areas have been extensively targeted to test anti-HIV prophylactic strategies. We hypothesize that in women with high levels of genital exposure to semen changes in cervico-vaginal mucosal and/or systemic immune activation will contribute to a decreased susceptibility to HIV-1 infection. To address this question, we assessed sexual activity and immune activation status (in peripheral blood), as well as cellular infiltrates and gene expression in ectocervical mucosa biopsies in female sex workers (FSWs; n=50), as compared with control women (CG; n=32). FSWs had low-to-absent HIV-1-specific immune responses with significantly lower CD38 expression on circulating CD4(+) or CD8(+) T-cells (both: PHIV-1 integration and replication. A correlative relationship between semen exposure and elevated type-1 IFN expression in FSWs was also established. Overall, our data suggest that long-term condomless sex work can result in multiple changes within the cervico-vaginal compartment that would contribute to sustaining a lower susceptibility for HIV-1 infection in the absence of HIV-specific responses.
Testing of viscous anti-HIV microbicides using Lactobacillus.
Moncla, B J; Pryke, K; Rohan, L C; Yang, H
2012-02-01
The development of topical microbicides for intravaginal use to prevent HIV infection requires that the drugs and formulated products be nontoxic to the endogenous vaginal Lactobacillus. In 30min exposure tests we found dapivirine, tenofovir and UC781 (reverse transcriptase inhibitor anti-HIV drugs) as pure drugs or formulated as film or gel products were not deleterious to Lactobacillus species; however, PSC-RANTES (a synthetic CCR5 antagonist) killed 2 strains of Lactobacillus jensenii. To demonstrate the toxicity of formulated products a new assay was developed for use with viscous and non-viscous samples that we have termed the Lactobacillus toxicity test. We found that the vortex mixing of vaginal Lactobacillus species can lead to reductions in bacterial viability. Lactobacillus can survive briefly, about 2s, but viability declines with increased vortex mixing. The addition of heat inactivated serum or bovine serum albumin, but not glycerol, prevented the decrease in bacterial viability. Bacillus atrophaeus spores also demonstrated loss of viability upon extended mixing. We observed that many of the excipients used in film formulation and the films themselves also afford protection from the killing during vortex mixing. This method is of relevance for toxicity for cidal activities of viscous products. Copyright © 2011 Elsevier B.V. All rights reserved.
Gargan, Siobhan; Ahmed, Suaad; Mahony, Rebecca; Bannan, Ciaran; Napoletano, Silvia; O'Farrelly, Cliona; Borrow, Persephone; Bergin, Colm; Stevenson, Nigel J
2018-04-01
Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components. We found that STAT1 and STAT3 are specifically reduced in HEK293T cells expressing Vif and that full length, infectious HIV-1 IIIB strain promotes their degradation in a Vif-dependent manner. HIV-1 IIIB infection of myeloid ThP-1 cells also reduced the IFN-α-mediated induction of the anti-viral gene, ISG15, but not MxA, revealing a functional consequence of this HIV-1-mediated immune evasion strategy. Interestingly, while total STAT levels were not reduced upon in vitro IIIB infection of primary human PBMCs, IFN-α-mediated phosphorylation of STAT1 and STAT3 and ISG induction were starkly reduced, with removal of Vif (IIIBΔVif), partially restoring pSTATs, ISG15 and MxB induction. Similarly, pSTAT1 and pSTAT3 expression and IFN-α-induced ISG15 were reduced in PBMCs from HIV-infected patients, compared to healthy controls. Furthermore, IFN-α pre-treatment of a CEM T lymphoblast cells significantly inhibited HIV infection/replication (measured by cellular p24), only in the absence of Vif (IIIBΔVif), but was unable to suppress full length IIIB infection. When analysing the mechanism by which Vif might target the JAK/STAT pathway, we found Vif interacts with both STAT1 and STAT3, (but not STAT2), and its expression promotes ubiquitination and MG132-sensitive, proteosomal degradation of both proteins. Vif's Elongin-Cullin-SOCS-box binding motif enables the formation of an active E3 ligase complex, which we found to be required for Vif's degradation of STAT1 and STAT3. In fact, the E3 ligase scaffold proteins, Cul5 and Rbx2, were also found to be
A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats
Energy Technology Data Exchange (ETDEWEB)
Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others
2012-07-27
Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.
A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats
International Nuclear Information System (INIS)
Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Naito, Takeshi; Kawaji, Kumi; Kajiwara, Kazumi; Hattori, Toshio; Matsuoka, Masao; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka
2012-01-01
Highlights: ► We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. ► The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. ► In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1 IIIB and HIV-1 BaL as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1 IIIB activity, whereas fusion inhibitors showed both anti-HIV-1 IIIB and anti-HIV-1 BaL activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, “phenotypic drug evaluation”, may be applicable for the evaluation of various antiviral drugs in vivo.
Directory of Open Access Journals (Sweden)
Nadja Rodrigues de Melo
2006-09-01
Full Text Available Declining incidence of oropharyngeal candidosis and opportunistic infections over recent years can be attributed to the use of highly active anti-retroviral therapy (HAART. Infection with C. albicans generally involves adherence and colonization of superficial tissues. During this process, budding yeasts are able to transform to hyphae and penetrate into the deep tissue. Using the biocell tracer system, C. albicans hyphal growth was dynamically observed at the cellular level. Ritonavir was effective in the inhibition of hyphal growth with growth rate of 0.8 mum/min. This study showed the in vitro effect of HIV anti-retroviral drug on the growth rate of the C. albicans hyphae.O declínio na incidência de candidose orofaríngea e infecções oportunistas associadas a infecção pelo HIV tem sido atribuído a introdução da terapia antiretroviral combinada (HAART. Infecção por C. albicans envolve aderência e colonização da mucosa superficial. Durante este processo leveduras são capazes de transformar-se na forma de hifas e penetrar nos tecidos mais profundos. Usando o sistema "Bio-Cell Tracer", o crescimento de hifas de C. albicans foi observado dinamicamente a nível celular. Ritonavir, inibidor de protease do HIV, foi efetivo na inibição do crescimento de hifas com media de 0.8 mim/min.O presente estudo demonstrou o efeito in vitro de um agente anti-retroviral HIV sobre o crescimento de hifas de C. albicans.
Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).
Yamamoto, Nobuto; Ushijima, Naofumi; Koga, Yoshihiko
2009-01-01
Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.
Immunologic Intervention in HIV Infection: Anti-Polymerase Responses and Hormonal Regulation.
1992-05-01
34), has serious physical ad psyhdologic cosequn , including further compromise of irmmu status in AIMS (1). Dr. D. Kotler of Columbia University recently...nutritional factors in the induction of immunologic abnormalities in HIV-positive homosexual men. J. AIDS 2:235, 1989. 2. Kotler D, Nutrition in AIDS...1051, 1990. 14. Korq X-B, Zhu Q-Y, Vidal PM, Watanole AM, Polsky B, Armstrong D, Ostrandz M, lang SA Jr, Rxthors E, Cmaa T-C. Cmparisons of anti-HIV
Landa, Premysl; Skalova, Lenka; Bousova, Iva; Kutil, Zsofia; Langhansova, Lenka; Lou, Ji-Dong; Vanek, Tomas
2014-01-01
The aim of this study was to evaluate in vitro anti-proliferative (tested on MCF-7, MDA-MB-231, and MCF-10A cell lines) and anti-inflammatory (evaluated as inhibition of prostaglandin E2 synthesis catalyzed by cyclooxygenase-2) effect of various extracts from Vaccinium bracteatum leaves and fruits. The highest anti-proliferative effect possessed leaf dichloromethane extract with IC50 values ranging from 93 to 198 μg/mL. In the case of cyclooxygenase-2 inhibition, n-hexane, dichloromethane, and ethanol fruit extracts showed the best activity with IC50 values = 2.0, 5.4, and 12.7 μg/mL, respectively. These results indicate that V. bracteatum leaves and fruits could be useful source of anti-cancer and anti-inflammatory compounds.
Berhane, Tsegay; Yami, Alemishet; Alemseged, Fessahaye; Yemane, Tilahun; Hamza, Leja; Kassim, Mehedi; Deribe, Kebede
2012-01-01
Use of highly active antiretroviral therapy has led to significant reductions in morbidity and mortality rates. However, these agents had also given rise to the metabolic and morphologic abnormalities which are modifiable risk factors for cardiovascular diseases. Evidences elsewhere indicate growing in prevalence of these problems but studies are lacking in Ethiopia. This study was conducted to determine the prevalence of HIV-associated lipodystrophy and metabolic syndrome in patients taking highly active antiretroviral therapy. A cross-sectional study was conducted in 2010 on a sample of 313 patients taking highly active antiretroviral therapy in Jimma University specialized hospital. Structured questionnaire was used to assess patients' sociodemographic characteristics and clinical manifestations of metabolic abnormalities. Checklists were used for reviewing charts about clinical manifestations of metabolic abnormalities and immunologic profile of patients. Data was cleaned, entered in and analyzed using SPSS for windows version 16.0. Metabolic syndrome was detected in 21.1% and HIV-lipodystrophy was detected 12.1% of patients. The factors found to be independently associated with metabolic syndrome were taking the antiretroviral therapy for more than 12 months (AOR=4.2; 95% CI=1.24-14.23) and female sex (AOR=2.30; 95% CI=1.0-5.27) and the factor found to be independently associated with HIV-lipodystrophy was taking the antiretroviral therapy (AOR=3.59; 95% CI=1.03-12.54) for more than 12 months. Metabolic abnormalities were relatively common in the study population. The problems were higher among those who took anti-retroviral treatment for longer duration. Therefore, regular screening for and taking action against the metabolic abnormalities is mandatory.
International Nuclear Information System (INIS)
Du Li; Zhao Yaxue; Chen, Jing; Yang Liumeng; Zheng Yongtang; Tang Yun; Shen Xu; Jiang Hualiang
2008-01-01
Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl) -1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery
Nullbasic, a potent anti-HIV tat mutant, induces CRM1-dependent disruption of HIV rev trafficking.
Directory of Open Access Journals (Sweden)
Min-Hsuan Lin
Full Text Available Nullbasic, a mutant of the HIV-1 Tat protein, has anti-HIV-1 activity through mechanisms that include inhibition of Rev function and redistribution of the HIV-1 Rev protein from the nucleolus to the nucleoplasm and cytoplasm. Here we investigate the mechanism of this effect for the first time, establishing that redistribution of Rev by Nullbasic is not due to direct interaction between the two proteins. Rather, Nullbasic affects subcellular localization of cellular proteins that regulate Rev trafficking. In particular, Nullbasic induced redistribution of exportin 1 (CRM1, nucleophosmin (B23 and nucleolin (C23 from the nucleolus to the nucleus when Rev was coexpressed, but never in its absence. Inhibition of the Rev:CRM1 interaction by leptomycin B or a non-interacting RevM10 mutant completely blocked redistribution of Rev by Nullbasic. Finally, Nullbasic did not inhibit importin β- or transportin 1-mediated nuclear import, suggesting that cytoplasmic accumulation of Rev was due to increased export by CRM1. Overall, our data support the conclusion that CRM1-dependent subcellular redistribution of Rev from the nucleolus by Nullbasic is not through general perturbation of either nuclear import or export. Rather, Nullbasic appears to interact with and disrupt specific components of a Rev trafficking complex required for its nucleocytoplasmic shuttling and, in particular, its nucleolar accumulation.
Plant-based anti-HIV-1 strategies: vaccine molecules and antiviral approaches.
Scotti, Nunzia; Buonaguro, Luigi; Tornesello, Maria Lina; Cardi, Teodoro; Buonaguro, Franco Maria
2010-08-01
The introduction of highly active antiretroviral therapy has drastically changed HIV infection from an acute, very deadly, to a chronic, long-lasting, mild disease. However, this requires continuous care management, which is difficult to implement worldwide, especially in developing countries. Sky-rocketing costs of HIV-positive subjects and the limited success of preventive recommendations mean that a vaccine is urgently needed, which could be the only effective strategy for the real control of the AIDS pandemic. To be effective, vaccination will need to be accessible, affordable and directed against multiple antigens. Plant-based vaccines, which are easy to produce and administer, and require no cold chain for their heat stability are, in principle, suited to such a strategy. More recently, it has been shown that even highly immunogenic, enveloped plant-based vaccines can be produced at a competitive and more efficient rate than conventional strategies. The high variability of HIV epitopes and the need to stimulate both humoral neutralizing antibodies and cellular immunity suggest the importance of using the plant system: it offers a wide range of possible strategies, from single-epitope to multicomponent vaccines, modulators of the immune response (adjuvants) and preventive molecules (microbicides), either alone or in association with plant-derived monoclonal antibodies, besides the potential use of the latter as therapeutic agents. Furthermore, plant-based anti-HIV strategies can be administered not only parenterally but also by the more convenient and safer oral route, which is a more suitable approach for possible mass vaccination.
International Nuclear Information System (INIS)
Offiah, Curtis E.; Naseer, Aisha
2016-01-01
Cryptococcus neoformans infection is the most common fungal infection of the central nervous system (CNS) in advanced human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients, but remains a relatively uncommon CNS infection in both the immunocompromised and immunocompetent patient population, rendering it a somewhat elusive and frequently overlooked diagnosis. The morbidity and mortality associated with CNS cryptococcal infection can be significantly reduced by early recognition of the imaging appearances by the radiologist in order to focus and expedite clinical management and treatment. The emergence and evolution of anti-retroviral therapy have also impacted significantly on the imaging appearances, morbidity, and mortality of this neuro-infection. The constellation of varied imaging appearances associated with cryptococcal CNS infection in the HIV and AIDS population in the era of highly active anti-retroviral therapy (HAART) will be presented in this review.
Potential use of rapamycin in HIV infection
DEFF Research Database (Denmark)
Donia, Marco; McCubrey, James A; Bendtzen, Klaus
2010-01-01
The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies......, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV-1 infection....... indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1...
Esposito, Francesca; Mandrone, Manuela; Del Vecchio, Claudia; Carli, Ilaria; Distinto, Simona; Corona, Angela; Lianza, Mariacaterina; Piano, Dario; Tacchini, Massimo; Maccioni, Elias; Cottiglia, Filippo; Saccon, Elisa; Poli, Ferruccio; Parolin, Cristina; Tramontano, Enzo
2017-08-31
Despite the availability of several anti-retrovirals, there is still an urgent need for developing novel therapeutic strategies and finding new drugs against underexplored HIV-1 targets. Among them, there are the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) function and the cellular α-glucosidase, involved in the control mechanisms of N-linked glycoproteins formation in the endoplasmic reticulum. It is known that many natural compounds, such as pentacyclic triterpenes, are a promising class of HIV-1 inhibitors. Hence, here we tested the pentacyclic triterpene Lupeol, showing that it inhibits the HIV-1 RT-associated RNase H function. We then performed combination studies of Lupeol and the active site RNase H inhibitor RDS1759, and blind docking calculations, demonstrating that Lupeol binds to an HIV-1 RT allosteric pocket. On the bases of these results and searching for potential multitarget active drug supplement, we also investigated the anti-HIV-1 activity of Hemidesmus indicus, an Ayurveda medicinal plant containing Lupeol. Results supported the potential of this plant as a valuable multitarget active drug source. In fact, by virtue of its numerous active metabolites, H. indicus was able to inhibit not only the RT-associated RNase H function, but also the HIV-1 RT-associated RNA-dependent DNA polymerase activity and the cellular α-glucosidase. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
EASY-HIT: HIV full-replication technology for broad discovery of multiple classes of HIV inhibitors.
Kremb, Stephan; Helfer, Markus; Heller, Werner; Hoffmann, Dieter; Wolff, Horst; Kleinschmidt, Andrea; Cepok, Sabine; Hemmer, Bernhard; Durner, Jörg; Brack-Werner, Ruth
2010-12-01
HIV replication assays are important tools for HIV drug discovery efforts. Here, we present a full HIV replication system (EASY-HIT) for the identification and analysis of HIV inhibitors. This technology is based on adherently growing HIV-susceptible cells, with a stable fluorescent reporter gene activated by HIV Tat and Rev. A fluorescence-based assay was designed that measures HIV infection by two parameters relating to the early and the late phases of HIV replication, respectively. Validation of the assay with a panel of nine reference inhibitors yielded effective inhibitory concentrations consistent with published data and allowed discrimination between inhibitors of early and late phases of HIV replication. Finer resolution of the effects of reference drugs on different steps of HIV replication was achieved in secondary time-of-addition assays. The EASY-HIT assay yielded high Z' scores (>0.9) and signal stabilities, confirming its robustness. Screening of the LOPAC(1280) library identified 10 compounds (0.8%), of which eight were known to inhibit HIV, validating the suitability of this assay for screening applications. Studies evaluating anti-HIV activities of natural products with the EASY-HIT technology led to the identification of three novel inhibitory compounds that apparently act at different steps of HIV-1 replication. Furthermore, we demonstrate successful evaluation of plant extracts for HIV-inhibitory activities, suggesting application of this technology for the surveillance of biological extracts with anti-HIV activities. We conclude that the EASY-HIT technology is a versatile tool for the discovery and characterization of HIV inhibitors.
Agarwal, Atima; Sankaran, Sumathi; Vajpayee, Madhu; Sreenivas, V; Seth, Pradeep; Dandekar, Satya
2014-01-01
Background Assays with specificity and cost effectiveness are needed for the measurement of HIV-1 burden to monitor disease progression or response to anti-retroviral therapy (ART) in HIV-1 subtype C infected patients. Objectives The objective of this study was to develop and validate an affordable; one step Real-Time RT-PCR assay with high specificity and sensitivity to measure plasma HIV-1 loads in HIV-1 subtype C infected patients. Results We developed an RT-PCR assay to detect and quantitate plasma HIV-1 levels in HIV-1 subtype C infected patients. An inverse correlation between plasma viral loads (PVL) and CD4+ T-cell numbers was detected at all CDC stages. Significant correlations were found between CD8+ T-cell activation and PVL, as well as with the clinical and immunological status of the patients. Conclusions The RT-PCR assay provides a sensitive method to measure PVL in HIV-1 subtype C infected patients. Viral loads correlated with immune activation and can be used to monitor HIV care in India. PMID:17962068
Artico, M; Di Santo, R; Costi, R; Novellino, E; Greco, G; Massa, S; Tramontano, E; Marongiu, M E; De Montis, A; La Colla, P
1998-10-08
Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the
Clinical outcomes and immune benefits of anti-epileptic drug therapy in HIV/AIDS
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Krentz Hartmut B
2010-06-01
Full Text Available Abstract Background Anti-epileptic drugs (AEDs are frequently prescribed to persons with HIV/AIDS receiving combination antiretroviral therapy (cART although the extent of AED use and their interactions with cART are uncertain. Herein, AED usage, associated toxicities and immune consequences were investigated. Methods HIV replication was analysed in proliferating human T cells during AED exposure. Patients receiving AEDs in a geographically-based HIV care program were assessed using clinical and laboratory variables in addition to assessing AED indication, type, and cumulative exposures. Results Valproate suppressed proliferation in vitro of both HIV-infected and uninfected T cells (p 0.05 but AED exposures did not affect HIV production in vitro. Among 1345 HIV/AIDS persons in active care between 2001 and 2007, 169 individuals were exposed to AEDs for the following indications: peripheral neuropathy/neuropathic pain (60%, seizure/epilepsy (24%, mood disorder (13% and movement disorder (2%. The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin, followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine and valproate. In a nested cohort of 55 AED-treated patients receiving cART and aviremic, chronic exposure to sodium and calcium channel blocking AEDs was associated with increased CD4+ T cell levels (p 0.05 with no change in CD8+ T cell levels over 12 months from the beginning of AED therapy. Conclusions AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.
Control of HIV infection by IFN-α: implications for latency and a cure.
Bourke, Nollaig M; Napoletano, Silvia; Bannan, Ciaran; Ahmed, Suaad; Bergin, Colm; McKnight, Áine; Stevenson, Nigel J
2018-03-01
Viral infections, including HIV, trigger the production of type I interferons (IFNs), which in turn, activate a signalling cascade that ultimately culminates with the expression of anti-viral proteins. Mounting evidence suggests that type I IFNs, in particular IFN-α, play a pivotal role in limiting acute HIV infection. Highly active anti-retroviral treatment reduces viral load and increases life expectancy in HIV positive patients; however, it fails to fully eliminate latent HIV reservoirs. To revisit HIV as a curable disease, this article reviews a body of literature that highlights type I IFNs as mediators in the control of HIV infection, with particular focus on the anti-HIV restriction factors induced and/or activated by IFN-α. In addition, we discuss the relevance of type I IFN treatment in the context of HIV latency reversal, novel therapeutic intervention strategies and the potential for full HIV clearance.
International Nuclear Information System (INIS)
Hossain, M.M.; Tsuchie, H.; Detorio, M.A.; Shirono, H.; Hara, C.; Nishimoto, A.; Saji, A.; Koga, J.; Takata, N.; Maniar, J.K.; Saple, D.G.; Taniguchi, K.; Kageyama, S.; Ichimura, H.; Kurimura, T.
1998-01-01
A search for gene(s) associated with anti-human immunodeficiency virus type 1 (HIV-l) activity of CD8 + T cells was attempted using molecular cloning and the relation between the anti-HIV activity of CD8 + T cells and the interleukin-9 receptor a chain (IL-9R-α) mRNA expression from the cDNA clones obtained was examined. The anti-HIV-l activity of CD8 + T cell culture supernatants was assessed by measuring the level of HIV-l replication in a CD4 + T cell line transfected with an infectious HIV-l DNA clone. IL-9R-a mRNA was assayed by reverse transcriptase-polymerase chain reaction (RT-PCR). Of 5 cases showing high level of anti-HIV-l activity (more than 80% suppression of HIV-l replication), the mRNA was detected in 4 cases. Of 10 cases showing low level of anti-HIV-l activity (less than 80% suppression of HIV-l replication), the mRNA was detected in one case. Soluble recombinant human IL-9 receptor (rhIL-9sR) did not suppress HIV-l replication at a concentration of 1 μg/ml. These data suggest that the IL-9R-a mRNA formation in CD8 + T cells may correlate with and play some role in the anti-HIV-l activity of CD8+ T cells from HIV-l-infected individuals. Key words: CD8+ T cells; anti-HIV-l activity; cytokines; interleukin-9 receptor (authors)
Synthesis, Analgesic and Anti-inflammatory Activities of 3- Ethyl-2 ...
African Journals Online (AJOL)
4(3H)-ones and evaluate them for their analgesic and anti-inflammatory activities. Methods: The compounds, 3-ethyl-2-substituted amino-quinazolin-4(3H)-ones, were synthesized by reacting the amino group of 3-ethyl-2-hydrazino ...
The impact of pregnancy on anti-HIV activity of cervicovaginal secretions.
Hughes, Brenna L; Dutt, Riana; Raker, Christina; Barthelemy, Melody; Rossoll, Richard M; Ramratnam, Bharat; Wira, Charles R; Cu-Uvin, Susan
2016-12-01
Mucosal immunity of the female genital tract plays a critical role in defense against sexually transmitted infections like HIV. Pregnancy is associated with both structural and immunologic alterations in the genital mucosa, but the impact of these changes on its ability to suppress HIV infection is unknown. Current epidemiologic data are conflicting as to whether pregnancy increases the risk of HIV acquisition. The purpose of this study was to define the association between antimicrobial peptides and chemokines in cervicovaginal secretions and in vitro HIV infectivity among pregnant and nonpregnant women. Forty pregnant and 37 nonpregnant women were enrolled in a prospective longitudinal cohort study at a single tertiary care women's hospital in Providence, RI. Cervicovaginal lavage was performed at each study visit. For pregnant women, study visits occurred once per trimester, and there was an optional postpartum visit. For nonpregnant women, study visits occurred across a single cycle that was timed to occur in the proliferative, ovulatory, and secretory phases based on the presumption of a regular menstrual cycle. The impact of cervicovaginal lavage on HIV infectivity was evaluated using a TZM-bl assay and compared between pregnant and nonpregnant women for each visit. The previously validated TZM-bl assay, which uses a luciferase reporting gene to indicate HIV infection of TZM-bl cells, was measured with a luminometer with higher relative light units that indicate greater levels of in vitro HIV infection. Immune mediators were measured with a multiplex bead assay. HIV infectivity and median concentration of each mediator were compared between pregnant and nonpregnant groups with the Wilcoxon rank sum test. Cervicovaginal fluid from pregnant and nonpregnant women significantly decreased HIV infectivity in both groups compared with positive control (virus only; PHIV infectivity in both groups across all visits, except at the postpartum visit in the pregnant
Sari, Yulia; Haryati, Sri; Prasetyo, Afiono Agung; Hartono, Adnan, Zainal Arifin
2017-02-01
The human leukocyte antigen (HLA)-DQB1 gene polymorphisms may associated with the infection risk of Toxoplasma gondii in HIV patients. The HLA-DQB1*0402 in HIV-1-positive patients could be considered risk factors for developing neurological opportunistic infections, mainly Toxoplasma encephalitis. However, the HLA-DQB1*0402 gene polymorphisms status in the Javanese HIV patients is unknown. This study evaluated the prevalence of HLA-DQB*0402 alleles polymorphisms in Javanese HIV patients with positive anti-Toxoplasma gondii IgM status. Since 2009 our research group performing a molecular epidemiology of blood borne viruses in Central Java Indonesia, by collecting the epidemiological and clinical data from the high risk communities. All blood samples were screened for blood borne pathogens by serological and molecular assays including for HIV and Toxoplasma gondii. The genomic DNA was isolated from the whole blood samples. Genetic polymorphisms of HLA-DQB1*0402 alleles were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique. The genotypes were defined according to generated fragment patterns in the agarose gel electrophoresis analysis of PCR products. All of the samples were tested at least in duplicate. HLA-DQB1*0402 alleles were detected in 20.8% (16/77) patients and not detected in all HIV positive samples with negative anti-Toxoplasma gondii IgM status (n= 200). The HLA-DQB1*0402 alleles polymorphisms were detected in Javanese HIV patients with positive anti-Toxoplasma gondii IgM. The polymorphisms found may have association with the infection risk of Toxoplasma gondii in HIV patients.
Potential Role of Vδ2+ γδ T Cells in Regulation of Immune Activation in Primary HIV Infection
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Nupur Bhatnagar
2017-09-01
Full Text Available Although conventional regulatory T cells (Tregs are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI. Our previous data suggested that double negative (DN T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI. In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT, we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+ γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro
Peng, Chunte Sam; Fedeles, Bogdan I.; Singh, Vipender; Li, Deyu; Amariuta, Tiffany; Essigmann, John M.; Tokmakoff, Andrei
2015-01-01
The anti-HIV drug KP1212 was designed to intentionally increase the mutation rate of HIV, thereby causing viral population collapse. Its mutagenicity and thus antiviral activity was proposed to be the result of tautomerization. We used 2D IR spectroscopy to identify rapidly interconverting tautomers under physiological conditions. The traditionally rare enol–imino tautomer for nucleobases was found to be the major species for KP1212, providing a structural support for the tautomer hypothesis....
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Ussama M Abdel-Motal
Full Text Available Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS.This study tested the hypothesis that adeno-associated virus (AAV-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc, or "minibody" was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1(bal in an organotypic human vaginal epithelial cell (VEC model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP.This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.
Tietjen, Ian; Ngwenya, Barbara N; Fotso, Ghislain; Williams, David E; Simonambango, Sundana; Ngadjui, Bonaventure T; Andersen, Raymond J; Brockman, Mark A; Brumme, Zabrina L; Andrae-Marobela, Kerstin
2018-01-30
. These data, combined with self-reported health effects and previously-described in vitro anti-HIV activities of this traditional 3-step regimen, support the utility of longitudinal observational studies of patients undergoing this regimen to quantify its effects on plasma viral loads and HIV reservoir size in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.
Anti-Stigma HIV-Related Social Advertising: No Evidence for Side Effects on Condom Use.
Arendt, Florian; Hauck, Patricia; Mayr, Johanna; Negwer, Flavia
2017-10-17
Recent campaigns try to reduce social stigma associated with persons living with HIV. For example, a German campaign raised awareness that infection is unlikely in low-risk day-to-day interactions. Research has yet to show that there are no harmful side effects. This is essential because such messages promote a less threatening picture of HIV and thus may unintentionally increase complacency. We tested the possible side effects on the willingness to have sex without condoms. An experiment was conducted in which participants were exposed to anti-stigma messages or not. Anti-stigma messages did not elicit an increase in the willingness to have sex without condoms.
Abbas, Safinaz E; Awadallah, Fadi M; Ibrahim, Nashwa A; Gouda, Ahmed M
2010-02-01
Synthesis of several substituted pyrrolizines 10a-f, 11a-f, 13a-c, pyrimidopyrrolizines 14a-c, 15a-c, and pyrrolizinopyrimidoisoindoles 12a-c was discussed. The starting compounds 6-amino-7-cyano-N-(4-(un)substitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 9a-c were reacted with different aldehydes, acid chlorides, and acid anhydrides to give the target compounds. The structures of the new compounds were characterized by spectral and elemental analyses. All compounds were tested for their anti-inflammatory activity using the carrageenan-induced rat paw oedema model and exhibited weak to good activities compared to ketorolac as the reference drug. Also, analgesic activity of selected compounds, which are the most active in the anti-inflammatory screening, was measured using the acetic acid-induced writhing model; revealing activities comparable to or higher than ketorolac. Ulcer indices for the most active compounds were calculated and some compounds showed no or minimal ulcerogenic effect compared to ketorolac. Copyright 2009 Elsevier Masson SAS. All rights reserved.
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
Hagiwara, Kyoji; Ishii, Hideki; Murakami, Tomoyuki; Takeshima, Shin-nosuke; Chutiwitoonchai, Nopporn; Kodama, Eiichi N; Kawaji, Kumi; Kondoh, Yasumitsu; Honda, Kaori; Osada, Hiroyuki; Tsunetsugu-Yokota, Yasuko; Suzuki, Masaaki; Aida, Yoko
2015-01-01
The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
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Kyoji Hagiwara
Full Text Available The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1 therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3 of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.
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Ana Luiza Chaves Valadão
2015-06-01
Full Text Available Ipecac alkaloids are secondary metabolites produced in the medicinal plant Psychotria ipecacuanha. Emetine is the main alkaloid of ipecac and one of the active compounds in syrup of Ipecac with emetic property. Here we evaluated emetine’s potential as an antiviral agent against Human Immunodeficiency Virus. We performed in vitro Reverse Transcriptase (RT Assay and Natural Endogenous Reverse Transcriptase Activity Assay (NERT to evaluate HIV RT inhibition. Emetine molecular docking on HIV-1 RT was also analyzed. Phenotypic assays were performed in non-lymphocytic and in Peripheral Blood Mononuclear Cells (PBMC with HIV-1 wild-type and HIV-harboring RT-resistant mutation to Nucleoside Reverse Transcriptase Inhibitors (M184V. Our results showed that HIV-1 RT was blocked in the presence of emetine in both models: in vitro reactions with isolated HIV-1 RT and intravirion, measured by NERT. Emetine revealed a strong potential of inhibiting HIV-1 replication in both cellular models, reaching 80% of reduction in HIV-1 infection, with low cytotoxic effect. Emetine also blocked HIV-1 infection of RT M184V mutant. These results suggest that emetine is able to penetrate in intact HIV particles, and bind and block reverse transcription reaction, suggesting that it can be used as anti-HIV microbicide. Taken together, our findings provide additional pharmacological information on the potential therapeutic effects of emetine.
Non-adherence to anti-TB drugs among TB/HIV co-infected patients ...
African Journals Online (AJOL)
Non-adherence to anti-TB drugs among TB/HIV co-infected patients in Mbarara Hospital ... and its associated factors have not been studied in these patients in Uganda. ... Methods: A cross-sectional study with qualitative and quantitative data ...
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Brendan A I Payne
Full Text Available Modern anti-retroviral therapy is highly effective at suppressing viral replication and restoring immune function in HIV-infected persons. However, such individuals show reduced physiological performance and increased frailty compared with age-matched uninfected persons. Contemporary anti-retroviral therapy is thought to be largely free from neuromuscular complications, whereas several anti-retroviral drugs previously in common usage have been associated with mitochondrial toxicity. It has recently been established that patients with prior exposure to such drugs exhibit irreversible cellular and molecular mitochondrial defects. However the functional significance of such damage remains unknown. Here we use phosphorus magnetic resonance spectroscopy ((31P-MRS to measure in vivo muscle mitochondrial oxidative function, in patients treated with contemporary anti-retroviral therapy, and compare with biopsy findings (cytochrome c oxidase (COX histochemistry. We show that dynamic oxidative function (post-exertional ATP (adenosine triphosphate resynthesis was largely maintained in the face of mild to moderate COX defects (affecting up to ∼10% of fibers: τ½ ADP (half-life of adenosine diphosphate clearance, HIV-infected 22.1±9.9 s, HIV-uninfected 18.8±4.4 s, p = 0.09. In contrast, HIV-infected patients had a significant derangement of resting state ATP metabolism compared with controls: ADP/ATP ratio, HIV-infected 1.24±0.08×10(-3, HIV-uninfected 1.16±0.05×10(-3, p = 0.001. These observations are broadly reassuring in that they suggest that in vivo mitochondrial function in patients on contemporary anti-retroviral therapy is largely maintained at the whole organ level, despite histochemical (COX defects within individual cells. Basal energy requirements may nevertheless be increased.
The epidemiology of HIV infection in Morocco: systematic review and data synthesis
Kouyoumjian, S P; Mumtaz, G R; Hilmi, N; Zidouh, A; El Rhilani, H; Alami, K; Bennani, A; Gouws, E; Ghys, P D; Abu-Raddad, L J
2013-01-01
Summary Morocco has made significant strides in building its HIV research capacity. Based on a wealth of empirical data, the objective of this study was to conduct a comprehensive and systematic literature review and analytical synthesis of HIV epidemiological evidence in this country. Data were retrieved using three major sources of literature and data. HIV transmission dynamics were found to be focused in high-risk populations, with female sex workers (FSWs) and clients contributing the largest share of new HIV infections. There is a pattern of emerging epidemics among some high-risk populations, and some epidemics, particularly among FSWs, appear to be established and stable. The scale of the local HIV epidemics and populations affected show highly heterogeneous geographical distribution. To optimize the national HIV response, surveillance and prevention efforts need to be expanded among high-risk populations and in geographic settings where low intensity and possibly concentrated HIV epidemics are emerging or are already endemic. PMID:23970764
Adlar, F. R.; Bela, B.
2017-08-01
To anticipate the potential use of anti-integrase drugs in Indonesia for treatment of HIV-1 infection, the development of a drug resistance genotyping assay for anti-integrase is crucial in identifying the genetic drug resistance profile of Indonesian HIV-1 strains. This experiment aimed to amplify a target region in the integrase gene of Indonesian HIV-1 subtypes CRF01_AE and B that contain genetic mutations known to confer resistance to anti-integrase drug. Eleven archived plasma samples from individuals living with HIV-1 were obtained from the Virology and Cancer Pathobiology Research Center for Health Service (VCPRC FKUI-RSCM) laboratory. One of the plasma samples contained HIV-1 subtype B, and the remaining plasma samples contained subtype CRF01_AE. The target regions for all samples were amplified through RT-PCR, with an annealing temperature of 55 °C, using the primer pair AE_POL 4086F and AE_POL 5232R that were designed by VCPRC FKUI-RSCM. The results of this experiment show that 18.2% (2/11) of the samples were successfully amplified using the one-step RT-PCR. While the primer pair was effective in amplifying the target region in the integrase gene sequence for subtype B (100%; 1/1), it had a low efficacy (10%, 1/10) for subtype CRF01_AE. In conclusion, the primer pair can be used to amplify the target region in Indonesian HIV-1 strain subtypes CRF01_AE and B. However, optimization of the PCR condition and an increased number of samples would help to determine an accurate representation of the efficacy of the primer pair.
Gao, Lijie; Wang, Yunqi; Li, Yi; Dong, Ya; Yang, Aimin; Zhang, Jie; Li, Fengying; Zhang, Rongqiang
2018-07-01
Comprehensive bioinformatics analyses were performed to explore the key biomarkers in response to HIV infection of CD4 + and CD8 + T cells. The numbers of CD4 + and CD8 + T cells of HIV infected individuals were analyzed and the GEO database (GSE6740) was screened for differentially expressed genes (DEGs) in HIV infected CD4 + and CD8 + T cells. Gene Ontology enrichment, KEGG pathway analyses, and protein-protein interaction (PPI) network were performed to identify the key pathway and core proteins in anti-HIV virus process of CD4 + and CD8 + T cells. Finally, we analyzed the expressions of key proteins in HIV-infected T cells (GSE6740 dataset) and peripheral blood mononuclear cells(PBMCs) (GSE511 dataset). 1) CD4 + T cells counts and ratio of CD4 + /CD8 + T cells decreased while CD8 + T cells counts increased in HIV positive individuals; 2) 517 DEGs were found in HIV infected CD4 + and CD8 + T cells at acute and chronic stage with the criterial of P-value T cells. The main biological processes of the DEGs were response to virus and defense response to virus. At chronic stage, ISG15 protein, in conjunction with IFN-1 pathway might play key roles in anti-HIV responses of CD4 + T cells; and 4) The expression of ISG15 increased in both T cells and PBMCs after HIV infection. Gene expression profile of CD4 + and CD8 + T cells changed significantly in HIV infection, in which ISG15 gene may play a central role in activating the natural antiviral process of immune cells. © 2018 Wiley Periodicals, Inc.
HIV-1 protease inhibitory substances from Cassia garrettiana
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Jindaporn Puripattanvong
2007-01-01
Full Text Available Cassia garrettiana Craib, a Thai medicinal plant locally known as Samae-sarn, was investigated for its active constituents against HIV-1 protease (HIV-1 PR. Bioassay-guided fractionation of the heart woodof this plant led to the isolation of a stilbene derivative (1, piceatannol and an anthraquinone derivative (2, chrysophanol. Piceatannol exhibited appreciable inhibitory effect against HIV-1 PR with an IC50 value of25.4 μg/ml, whereas that of chrysophanol was 73.5 μg/ml. In addition, other two stilbenoids together with three anthraquinone derivatives were also investigated for their anti-HIV-1 PR activities. The resultindicated that resveratrol possessed anti-HIV-1 PR activity with an IC50 value of 85.0 μg/ml, whereas other stilbenoid (oxyresveratrol and anthraquinone derivatives (emodin, aloe-emodin, rhein were inactive (IC50 > 100 μg/ml.
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Andrabi Raiees
2012-09-01
Full Text Available Abstract Background Analysis of human monoclonal antibodies (mAbs developed from HIV-1 infected donors have enormously contributed to the identification of neutralization sensitive epitopes on the HIV-1 envelope glycoprotein. The third variable region (V3 is a crucial target on gp120, primarily due to its involvement in co-receptor (CXCR4 or CCR5 binding and presence of epitopes recognized by broadly neutralizing antibodies. Methods Thirty-three HIV-1 seropositive drug naive patients (18 males and 15 females within the age range of 20–57 years (median = 33 years were recruited in this study for mAb production. The mAbs were selected from EBV transformed cultures with conformationally constrained Cholera-toxin-B containing V3C (V3C-CTB fusion protein. We tested the mAbs for their binding with HIV-1 derived proteins and peptides by ELISA and for neutralization against HIV-1 viruses by TZM-bl assays. Results We isolated three anti-V3 mAbs, 277, 903 and 904 from the cells of different individuals. The ELISA binding revealed a subtype-C and subtype-A specific binding of antibody 277 and 903 while mAb 904 exhibited cross reactivity also with subtype-B V3. Epitope mapping of mAbs with overlapping V3 peptides showed exclusive binding to V3 crown. The antibodies displayed high and low neutralizing activity against 2/5 tier 1 and 1/6 tier 2 viruses respectively. Overall, we observed a resistance of the tier 2 viruses to neutralization by the anti-V3 mAbs, despite the exposure of the epitopes recognized by these antibodies on two representative native viruses (Du156.12 and JRFL, suggesting that the affinity of mAb might equally be crucial for neutralization, as the epitope recognition. Conclusions Our study suggests that the anti-V3 antibodies derived from subtype-C infected Indian patients display neutralization potential against tier 1 viruses while such activity may be limited against more resistant tier 2 viruses. Defining the fine epitope
Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11.
Li, Manqing; Kao, Elaine; Gao, Xia; Sandig, Hilary; Limmer, Kirsten; Pavon-Eternod, Mariana; Jones, Thomas E; Landry, Sebastien; Pan, Tao; Weitzman, Matthew D; David, Michael
2012-11-01
In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.
Jabeen, Erum; Janjua, Naveed Kausar; Ahmed, Safeer; Murtaza, Iram; Ali, Tahir; Masood, Nosheen; Rizvi, Aysha Sarfraz; Murtaza, Gulam
2017-12-01
The current study is aimed at the synthesis of Cu (II) and Fe (III) complexes of three flavonoids {morin (mor), quercetin (quer) and primuletin (prim)} and characterization through UV-Vis spectroscopy, cyclic voltammetry, FTIR, and thermal analysis. Structure prediction through DFT calculation was supported by experimental data. Benesi-Hildebrand equation was modified to function for 1:2 Cu-flavonoid and 1:3 Fe-flavonoid complexes. DFT predictions revealed that out of poly chelation sites present in morin and quercetin, 3-OH site was utilized as preferable chelation site while primuletin chelated through 5-OH position. In-vivo trials revealed the complexes to have better anti-diabetic potential than respective flavonoid. Fls/M-Fls proved as antagonistic to Alloxan induced diabetes and also retained anti-diabetic activity even in the presence of (2-hydroxypropyl)-β-cyclodextrin (HPβCD).
Novel dual small-molecule HIV inhibitors: scaffolds and discovery strategies.
Song, Anran; Yu, Haiqing; Wang, Changyuan; Zhu, Xingqi; Liu, Kexin; Ma, Xiaodong
2015-01-01
Searching for safe and effective treatments for HIV infection is still a great challenge worldwide in spite of the 27 marketed anti-HIV drugs and the powerful highly active antiretroviral therapy (HAART). As a promising prospect for generation of new HIV therapy drugs, multiple ligands (MDLs) were greatly focused on recently due to their lower toxicity, simplified dosing and patient adherence than single-target drugs. Till now, by disrupting two active sites or steps of HIV replications, a number of HIV dual inhibitors, such as CD4-gssucap120 inhibitors, CXCR4-gp20 inhibitors, RT-CXCR4 inhibitors, RT-protease inhibitors, RT-integrase inhibitors, and RTassociated functions inhibitors have been identified. Generally, these dual inhibitors were discovered mainly through screening approaches and design strategies. Of these compounds, the molecules bearing small skeletons exhibited strong anti-HIV activity and aroused great attention recently. Reviewing the progress of the dual small-molecule HIV inhibitors from the point of view of their scaffolds and discovery strategies will provide valuable information for producing more effective anti-HIV drugs. In this regard, novel dual small-molecule HIV inhibitors were illustrated, and their discovery paradigms as the major contents were also summarized in this manuscript.
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James J Kobie
Full Text Available The induction of a broadly neutralizing antibody (BNAb response against HIV-1 would be a desirable feature of a protective vaccine. Vaccine strategies thus far have failed to elicit broadly neutralizing antibody responses; however a minority of HIV-infected patients do develop circulating BNAbs, from which several potent broadly neutralizing monoclonal antibodies (mAbs have been isolated. The findings that several BNmAbs exhibit autoreactivity and that autoreactive serum antibodies are observed in some HIV patients have advanced the possibility that enforcement of self-tolerance may contribute to the rarity of BNAbs. To examine the possible breakdown of tolerance in HIV patients, we utilized the 9G4 anti-idiotype antibody system, enabling resolution of both autoreactive VH4-34 gene-expressing B cells and serum antibodies. Compared with healthy controls, HIV patients had significantly elevated 9G4+ serum IgG antibody concentrations and frequencies of 9G4+ B cells, a finding characteristic of systemic lupus erythematosus (SLE patients, both of which positively correlated with HIV viral load. Compared to the global 9G4-IgD--memory B cell population, the 9G4+IgD--memory fraction in HIV patients was dominated by isotype switched IgG+ B cells, but had a more prominent bias toward "IgM only" memory. HIV envelope reactivity was observed both in the 9G4+ serum antibody and 9G4+ B cell population. 9G4+ IgG serum antibody levels positively correlated (r = 0.403, p = 0.0019 with the serum HIV BNAbs. Interestingly, other serum autoantibodies commonly found in SLE (anti-dsDNA, ANA, anti-CL did not correlate with serum HIV BNAbs. 9G4-associated autoreactivity is preferentially expanded in chronic HIV infection as compared to other SLE autoreactivities. Therefore, the 9G4 system provides an effective tool to examine autoreactivity in HIV patients. Our results suggest that the development of HIV BNAbs is not merely a consequence of a general breakdown in
Myint, Melissa; Bucki, Robert; Janmey, Paul A; Diamond, Scott L
2015-07-15
Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired. Copyright © 2015 Elsevier Ltd. All rights reserved.
DEFF Research Database (Denmark)
Storgaard, Morten
functional group tolerance. Unfortunately, these -aryl tetramic acids were too unreactive and ring opening toward the synthesis of the building block did not succeed. However, -aryl tetramic acids are still interesting compounds due to their potential biological activity. The building block 3.15 (P1......-catalyzed enantioselective synthesis of diaryl amines, which is an important class of compounds (Chapter 4). For example it is found in the third generation anti-histaminic agent levocetirizine. Development of efficient synthetic routes is therefore of considerably interest. The rhodium-catalyzed enantioselective synthesis...
Synthesis and Anti-Bacterial Activities of Some Novel Schiff Bases Derived from Aminophenazone
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Salman A Khan
2010-10-01
Full Text Available A series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one-containing Schiff bases were synthesized, characterized and screened for their antibacterial activities. The structures of the synthesized compounds were established by spectroscopic (FT-IR, 1H-NMR, 13C-NMR, MS and elemental analyses. The anti-bacterial activities (with MIC values of compounds were evaluated. The anti-bacterial screening results reveal that among the six compounds screened, four compounds showed moderate to good anti-bacterial activity. Among the tested compounds, the most effective compounds against four bacterial strains, viz. Escherichia coli, Staphylococcus aureus, Salmonella typhimurium and Streptococcus pyogenes, are [(2-Chlorobenzylideneamino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (4 and [(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yliminomethyl]benzonitrile (5 with MIC values of 6.25 μg/mL.
Semugoma, Paul; Beyrer, Chris; Baral, Stefan
2012-01-01
Uganda's response to the HIV epidemic has been lauded for its robustness and achievements. However, a key component of HIV prevention programming has been missing, for men who have sex with men (MSM). The main reason cited has been criminalization of male homosexual behavior. In 2009, the Anti-Homosexuality Bill (AHB) was introduced in the parliament to enhance existing anti-homosexuality law. A multi-disciplinary team made a Health Impact Assessment of the proposed AHB. The bill as tabled would severely increase punishments, increased closeting. Social capital of MSM would be eroded by clauses mandating reporting by friends, relatives, and acquaintances. Health-care professionals would have to inform on homosexuals. Mandatory HIV testing would be a blow to programming. Probable disclosure of HIV status in a public space (court) would also be a deterrent. Heftier punishments for those testing positive increases stigma and hobbles subsequent care. The AHB argues for exclusion, and more discrimination targeting persons living with HIV and sexual minorities. It will exacerbate the negative public health consequences of the existing legislation. The government of Uganda should review guidance documents published by authoritative bodies including the World Bank, World Health Organization to develop and bring to scale Human rights-affirming HIV prevention, treatment, and care responses.
Czech Academy of Sciences Publication Activity Database
Lamie, P.F.; Philoppes, J.N.; El-Gendy, A.O.; Rárová, Lucie; Grúz, Jiří
2015-01-01
Roč. 20, č. 9 (2015), s. 16620-16642 ISSN 1420-3049 R&D Projects: GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : synthesis * phthalimides * anti-microbial Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.465, year: 2015
Seroprevalence of anti-HCV and hepatitis B surface antigen in HIV infected patients
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Tankhiwale S
2003-01-01
Full Text Available Human immunodeficiency virus (HIV is known to influence the natural history of infections with certain hepatitis viruses and interactions between HIV and hepatitis viruses may potentiate HIV replication. There is high degree of epidemiological similarity between hepatitis B virus and HIV as regard to high-risk group and route of transmission. Transmission of hepatitis C virus (HCV through blood transfusion and intravenous drug abuse is well documented. Present study deals with the study of concurrent infection of HBV and HCV with HIV infection. In the study of 110 HIV seropositive patients, 34(30.4% were positive for HBV and 8(7.27% for HCV. The difference of concomitant infection was highly significant compared to controls. (p value < 0.0001. Heterosexual high risk behaviour was observed in 89(80.91% of 110 HIV positive patients, out of which 23(25.8% and 5(5.62% were HBsAg and anti-HCV positive respectively. History of transmission was unclear in remaining patients. Concomitant infection of HIV and HBV was found to be significantly more in the symptomatic group (40.68% compared to asymptomatic group (19.6%. As HIV infection is known to affect the natural history of both HBV and HCV infection, screening of their concurrent association is necessary.
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Slava eRom
2015-08-01
Full Text Available The transcription of HIV-1 (HIV is regulated by complex mechanisms involving various cellular factors and virus-encoded transactivators. Poly(ADP-ribose polymerase 1 (PARP-1 inhibition has emerged recently as a potent anti-inflammatory tool, since PARP-1 is involved in the regulation of some genes through its interaction with various transcription factors. We propose a novel approach to diminish HIV replication via PARP-1 inhibition using human primary monocyte-derived macrophages (MDM as an in vitro model system. PARP-1 inhibitors were able to reduce HIV replication in MDM by 60-80% after 7 days infection. Long Terminal Repeat (LTR acts as a switch in virus replication and can be triggered by several agents such as: Tat, tumor necrosis factor α (TNFα, and phorbol 12-myristate 13-acetate (PMA. Overexpression of Tat in MDM transfected with an LTR reporter plasmid led to a 4.2-fold increase in LTR activation; PARP inhibition resulted in 70% reduction of LTR activity. LTR activity, which increased 3-fold after PMA or TNFα treatment, was reduced by PARP inhibition (by 85-95%. MDM treated with PARP inhibitors showed 90% reduction in NFκB activity (known to mediate PMA- and TNFα-induced HIV LTR activation. Cytoskeleton rearrangements are important in effective HIV-1 infection. PARP inactivation reduced actin cytoskeleton rearrangements by affecting Rho GTPase machinery. These findings suggest that HIV replication in MDM could be suppressed by PARP inhibition via NFκB suppression, diminution of LTR activation and its effects on the cytoskeleton. PARP appears to be essential for HIV replication and its inhibition may provide a potent approach to treatment of HIV infection.
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Maneesh Singh
Full Text Available Cord blood hematopoietic progenitor cells (CB-HPCs transplanted immunodeficient NOD/LtsZ-scidIL2Rγ(null (NSG and NOD/SCID/IL2Rγ(null (NOG mice need efficient human cell engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI is a classical myeloablation regimen used to improve engraftment levels of human cells in these humanized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to transplant HPCs in neonatal and adult NSG mice. In the present study, we further ameliorated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3-4 week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efficiency of human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and increased CD3+T cell levels, with better lymphoid tissue development and prolonged human cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation of inflammation marker and microbial translocation after HIV-1 infection. Humanized NSG mice reconstituted according to our new protocol produced, moderate cellular and humoral immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted according to our easy to use protocol will provide a better in vivo model for HIV-1 replication and anti-HIV-1 therapy trials.
The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro.
Kuciak, Monika; Gabus, Caroline; Ivanyi-Nagy, Roland; Semrad, Katharina; Storchak, Roman; Chaloin, Olivier; Muller, Sylviane; Mély, Yves; Darlix, Jean-Luc
2008-06-01
The human immunodeficiency virus type 1 (HIV-1) is a primate lentivirus that causes the acquired immunodeficiency syndrome (AIDS). In addition to the virion structural proteins and enzyme precursors, that are Gag, Env and Pol, HIV-1 encodes several regulatory proteins, notably a small nuclear transcriptional activator named Tat. The Tat protein is absolutely required for virus replication since it controls proviral DNA transcription to generate the full-length viral mRNA. Tat can also regulate mRNA capping and splicing and was recently found to interfere with the cellular mi- and siRNA machinery. Because of its extensive interplay with nucleic acids, and its basic and disordered nature we speculated that Tat had nucleic acid-chaperoning properties. This prompted us to examine in vitro the nucleic acid-chaperoning activities of Tat and Tat peptides made by chemical synthesis. Here we report that Tat has potent nucleic acid-chaperoning activities according to the standard DNA annealing, DNA and RNA strand exchange, RNA ribozyme cleavage and trans-splicing assays. The active Tat(44-61) peptide identified here corresponds to the smallest known sequence with DNA/RNA chaperoning properties.
Benslimane, A F; Pouchus, Y F; Verbist, J F; Petit, J Y; Khettab, E N; Welin, L; Brion, J D
1992-01-01
A new synthesis is proposed for cordiachromene A (CCA), a bioactive component of the ascidian Aplidium antillense Gravier, using a method producing a racemic mixture. The anti-inflammatory activities of a natural extract and a chemically synthetic form of CCA were assessed in vivo by carrageenan-induced rat-paw edema. The activity of synthetic CCA was confirmed by a test on kaolin-induced granuloma in the rat. Strong activities were measured for both CCA, but comparison of results of the first test suggests that only the natural optically active isomer has an anti-inflammatory effect. CCA is similar to indomethacin in its effect on carrageenan-induced rat-paw edema and ten times as active as phenylbutazone.
Madhi, Shabir A; Kuwanda, Locadiah; Saarinen, Leena; Cutland, Clare; Mothupi, Rosalia; Käyhty, Helena; Klugman, Keith P
2005-12-01
The quantitative (anti-Hib capsular polysaccharide antibody concentrations; anti-HibPS) and qualitative (bactericidal activity and avidity) aspects in immune responses to Haemophilus influenzae type b polyribosyl ribitol phospshate-CRM(197) conjugate vaccine (HibCV; HibTiter) were evaluated in 66 HIV infected children not receiving anti-retroviral therapy and 127 HIV uninfected children. Surveillance was conducted for invasive Hib disease in a cohort of 39,865 (approximately 6.4% of whom were HIV infected) children from March 1998 to June 2004. HIV infected children had lower anti-HibPS geometric mean antibody concentrations 1 month post-immunisation than HIV uninfected children (Por=1.0 microg/ml (RR 0.54; 95% CI 0.43-0.69). A lower proportion of HIV infected children than HIV uninfected children (RR 0.78; 95% CI 0.66-0.93) had measurable anti-Hib serum bactericidal activity (SBA) and the HibPS antibody concentration required for 50% killing of Hib bacteria was greater among HIV infected than HIV uninfected children (P=0.001). The estimated risk of HibCV failure was 35.1-fold greater (95% CI 14.6-84.6) amongst HIV infected than HIV uninfected children.
The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection
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Assunta Venuti
2017-10-01
Full Text Available The CC chemokine receptor 5 (CCR5 is responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, although it is expressed on different cell types. It has been shown to act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV. Natural reactive antibodies (Abs recognizing first loop (ECL1 of CCR5 have been detected in several pools of immunoglobulins from healthy donors and from several cohorts of either HIV-exposed but uninfected subjects (ESN or HIV-infected individuals who control disease progression (LTNP as well. The reason of development of anti-CCR5 Abs in the absence of autoimmune disease is still unknown; however, the presence of these Abs specific for CCR5 or for other immune receptors and mediators probably is related to homeostasis maintenance. The majority of anti-CCR5 Abs is directed to HIV binding site (N-terminus and ECL2 of the receptor. Conversely, it is well known that ECL1 of CCR5 does not bind HIV; thus, the anti-CCR5 Abs directed to ECL1 elicit a long-lasting internalization of CCR5 but not interfere with HIV binding directly; these Abs block HIV infection in either epithelial cells or CD4+ T lymphocytes and the mechanism differs from those ones described for all other CCR5-specific ligands. The Ab-mediated CCR5 internalization allows the formation of a stable signalosome by interaction of CCR5, β-arrestin2 and ERK1 proteins. The signalosome degradation and the subsequent de novo proteins synthesis determine the CCR5 reappearance on the cell membrane with a very long-lasting kinetics (8 days. The use of monoclonal Abs to CCR5 with particular characteristics and mode of action may represent a novel mode to fight viral infection in either vaccinal or therapeutic strategies.
HIV antibodies for treatment of HIV infection.
Margolis, David M; Koup, Richard A; Ferrari, Guido
2017-01-01
The bar is high to improve on current combination antiretroviral therapy (ART), now highly effective, safe, and simple. However, antibodies that bind the HIV envelope are able to uniquely target the virus as it seeks to enter new target cells, or as it is expressed from previously infected cells. Furthermore, the use of antibodies against HIV as a therapeutic may offer advantages. Antibodies can have long half-lives, and are being considered as partners for long-acting antiretrovirals for use in therapy or prevention of HIV infection. Early studies in animal models and in clinical trials suggest that such antibodies can have antiviral activity but, as with small-molecule antiretrovirals, the issues of viral escape and resistance will have to be addressed. Most promising, however, are the unique properties of anti-HIV antibodies: the potential ability to opsonize viral particles, to direct antibody-dependent cellular cytotoxicity (ADCC) against actively infected cells, and ultimately the ability to direct the clearance of HIV-infected cells by effector cells of the immune system. These distinctive activities suggest that HIV antibodies and their derivatives may play an important role in the next frontier of HIV therapeutics, the effort to develop treatments that could lead to an HIV cure. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
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Viraj Kulkarni
2017-11-01
Full Text Available HIV infection not only destroys CD4+ T cells but also inflicts serious damage to the B-cell compartment, such as lymphadenopathy, destruction of normal B-cell follicle architecture, polyclonal hypergammaglobulinemia, increased apoptosis of B cells, and irreversible loss of memory B-cell responses with advanced HIV disease. Subepithelial B cells and plasma cells are also affected, which results in loss of mucosal IgG and IgA antibodies. This leaves the mucosal barrier vulnerable to bacterial translocation. The ensuing immune activation in mucosal tissues adds fuel to the fire of local HIV replication. We postulate that compromised mucosal antibody defenses also facilitate superinfection of HIV-positive individuals with new HIV strains. This in turn sets the stage for the generation of circulating recombinant forms of HIV. What can the mucosal B-cell compartment contribute to protect a healthy, uninfected host against mucosal HIV transmission? Here, we discuss proof-of-principle studies we have performed using passive mucosal immunization, i.e., topical administration of preformed anti-HIV monoclonal antibodies (mAbs as IgG1, dimeric IgA1 (dIgA1, and dIgA2 isotypes, alone or in combination. Our data indicate that mucosally applied anti-HIV envelope mAbs can provide potent protection against mucosal transmission of simian-human immunodeficiency virus. Our review also discusses the induction of mucosal antibody defenses by active vaccination and potential strategies to interrupt the vicious cycle of bacterial translocation, immune activation, and stimulation of HIV replication in individuals with damaged mucosal barriers.
Bactericidal Immunity to Salmonella in Africans and Mechanisms Causing Its Failure in HIV Infection.
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Yun Shan Goh
2016-04-01
Full Text Available Nontyphoidal strains of Salmonella are a leading cause of death among HIV-infected Africans. Antibody-induced complement-mediated killing protects healthy Africans against Salmonella, but increased levels of anti-lipopolysaccharide (LPS antibodies in some HIV-infected African adults block this killing. The objective was to understand how these high levels of anti-LPS antibodies interfere with the killing of Salmonella.Sera and affinity-purified antibodies from African HIV-infected adults that failed to kill invasive S. Typhimurium D23580 were compared to sera from HIV-uninfected and HIV-infected subjects with bactericidal activity. The failure of sera from certain HIV-infected subjects to kill Salmonella was found to be due to an inherent inhibitory effect of anti-LPS antibodies. This inhibition was concentration-dependent and strongly associated with IgA and IgG2 anti-LPS antibodies (p<0.0001 for both. IgG anti-LPS antibodies, from sera of HIV-infected individuals that inhibit killing at high concentration, induced killing when diluted. Conversely, IgG, from sera of HIV-uninfected adults that induce killing, inhibited killing when concentrated. IgM anti-LPS antibodies from all subjects also induced Salmonella killing. Finally, the inhibitory effect of high concentrations of anti-LPS antibodies is seen with IgM as well as IgG and IgA. No correlation was found between affinity or avidity, or complement deposition or consumption, and inhibition of killing.IgG and IgM classes of anti-S. Typhimurium LPS antibodies from HIV-infected and HIV-uninfected individuals are bactericidal, while at very high concentrations, anti-LPS antibodies of all classes inhibit in vitro killing of Salmonella. This could be due to a variety of mechanisms relating to the poor ability of IgA and IgG2 to activate complement, and deposition of complement at sites where it cannot insert in the bacterial membrane. Vaccine trials are required to understand the significance of
[Asymmetry in international relations, industrial property rights and anti-HIV medication].
Costa-Couto, Maria Helena; Nascimento, Alvaro César
2008-01-01
This paper analyzes the asymmetry in the international relations as refers to the recognition of industrial property rights in the pharmaceutical industry. It focuses on the impact of such relations upon the access to ARV medication, an issue of worldwide interest due to its connection with the development of the nations. Clashing interests and the position taken by some countries in their patent laws point to a scenario less favorable for the access of peripheral countries to anti-HIV/AIDS medication. On the other hand, it seems that the success of the Brazilian STD/AIDS program in negotiating ARV prices will open new possibilities. The solution may be the internal strengthening of the National States and the active role played by the Agencies of the United Nations System in defense of the collective human interests.
Anti-Inflammatory and Analgesic Activities of a Novel Biflavonoid from Shells of Camellia oleifera
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Yong Ye
2012-09-01
Full Text Available Shells are by-products of oil production from Camellia oleifera which have not been harnessed effectively. The purpose of this research is to isolate flavonoid from shells of Camellia oleifera and evaluate its anti-inflammatory and analgesic effects. The flavonoid was identified as bimolecular kaempferol structure by UV, MS, 1H NMR and 13C NMR spectra, which is a new biflavonoid and first found in Camellia oleifera. It showed dose-dependent anti-inflammatory activity by carrageenin-induced paw oedema in rats and croton oil induced ear inflammation in mice, and analgesic activity by hot plate test and acetic acid induced writhing. The mechanism of anti-inflammation of biflavonoid is related to both bradykinin and prostaglandins synthesis inhibition. The biflavonoid showed both central and peripheral analgesic effects different from aspirin, inhibition of the synthesis or action of prostaglandins may contribute to analgesic effect of biflavonoid. The biflavonoid significantly decreased malonaldehyde (MDA and increased superoxidase dismutase (SOD and Glutathione peroxidase (GSH-Px activity in serum (p < 0.01, revealed strong free radical scavenging activity in vivo. It indicates the biflavonoid can control inflammation and pain by eliminating free radical so as to inhibit the mediators and decrease the prostaglandins. The biflavonoid can be used as a prospective medicine for inflammation and pain.
Shafi, Syed; Alam, Mohammad Mahboob; Mulakayala, Naveen; Mulakayala, Chaitanya; Vanaja, G; Kalle, Arunasree M; Pallu, Reddanna; Alam, M S
2012-03-01
A focused library of novel bis-heterocycles encompassing 2-mercapto benzothiazole and 1,2,3-triazoles were synthesized using click chemistry approach. The synthesized compounds have been tested for their anti-inflammatory activity by using biochemical cyclooxygenase (COX) activity assays and carrageenan-induced hind paw edema. Among the tested compounds, compound 4d demonstrated a potent selective COX-2 inhibition with COX-2/COX-1 ratio of 0.44. Results from carrageenan-induced hind paw edema showed that compounds 4a, 4d, 4e and 4f posses significant anti-inflammatory activity as compared to the standard drug Ibuprofen. The compounds showing significant activity were further subjected to anti-nociceptive activity by writhing test. These four compounds have shown comparable activity with the standard Ibuprofen. Further ulcerogenic studies shows that none of these compounds causing gastric ulceration. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Anti-HIV-1 integrase activity of medicinal plants used as self medication by AIDS patients
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Sopa Kummee
2006-07-01
Full Text Available The extracts of selected medicinal plants used as self medication by AIDS patients were investigated for their inhibitory activities against HIV-1 integrase (HIV-1 IN using the multiplate integration assay (MIA. Of these, the water extract of Eclipta prostrata (whole plant exhibited the most potent inhibitory activity with an IC50 value of 4.8 μg/ml, followed by the methanol extract of Eclipta prostrata (whole plant, IC50 = 21.1 μg/ ml, the water extract of Barleria lupulina (stem, IC50 = 26.4 μg/ml, the chloroform extract of Barleria lupulina (stem, IC50 = 33.0 μg/ml, the methanol extract of Barleria lupulina (stem, IC50 = 38.2 μg/ml and the chloroform extract of Piper betle (leaf, IC50 = 39.3 μg/ml, respectively.
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Ghosh, Arun K.; Sean Fyvie, W.; Brindisi, Margherita; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki
2017-11-01
Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
Pusch, O.; Kalyanaraman, R.; Tucker, L.D.; Wells, J.; Rmanratnam, B.; Boden, D.
2006-01-01
Objectives: To engineer Lactobacillus spp. to secrete HIV-1 fusion inhibitors with potent neutralizing activity against primary HIV-1 isolates. Methods: HIV-1 fusion inhibitors (FI-1, FI-2, and FI-3) were introduced into the previously developed shuttle vector pTSV2 and transformed in L. plantarum
Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat.
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Lisa Muniz
Full Text Available The human immunodeficiency virus 1 (HIV-1 transcriptional transactivator (Tat is essential for synthesis of full-length transcripts from the integrated viral genome by RNA polymerase II (Pol II. Tat recruits the host positive transcription elongation factor b (P-TEFb to the HIV-1 promoter through binding to the transactivator RNA (TAR at the 5'-end of the nascent HIV transcript. P-TEFb is a general Pol II transcription factor; its cellular activity is controlled by the 7SK small nuclear RNA (snRNA and the HEXIM1 protein, which sequester P-TEFb into transcriptionally inactive 7SK/HEXIM/P-TEFb snRNP. Besides targeting P-TEFb to HIV transcription, Tat also increases the nuclear level of active P-TEFb through promoting its dissociation from the 7SK/HEXIM/P-TEFb RNP by an unclear mechanism. In this study, by using in vitro and in vivo RNA-protein binding assays, we demonstrate that HIV-1 Tat binds with high specificity and efficiency to an evolutionarily highly conserved stem-bulge-stem motif of the 5'-hairpin of human 7SK snRNA. The newly discovered Tat-binding motif of 7SK is structurally and functionally indistinguishable from the extensively characterized Tat-binding site of HIV TAR and importantly, it is imbedded in the HEXIM-binding elements of 7SK snRNA. We show that Tat efficiently replaces HEXIM1 on the 7SK snRNA in vivo and therefore, it promotes the disassembly of the 7SK/HEXIM/P-TEFb negative transcriptional regulatory snRNP to augment the nuclear level of active P-TEFb. This is the first demonstration that HIV-1 specifically targets an important cellular regulatory RNA, most probably to promote viral transcription and replication. Demonstration that the human 7SK snRNA carries a TAR RNA-like Tat-binding element that is essential for the normal transcriptional regulatory function of 7SK questions the viability of HIV therapeutic approaches based on small drugs blocking the Tat-binding site of HIV TAR.
APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element.
Nowarski, Roni; Prabhu, Ponnandy; Kenig, Edan; Smith, Yoav; Britan-Rosich, Elena; Kotler, Moshe
2014-07-29
Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription. Copyright © 2014 Elsevier Ltd. All rights reserved.
DEFF Research Database (Denmark)
De Wit, Stephane; Sabin, Caroline A; Weber, Rainer
2008-01-01
OBJECTIVE: The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated...... with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS: D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes...
O'Brien, Kelly K; Solomon, Patricia; Trentham, Barry; MacLachlan, Duncan; MacDermid, Joy; Tynan, Anne-Marie; Baxter, Larry; Casey, Alan; Chegwidden, William; Robinson, Greg; Tran, Todd; Wu, Janet; Zack, Elisse
2014-01-01
Objective Our aim was to develop evidence-informed recommendations for rehabilitation with older adults living with HIV. Design We conducted a knowledge synthesis, combining research evidence specific to HIV, rehabilitation and ageing, with evidence on rehabilitation interventions for common comorbidities experienced by older adults with HIV. Methods We included highly relevant HIV-specific research addressing rehabilitation and ageing (stream A) and high-quality evidence on the effectiveness of rehabilitation interventions for common comorbidities experienced by older adults ageing with HIV (stream B). We extracted and synthesised relevant data from the evidence to draft evidence-informed recommendations for rehabilitation. Draft recommendations were refined based on people living with HIV (PLHIV) and clinician experience, values and preferences, reviewed by an interprofessional team for Grading of Recommendations Assessment, Development, and Evaluation (GRADE) (quality) rating and revision and then circulated to PLHIV and clinicians for external endorsement and final refinement. We then devised overarching recommendations to broadly guide rehabilitation with older adults living with HIV. Results This synthesis yielded 8 overarching and 52 specific recommendations. Thirty-six specific recommendations were derived from 108 moderate-level or high-level research articles (meta-analyses and systematic reviews) that described the effectiveness of rehabilitation interventions for comorbidities that may be experienced by older adults with HIV. Recommendations addressed rehabilitation interventions across eight health conditions: bone and joint disorders, cancer, stroke, cardiovascular disease, mental health challenges, cognitive impairments, chronic obstructive pulmonary disease and diabetes. Sixteen specific recommendations were derived from 42 research articles specific to rehabilitation with older adults with HIV. The quality of evidence from which these
Cuyàs, Elisabet; Martin-Castillo, Begoña; Corominas-Faja, Bruna; Massaguer, Anna; Bosch-Barrera, Joaquim; Menendez, Javier A
2015-01-01
Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues.
Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7.
Saha, Mrinmoy; Scerba, Michael T; Shank, Nathaniel I; Hartman, Tracy L; Buchholz, Caitlin A; Buckheit, Robert W; Durell, Stewart R; Appella, Daniel H
2017-05-22
Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and is an attractive target for drug development. However, the development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this study, a series of novel 2-mercaptobenzamide prodrugs were investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules were synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti-HIV activity. Wide ranges of antiviral activity were observed, with IC 50 values ranging from 1 to 100 μm depending on subtle changes to the substituents on the aromatic ring and side chain. Results from these structure-activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti-HIV activity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity.
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Rui Jia
Full Text Available The interferon-inducible transmembrane (IFITM proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1 strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3 is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Δ(117-125, which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Δ(117-125 mutant diminishes HIV-1NL4-3 entry by 3-fold. This inhibition correlates with the predominant localization of Δ(117-125 to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Δ(117-125, mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization.
Moonsamy, Suri; Bhakat, Soumendranath; Soliman, Mahmoud E S
2015-01-01
The first account on the dynamic features of Nef or negative factor, a small myristoylated protein located in the cytoplasm believes to increase HIV-1 viral titer level, is reported herein. Due to its major role in HIV-1 pathogenicity, Nef protein is considered an emerging target in anti-HIV drug design and discovery process. In this study, comparative long-range all-atom molecular dynamics simulations were employed for apo and bound protein to unveil molecular mechanism of HIV-Nef dimerization and inhibition. Results clearly revealed that B9, a newly discovered Nef inhibitor, binds at the dimeric interface of Nef protein and caused significant separation between orthogonally opposed residues, namely Asp108, Leu112 and Gln104. Large differences in magnitudes were observed in the radius of gyration (∼1.5 Å), per-residue fluctuation (∼2 Å), C-alpha deviations (∼2 Å) which confirm a comparatively more flexible nature of apo conformation due to rapid dimeric association. Compared to the bound conformer, a more globally correlated motion in case of apo structure of HIV-Nef confirms the process of dimeric association. This clearly highlights the process of inhibition as a result of ligand binding. The difference in principal component analysis (PCA) scatter plot and per-residue mobility plot across first two normal modes further justifies the same findings. The in-depth dynamic analyses of Nef protein presented in this report would serve crucial in understanding its function and inhibition mechanisms. Information on inhibitor binding mode would also assist in designing of potential inhibitors against this important HIV target.
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Eliana Amaral
2006-11-01
Full Text Available Há controvérsia sobre a relação entre o uso de contraceptivos hormonais e o risco de adquirir o vírus da imunodeficiência humana (HIV, e pouco se sabe sobre os efeitos da contracepção hormonal em mulheres infectadas (efeitos colaterais, distúrbios menstruais, progressão da doença, interações com terapias anti-retrovirais. O objetivo deste artigo foi revisar os dados disponíveis quanto à vulnerabilidade ao HIV e à sua transmissibilidade na vigência do uso de contraceptivos hormonais bem como as conseqüências potenciais do uso desses contraceptivos por mulheres HIV-positivas sob terapia anti-retroviral (TARV, com ênfase nas interações medicamentosas. Concluiu-se que ainda não é possível elaborar recomendações, baseadas em evidências, sobre a contracepção hormonal em mulheres portadoras do HIV sob TARV. Assim, os infectologistas e os ginecologistas devem estar atentos às interações potenciais que possam representar aumento de efeitos adversos, individualizando a orientação sobre os esteróides contraceptivos, suas doses e vias de administração, considerando a TARV em uso.There is much controversy regarding the realtionship between the use of hormonal contraceptives and the risk of acquiring human immunodeficiency virus (HIV, and little is known about the effects of hormonal contraception in HIV-infected women (adverse events, menstrual disorders, disease progression, antiretroviral therapy interactions. The aim of the present study was to review available data regarding HIV vulnerability and transmission associated with hormonal contraceptives and the use of these contraceptives by women on antiretroviral therapy, with emphasis on drug interactions. In conclusion, it was not possible to offer evidence-based recommendations for the use of hormonal contraceptives among HIV-infected women under antiretroviral therapy. Infectious disease specialists and gynecologists providing care should be cautious about potential
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Jones Maureen
2010-07-01
Full Text Available Abstract Background At present, there is no effective vaccine or other approved product for the prevention of sexually transmitted human immunodeficiency virus type 1 (HIV-1 infection. It has been reported that women in resource-poor communities use vaginally applied citrus juices as topical microbicides. These easily accessible food products have historically been applied to prevent pregnancy and sexually transmitted diseases. The aim of this study was to evaluate the efficacy and cytotoxicity of these substances using an established topical microbicide testing algorithm. Freshly squeezed lemon and lime juice and household vinegar were tested in their original state or in pH neutralized form for efficacy and cytotoxicity in the CCR5-tropic cell-free entry and cell-associated transmission assays, CXCR4-tropic entry and fusion assays, and in a human PBMC-based anti-HIV-1 assay. These products were also tested for their effect on viability of cervico-vaginal cell lines, human cervical explant tissues, and beneficial Lactobacillus species. Results Natural lime and lemon juice and household vinegar demonstrated anti-HIV-1 activity and cytotoxicity in transformed cell lines. Neutralization of the products reduced both anti-HIV-1 activity and cytotoxicity, resulting in a low therapeutic window for both acidic and neutralized formulations. For the natural juices and vinegar, the IC50 was ≤ 3.5 (0.8-3.5% and the TC50 ≤ 6.3 (1.0-6.3%. All three liquid products inhibited viability of beneficial Lactobacillus species associated with vaginal health. Comparison of three different toxicity endpoints in the cervical HeLa cell line revealed that all three products affected membrane integrity, cytosolic enzyme release, and dehydrogenase enzyme activity in living cells. The juices and vinegar also exerted strong cytotoxicity in cervico-vaginal cell lines, mainly due to their acidic pH. In human cervical explant tissues, treatment with 5% lemon or lime juice
Resistance of Subtype C HIV-1 Strains to Anti-V3 Loop Antibodies
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David Almond
2012-01-01
Full Text Available HIV-1’s subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the consensus C V3 loop crown, visualized by ab initio folding, suggested that the resistance derives from structural rigidity and non-β-strand secondary protein structure in the N-terminal strand of the β-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-β-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research.
Hønge, Bl; Jespersen, S; Medina, C; Té, Ds; da Silva, Zj; Ostergaard, L; Laursen, Al; Wejse, C; Krarup, H; Erikstrup, C
2014-10-01
In the case of coinfection with HIV and hepatitis B virus (HBV) and/or hepatitis C virus (HCV), hepatic disease progression is often accelerated, with higher rates of liver cirrhosis and liver-related mortality. We aimed to evaluate the performance of the rapid tests used routinely to detect HBV surface antigen (HBsAg) and anti-HCV among HIV-infected patients in Guinea-Bissau. Blood samples from HIV-infected patients in Guinea-Bissau were stored after testing for HBsAg and anti-HCV with rapid tests. Samples were subsequently re-tested for HBsAg and anti-HCV in Denmark. Two rapid tests were used in Guinea-Bissau: HBsAg Strip Ref 2034 (VEDA.LAB, Alençon, France; sensitivity 62.3%; specificity 99.2%) and HEPA-SCAN (Bhat Bio-Tech, Bangalore, India; sensitivity 57.1%; specificity 99.7%). In the two tests the ability to obtain the correct outcome depended on the antigen and antibody concentrations, respectively. Sex, age, CD4 cell count and antiretroviral therapy status did not differ between false negative and true positive samples in either of the tests. The study is limited by a low number of anti-HCV positive samples. New diagnostic rapid tests should always be evaluated in the setting in which they will be used before implementation. © 2014 British HIV Association.
Jayasundar, Rama; Ghatak, Somenath; Makhdoomi, Muzamil Ashraf; Luthra, Kalpana; Singh, Aruna; Velpandian, Thirumurthy
2018-01-03
Information from Ayurveda meeting the analytical challenges of modern technology is an area of immense relevance. Apart from the cerebral task of bringing together two different viewpoints, the question at the pragmatic level remains 'who benefits whom'. The aim is to highlight the challenges in integration of information (Ayurvedic) and technology using test examples of Nuclear Magnetic Resonance (NMR) metabolomics and anti-HIV-1 potential of select Ayurvedic medicinal plants. The other value added objective is implications and relevance of such work for Ayurveda. Six medicinal plants (Azadirachta indica, Tinospora cordifolia, Swertia chirata, Terminalia bellerica, Zingiber officinale and Symplocos racemosa) were studied using high resolution proton NMR spectroscopy based metabolomics and also evaluated for anti-HIV-1 activity on three pseudoviruses (ZM53 M.PB12, ZM109F.PB4, RHPA 4259.7). Of the six plants, T.bellerica and Z.officinale showed minimum cell cytotoxicity and maximum anti-HIV-1 potential. T.bellerica was effective against all the three HIV-1 pseudoviruses. Untargeted NMR profiling and multivariate analyses demonstrated that the six plants, all of which had different Ayurvedic pharmacological properties, showed maximum differences in the aromatic region of the spectra. The work adds onto the list of potential plants for anti-HIV-1 drug molecules. At the same time, it has drawn attention to the different perspectives of Ayurveda and Western medicine underscoring the inherent limitations of conceptual bilinguism between the two systems, especially in the context of medicinal plants. The study has also highlighted the potential of NMR metabolomics in study of plant extracts as used in Ayurveda. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.
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Leandro S Sangenito
Full Text Available BACKGROUND: Aspartic peptidase inhibitors have shown antimicrobial action against distinct microorganisms. Due to an increase in the occurrence of Chagas' disease/AIDS co-infection, we decided to explore the effects of HIV aspartic peptidase inhibitors (HIV-PIs on Trypanosoma cruzi, the etiologic agent of Chagas' disease. METHODOLOGY AND PRINCIPAL FINDINGS: HIV-PIs presented an anti-proliferative action on epimastigotes of T. cruzi clone Dm28c, with IC50 values ranging from 0.6 to 14 µM. The most effective inhibitors, ritonavir, lopinavir and nelfinavir, also had an anti-proliferative effect against different phylogenetic T. cruzi strains. The HIV-PIs induced some morphological alterations in clone Dm28c epimastigotes, as reduced cell size and swollen of the cellular body. Transmission electron microscopy revealed that the flagellar membrane, mitochondrion and reservosomes are the main targets of HIV-PIs in T. cruzi epimastigotes. Curiously, an increase in the epimastigote-into-trypomastigote differentiation process of clone Dm28c was observed, with many of these parasites presenting morphological alterations including the detachment of flagellum from the cell body. The pre-treatment with the most effective HIV-PIs drastically reduced the interaction process between epimastigotes and the invertebrate vector Rhodnius prolixus. It was also noted that HIV-PIs induced an increase in the expression of gp63-like and calpain-related molecules, and decreased the cruzipain expression in epimastigotes as judged by flow cytometry and immunoblotting assays. The hydrolysis of a cathepsin D fluorogenic substrate was inhibited by all HIV-PIs in a dose-dependent manner, showing that the aspartic peptidase could be a possible target to these drugs. Additionally, we verified that ritonavir, lopinavir and nelfinavir reduced drastically the viability of clone Dm28c trypomastigotes, causing many morphological damages. CONCLUSIONS AND SIGNIFICANCE: The results
de Rocquigny, H; Ficheux, D; Gabus, C; Fournié-Zaluski, M C; Darlix, J L; Roques, B P
1991-10-31
The nucleocapsid protein (NC) of the human immunodeficiency virus type 1 plays a crucial role in the formation of infectious viral particles and therefore should be a major target for the development of antiviral agents. This requires an investigation of NC protein structure and of its interactions with both primer tRNA(Lys,3) and genomic RNA. Nucleocapsid protein NCp7, which results from the maturation of NCp15, contains two zinc fingers flanked by sequences rich in basic and proline residues. Here we report the first synthesis of large quantities of NCp7 able to activate HIV-1 RNA dimerization and replication primer tRNA(Lys,3) annealing to the initiation site of reverse transcription. In addition UV spectroscopic analyses performed to characterize the Co2+ binding properties of each zinc finger suggest that the two fingers probably interact in NCp7.
Inhibition of HIV-1 entry by extracts derived from traditional Chinese medicinal herbal plants
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Song Xinming
2009-08-01
Full Text Available Abstract Background Highly active anti-retroviral therapy (HAART is the current HIV/AIDS treatment modality. Despite the fact that HAART is very effective in suppressing HIV-1 replication and reducing the mortality of HIV/AIDS patients, it has become increasingly clear that HAART does not offer an ultimate cure to HIV/AIDS. The high cost of the HAART regimen has impeded its delivery to over 90% of the HIV/AIDS population in the world. This reality has urgently called for the need to develop inexpensive alternative anti-HIV/AIDS therapy. This need has further manifested by recent clinical trial failures in anti-HIV-1 vaccines and microbicides. In the current study, we characterized a panel of extracts of traditional Chinese medicinal herbal plants for their activities against HIV-1 replication. Methods Crude and fractionated extracts were prepared from various parts of nine traditional Chinese medicinal herbal plants in Hainan Island, China. These extracts were first screened for their anti-HIV activity and cytotoxicity in human CD4+ Jurkat cells. Then, a single-round pseudotyped HIV-luciferase reporter virus system (HIV-Luc was used to identify potential anti-HIV mechanisms of these extracts. Results Two extracts, one from Euphorbiaceae, Trigonostema xyphophylloides (TXE and one from Dipterocarpaceae, Vatica astrotricha (VAD inhibited HIV-1 replication and syncytia formation in CD4+ Jurkat cells, and had little adverse effects on host cell proliferation and survival. TXE and VAD did not show any direct inhibitory effects on the HIV-1 RT enzymatic activity. Treatment of these two extracts during the infection significantly blocked infection of the reporter virus. However, pre-treatment of the reporter virus with the extracts and treatment of the extracts post-infection had little effects on the infectivity or gene expression of the reporter virus. Conclusion These results demonstrate that TXE and VAD inhibit HIV-1 replication likely by blocking
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Sadek B
2013-03-01
Full Text Available Bassem Sadek,1 Amar Mansuor Hamruoni,2 Abdu Adem1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, 2Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates Abstract: In this study, target compounds 5–12 were synthesized via acid amine coupling of ibuprofen and naproxen with methyl ester derivatives of amino acids, namely, l-proline, sarcosine, l-tyrosine, and l-glutamic acid. When tested for anti-inflammatory activity using the acute carrageenan-induced hind paw method in rats, compounds 5–12 showed significantly greater anti-inflammatory activity, in the range of 40.64%–87.82%, compared with a placebo control group (P < 0.001. Among the newly synthesized compounds 5–12, naproxen derivatives 9–12 with anti-inflammatory activity ranging between 66.99% and 87.82% showed significantly higher (P < 0.05 potency than ibuprofen derivatives 5–8 with inhibition in the range of 22.03%–52.91% and control groups of ibuprofen (76.34% or naproxen (75.59%, P < 0.05. Moreover, derivatives 9–12 derived from naproxen, in particular compounds 9 and 10 which achieved 83.91% and 87.82% inhibition of inflammation, respectively, showed significantly (P < 0.05 higher potency than naproxen derivatives 11 and 12. Notably, among naproxen derivatives 9–12, the gastric ulcerogenicity for 9 (ulcer index 11.73 and 10 (ulcer index 12.30 was found to be significantly lower (P < 0.05 than that of the active ibuprofen and naproxen control groups with ulcer indices of 22.87 and 24.13, respectively. On the other hand, naproxen derivatives 9–11 showed significant inhibition (P < 0.05 of prostaglandin E2 synthesis when compared with the active control group receiving indomethacin, suggesting a correlation between the observed low ulcerogenicity and effect on prostaglandin E2 synthesis for compounds 9 and 10. However
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Joshua R. Kane
2015-05-01
Full Text Available HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across the lentivirus genus, including primate (HIV-1 and simian immunodeficiency virus macaque [SIVmac] and non-primate (FIV, BIV, and MVV viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif requires no cofactor and that MVV Vif requires a novel cofactor, cyclophilin A (CYPA, for stable CRL complex formation and anti-APOBEC3 activity. We propose modular conservation of Vif complexes allows for potential exaptation of functions through the acquisition of non-CRL-associated host cofactors while preserving anti-APOBEC3 activity.
Mechanochemical Synthesis, In vivo Anti-malarial and Safety Evaluation of Amodiaquine-zinc Complex
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Arise Rotimi Olusanya
2017-09-01
Full Text Available So far, some prospective metal-based anti-malarial drugs have been developed. The mechanochemical synthesis and characterization of Zn (II complex with amodiaquine and its anti-malarial efficacy on Plasmodium berghei-infected mice and safety evaluation were described in this study.
Synthesis and anti-tubercular activity of 3-substituted benzo[b]thiophene-1,1-dioxides
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N. Susantha Chandrasekera
2014-10-01
Full Text Available We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure–activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM. Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM, but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM. We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.
Kankanala, Jayakanth; Kirby, Karen A; Huber, Andrew D; Casey, Mary C; Wilson, Daniel J; Sarafianos, Stefan G; Wang, Zhengqiang
2017-12-01
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC 50 = 0.04 μM) with decent antiviral potency (EC 50 = 7.4 μM) and no cytotoxicity (CC 50 > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC 50 = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Sifuvirtide, a potent HIV fusion inhibitor peptide
International Nuclear Information System (INIS)
Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang
2009-01-01
Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC 50 ), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC 50 ) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1 IIIB were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.
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Shalom Pôrto de Oliveira Assis
2012-01-01
Full Text Available Four new 1,2,3-triazole phthalimide derivatives with a potent anti-inflammatory activity have been synthesized in the good yields by the 1,3-dipolar cycloaddition reaction from N-(azido-alkylphthalimides and terminal alkynes. The anti-inflammatory activity was determined by injecting carrageenan through the plantar tissue of the right hind paw of Swiss white mice to produce inflammation. All the compounds 3a–c and 5a–c exhibited an important anti-inflammatory activity; the best activity was found for the compounds 3b and 5c, which showed to be able to decrease by 69% and 56.2% carrageenan-induced edema in mice. These compounds may also offer a future promise as a new anti-inflammatory agent.
Laure, Frédéric; Raharivelomanana, Phila; Butaud, Jean-François; Bianchini, Jean-Pierre; Gaydou, Emile M
2008-08-22
Various pyranocoumarins, calophyllolide, inophyllums B, C, G(1), G(2) and P, from Calophyllum inophyllum (Clusiaceae) leaves of French Polynesia (Austral, Marquesas, Society and Tuamotu archipelagos) have been determined in 136 leaf extracts using a high pressure liquid chromatography-UV-diode array detection (HPLC-UV-DAD) technique. Results show a wide range in chemical composition within trees growing on eighteen islands. The use of multivariate statistical analyses (PCA) shows geographical distribution of inophyllums and indicate those rich in HIV-1 active (+)-inophyllums. Inophyllum B and P contents (0.0-39.0 and 0.0-21.8 mg kg(-1), respectively) confirm the chemodiversity of this species within the large area of French Polynesia. The study suggests the presence of interesting chemotypes which could be used as plant source for anti-HIV-1 drugs.
Gamba, Elia; Mori, Mattia; Kovalenko, Lesia; Giannini, Alessia; Sosic, Alice; Saladini, Francesco; Fabris, Dan; Mély, Yves; Gatto, Barbara; Botta, Maurizio
2018-02-10
In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues. This approach provided valuable information on the structure-activity relationships of these compounds and, in the process, demonstrated that their anti-NC activity could be finely tuned by the addition of specific substituents to the initial benzoxazolinone scaffold. This study represents the starting point for the possible development of a new class of antiretroviral agents targeting the HIV-1 NC protein. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
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Xiao S
2018-04-01
Full Text Available Siyang Xiao,1,* Wenxin Zhang,1,* Hongjin Chen,1 Bo Fang,1 Yinda Qiu,2 Xianxin Chen,1 Lingfeng Chen,1 Sheng Shu,1 Yunjie Zhao,1 Zhiguo Liu,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; 2College of Life and Environmental Science, Wenzhou University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Purpose: The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS-stimulated murine primary macrophages. Results: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. Conclusion: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury. Keywords: indanone, acute lung injury, drug design, anti-inflammation, synthesis
Anti-retroviral therapy induced diabetes in a Nigerian | Bakari ...
African Journals Online (AJOL)
African Health Sciences ... Background:Anti-retroviral therapy (ART) using Highly Active Anti-retroviral Therapy (HAART) has led to ... HIV infected individuals on one hand, and side effects of chronic administration of these drugs on the other.
Nath Chatterjee, Amar; Roy, Priti Kumar
2012-02-01
Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction.
Current Peptide and Protein Candidates Challenging HIV Therapy beyond the Vaccine Era
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Koollawat Chupradit
2017-09-01
Full Text Available Human immunodeficiency virus (HIV is a causative agent of acquired immune deficiency syndrome (AIDS. Highly active antiretroviral therapy (HAART can slow down the replication of HIV-1, leading to an improvement in the survival of HIV-1-infected patients. However, drug toxicities and poor drug administration has led to the emergence of a drug-resistant strain. HIV-1 immunotherapy has been continuously developed, but antibody therapy and HIV vaccines take time to improve its efficiency and have limitations. HIV-1-specific chimeric antigen receptor (CAR-based immunotherapy founded on neutralizing antibodies is now being developed. In HIV-1 therapy, anti-HIV chimeric antigen receptors showed promising data in the suppression of HIV-1 replication; however, autologous transfusion is still a problem. This has led to the development of effective peptides and proteins for an alternative HIV-1 treatment. In this paper, we provide a comprehensive review of potent anti-HIV-1 peptides and proteins that reveal promising therapeutic activities. The inhibitory mechanisms of each therapeutic molecule in the different stages of the HIV-1 life cycle will be discussed herein.
Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana
2017-03-01
We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
McMahon, Moira A.; Shen, Lin; Siliciano, Robert F.
2014-01-01
Purpose of review With highly active anti-retroviral therapy (HAART), HIV-1 infection has become a manageable lifelong disease. Developing optimal treatment regimens requires understanding how to best measure anti-HIV activity in vitro and how drug dose response curves generated in vitro correlate with in vivo efficacy. Recent findings Several recent studies have indicated that conventional multi-round infectivity assays are inferior to single cycle assays at both low and high levels of inhibition. Multi-round infectivity assays can fail to detect subtle but clinically significant anti-HIV activity. The discoveries of the anti-HIV activity of the hepatitis B drug entecavir and the herpes simplex drug acyclovir were facilitated by single round infectivity assays. Recent studies using a single round infectivity assay have shown that a previously neglected parameter, the dose response curve slope, is an extremely important determinant of antiviral activity. Some antiretroviral drugs have steep slopes that result in extraordinary levels of antiviral activity. The instantaneous inhibitory potential (IIP), the log reduction in infectivity in a single round assay at clinical drug concentrations, has been proposed as a novel index for comparing antiviral activity. Summary Among in vitro measures of antiviral activity, single round infection assays have the advantage of measure instantaneous inhibition by a drug. Re-evaluating the antiviral activity of approved HIV-1 drugs has shown that the slope parameter is an important factor in drug activity. Determining the IIP by using a single round infectivity assay may provide important insights that can predict the in vivo efficacy of anti-HIV-1 drugs. PMID:19841584
Abdi, Mohammad; Rahbari, Rizgar; Khatooni, Zahed; Naseri, Nima; Najafi, Adel; Khodadadi, Iraj
2016-05-01
CD4(+) cell count, the common HIV infection screening test, is costly and unable to differentiate HIV monoinfection from its concurrent infection with hepatitis B or C virus. We aimed to ascertain diagnostic value of serum adenosine deaminase (ADA) activity as a useful tool to differentiate HIV mono- and co-infection. Blood samples were collected from 30 HIV-HBV and 30 HIV-HCV coinfected patients, 33 HIV positive subjects, and 72 controls. CD4(+) cell count, serum total ADA (tADA), and ADA1, and ADA2 isoenzyme activities were determined and their sensitivity and specificity were computed. tADA and ADA2 activities were significantly higher and CD4(+) counts were markedly lower in all patients compared with controls. Strong inverse agreements between CD4(+) cell counts and both tADA and ADA2 activities were observed. Serum tADA and ADA1 activities showed the highest specificity and the highest sensitivity, respectively, for differentiating HIV monoinfection from HIV-HBV and HIV-HCV coinfections. We showed strong agreement and correlation between CD4(+) cell count and ADA enzyme activity. Based on high ADA sensitivity and specificity, it is concluded that determination of ADA activity might be a novel diagnostic tool to distinguish of HIV monoinfection from its coinfection with HBV or HCV. © 2015 Wiley Periodicals, Inc.
International Nuclear Information System (INIS)
Buckner, Clarisa; Gines, Leoned G.; Saunders, Cheryl J.; Vojtech, Lucia; Srivastava, Indresh; Gettie, Agegnehu; Bohm, Rudolph; Blanchard, James; Barnett, Susan W.; Safrit, Jeffrey T.; Stamatatos, Leonidas
2004-01-01
The potential of vaccine-elicited anti-HIV envelope antibodies to control HIV-infection was evaluated by immunizing macaques with the HIV envelope protein and transiently depleting them of their CD8+ cells before intravenous challenge with the pathogenic CCR5-tropic SIV/HIV chimeric virus, SHIV SF162P4 . Although sterilizing immunity was not achieved, all vaccinated animals effectively controlled infection and remained free of disease for the duration of observation (over 3 years). In contrast, during the same period, the control animals progressed to disease. Both the vaccinees and the controls developed robust cell-mediated antiviral and neutralizing antibody responses following infection. A comparative analysis of these responses suggests that the more effective long-term control of infection by the vaccinated animals is due to the more rapid development of anti-HIV envelope antibodies. These studies suggest that priming by vaccination of B cell anti-HIV envelope responses maybe crucial for the long-term control of HIV infection
Goldenberg, Shira M; Duff, Putu; Krusi, Andrea
2015-12-16
Sex workers (SWs) experience a disproportionately high burden of HIV, with evidence indicating that complex and dynamic factors within work environments play a critical role in mitigating or producing HIV risks in sex work. In light of sweeping policy efforts to further criminalize sex work globally, coupled with emerging calls for structural responses situated in labour and human-rights frameworks, this meta-synthesis of the qualitative and ethnographic literature sought to examine SWs' narratives to elucidate the ways in which physical, social and policy features of diverse work environments influence SWs' agency to engage in HIV prevention. We conducted a meta-synthesis of qualitative and ethnographic studies published from 2008 to 2014 to elucidate SWs' narratives and lived experiences of the complex and nuanced ways in which physical, social, and policy features of indoor and outdoor work environments shape HIV prevention in the sex industry. Twenty-four qualitative and/or ethnographic studies were included in this meta-synthesis. SWs' narratives revealed the nuanced ways that physical, social, and policy features of work environments shaped HIV risk and interacted with macrostructural constraints (e.g., criminalization, stigma) and community determinants (e.g., sex worker empowerment initiatives) to shape SWs' agency in negotiating condom use. SWs' narratives revealed the ways in which the existence of occupational health and safety standards in indoor establishments, as well as protective practices of third parties (e.g., condom promotion) and other SWs/peers were critical ways of enhancing safety and sexual risk negotiation within indoor work environments. Additionally, working in settings where negative interactions with law enforcement were minimized (e.g., working in decriminalized contexts or environments in which peers/managers successfully deterred unjust policing practices) was critical for supporting SWs' agency to negotiate HIV prevention. Policy
Impact of HIV-related stigma on treatment adherence: systematic review and meta-synthesis
Katz, Ingrid T; Ryu, Annemarie E; Onuegbu, Afiachukwu G; Psaros, Christina; Weiser, Sheri D; Bangsberg, David R; Tsai, Alexander C
2013-01-01
Introduction Adherence to HIV antiretroviral therapy (ART) is a critical determinant of HIV-1 RNA viral suppression and health outcomes. It is generally accepted that HIV-related stigma is correlated with factors that may undermine ART adherence, but its relationship with ART adherence itself is not well established. We therefore undertook this review to systematically assess the relationship between HIV-related stigma and ART adherence. Methods We searched nine electronic databases for published and unpublished literature, with no language restrictions. First we screened the titles and abstracts for studies that potentially contained data on ART adherence. Then we reviewed the full text of these studies to identify articles that reported data on the relationship between ART adherence and either HIV-related stigma or serostatus disclosure. We used the method of meta-synthesis to summarize the findings from the qualitative studies. Results Our search protocol yielded 14,854 initial records. After eliminating duplicates and screening the titles and abstracts, we retrieved the full text of 960 journal articles, dissertations and unpublished conference abstracts for review. We included 75 studies conducted among 26,715 HIV-positive persons living in 32 countries worldwide, with less representation of work from Eastern Europe and Central Asia. Among the 34 qualitative studies, our meta-synthesis identified five distinct third-order labels through an inductive process that we categorized as themes and organized in a conceptual model spanning intrapersonal, interpersonal and structural levels. HIV-related stigma undermined ART adherence by compromising general psychological processes, such as adaptive coping and social support. We also identified psychological processes specific to HIV-positive persons driven by predominant stigmatizing attitudes and which undermined adherence, such as internalized stigma and concealment. Adaptive coping and social support were critical
Ejima, Tomohiko; Hirota, Mayuko; Mizukami, Tamio; Otsuka, Masami; Fujita, Mikako
2011-10-01
Human apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) 3G (A3G) is an antiviral protein that blocks HIV-1 replication. However, the antiviral activity of A3G is overcome by the HIV-1 protein Vif. This inhibitory function of Vif is related to its ability to degrade A3G in the proteasome. This finding prompted us to examine the activities of 4-(dimethylamino)-2,6-bis[(N-(2-[(2-nitrophenyl)dithio]ethyl)amino)methyl]pyridine (SN-2) and SN-3. We found that 5 µM SN-2 increases the expression of A3G to a level much higher than that observed in the absence of Vif, without affecting the level of Vif expression. The proteasome inhibitor MG-132 increased the level of both A3G and Vif expression. These results demonstrate that A3G is ubiquitinated and degraded in the proteasome by a factor other than Vif, and that SN-2 selectively inhibits these processes. Furthermore, 5 µM SN-2 significantly inhibited the MAGI cell infectivity of wild-type HIV-1. These findings may contribute to the development of a novel anti-HIV-1 drug.
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Khairia M. Youssef
2018-06-01
Full Text Available Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining carbamoylpiperidine analogs containing nipecotic acid scaffold were described. Then, a series of hybrids have been developed by introducing Free radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds showed effective AchE inhibitions, high selectivity over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of analogs containing nipecotic acid scaffold to serve in the design of N-benzyl-piperidine linked multipotent molecules for the treatment of Alzheimer Disease. Keywords: Synthesis, N-substituted-piperidines, Antioxidant activity, ATP chemiluminescence, Molecular modeling study
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Parvathi Chary
Full Text Available To aid in the characterization of the relationship of structure and function for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT, this investigation utilized DNAs containing benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE-modified primers and templates as a probe of the architecture of this complex. BPDE lesions that differed in their stereochemistry around the C10 position were covalently linked to N (6-adenine and positioned in either the primer or template strand of a duplex template-primer. HIV-1 RT exhibited a stereoisomer-specific and strand-specific difference in replication when the BPDE-lesion was placed in the template versus the primer strand. When the C10 R-BPDE adduct was positioned in the primer strand in duplex DNA, 5 nucleotides from the 3΄ end of the primer terminus, HIV-1 RT could not fully replicate the template, producing truncated products; this block to further synthesis did not affect rates of dissociation or DNA binding affinity. Additionally, when the adducts were in the same relative position, but located in the template strand, similar truncated products were observed with both the C10 R and C10 S BPDE adducts. These data suggest that the presence of covalently-linked intercalative DNA adducts distant from the active site can lead to termination of DNA synthesis catalyzed by HIV-1 RT.
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Rina Herowati
2016-12-01
Full Text Available Quercetin (3,3’4’,5,7-pentahydroxyflavone has been reported to show anti-inflammatory activity. However, its low oral bioavailability limits the application of quercetin in therapy. Ester derivatives of quercetin have been reported to have higher bioavailability than quercetin. This research aimed to study the anti-inflammatory activities and gastric ulcer-inducing properties of tetraacetylquercetinas well as tetrapivaloylquercetin. Synthesis of tetra-acyl derivatives of quercetin was conducted using acetic anhydride or pivaloyl chloride in the presence of pyridine and the structure was confirmed by 1H-NMR and 13C-NMR spectroscopy as well as elemental analysis. At a dose of 20 mg/kg bw, oral administration of quercetin only showed 20% inhibition activity on carragenan induced rat paw edema, while tetraacetyl and tetrapivaloyl derivatives at equimolar dose showed 11-33% and 5-15% inhibition activity respectively. Contrary to the gastric ulcer healing-promoting action of quercetin, tetraacetylquercetin caused mild gastric ulcers. However, no gastric ulcer was observed after administration of tetrapivaloylquercetin. It was concluded that acylation enhances the anti-inflammatory activity of quercetin but causes mild gastric ulcers in the case of tetraacetylation.
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Theodoridou Maria
2010-12-01
Full Text Available Abstract Background The psychosocial development of pediatric HIV patients has not been extensively evaluated. The study objectives were to evaluate whether emotional and social functions are differentially associated with HIV-related complications. Methods A matched case-control study design was conducted. The case group (n = 20 consisted of vertically infected children with HIV (aged 3-18 years receiving HAART in Greece. Each case was matched with two randomly selected healthy controls from a school-based population. CNS imaging and clinical findings were used to identify patients with HIV-related neuroimaging abnormalities. The Wechsler Intelligence Scale III and Griffiths Mental Abilities Scales were applied to assess cognitive abilities. The age specific Strengths and Difficulties Questionnaire was used to evaluate emotional adjustment and social skills. The Fisher's exact test, student's t-test, and Wilcoxon rank sum test were used to compare categorical, continuous, and ordinal scores, respectively, of the above scales between groups. Results HIV patients without neuroimaging abnormalities did not differ from patients with neuroimaging abnormalities with respect to either age at HAART initiation (p = 0.306 or months of HAART treatment (p = 0.964. While HIV patients without neuroimaging abnormalities had similar cognitive development with their healthy peers, patients with neuroimaging abnormalities had lower mean General (p = 0.027 and Practical (p = 0.042 Intelligence Quotient scores. HIV patients without neuroimaging abnormalities had an increased likelihood of both Abnormal Emotional Symptoms (p = 0.047 and Hyperactivity scores (p = 0.0009. In contrast, HIV patients with neuroimaging abnormalities had an increased likelihood of presenting with Abnormal Peer Problems (p = 0.033. Conclusions HIV patients without neuroimaging abnormalities are more likely to experience maladjustment with respect to their emotional and activity spheres
Anti-Inflammatory and Antimicrobial Actions of Vitamin D in Combating TB/HIV
Directory of Open Access Journals (Sweden)
Anna K. Coussens
2014-01-01
Full Text Available Tuberculosis (TB disease activation is now believed to arise due to a lack of inflammatory homeostatic control at either end of the spectrum of inflammation: either due to immunosuppression (decreased antimicrobial activity or due to immune activation (excess/aberrant inflammation. Vitamin D metabolites can increase antimicrobial activity in innate immune cells, which, in the context of HIV-1 coinfection, have insufficient T cell-mediated help to combat Mycobacterium tuberculosis (MTB infection. Moreover, maintaining vitamin D sufficiency prior to MTB infection enhances the innate antimicrobial response to T cell-mediated interferon-γ. Conversely, vitamin D can act to inhibit expression and secretion of a broad range of inflammatory mediators and matrix degrading enzymes driving immunopathology during active TB and antiretroviral- (ARV- mediated immune reconstitution inflammatory syndrome (IRIS. Adjunct vitamin D therapy during treatment of active TB may therefore reduce lung pathology and TB morbidity, accelerate resolution of cavitation and thereby decrease the chance of transmission, improve lung function following therapy, prevent relapse, and prevent IRIS in those initiating ARVs. Future clinical trials of vitamin D for TB prevention and treatment must be designed to detect the most appropriate primary endpoint, which in some cases should be anti-inflammatory and not antimicrobial.
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Supachai Sakkhachornphop
2015-01-01
Full Text Available The 3′-end processing (3′P of each viral long terminal repeat (LTR during human immunodeficiency virus type-1 (HIV-1 integration is a vital step in the HIV life cycle. Blocking the 3′P using 3′P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3′P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN, and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3′ end with biotin on the sense strand. Two nucleotides at the 3′ end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3′P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors.
Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide.
Gutiérrez-Venegas, Gloria; Contreras-Sánchez, Anabel; Ventura-Arroyo, Jairo Agustín
2014-10-01
Fisetin is an anti-inflammatory flavonoid; however, its anti-inflammatory mechanism is not yet understood. In this study, we evaluated the anti-inflammatory effect of fisetin and its association with mitogen-activated protein kinase (MAPK) and nuclear factor kappa-beta pathways in human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS) obtained from Porphyromonas gingivalis. The cell signaling, cell viability, and cyclooxygenase-2 (COX-2) expression of HGFs treated with various concentrations (0, 1, 5, 10, and 15 μM) of fisetin were measured by cell viability assay (MTT), Western blotting, and reverse transcriptase polymerase chain reaction analysis on COX-2. We found that fisetin significantly reduced the synthesis and expression of prostaglandin E2 in HGFs treated with LPS. Activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK was suppressed consistently by fisetin in HGFs treated with LPS. The data indicate that fisetin inhibits MAPK activation and COX-2 expression without affecting cell viability. These findings may be valuable for understanding the mechanism of the effect of fisetin on periodontal disease.
SYNTHESIS OF SUBSTITUTED FLAVONE DERIVATIVES AS ...
African Journals Online (AJOL)
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Flavone (2-phenylchromone) derivatives are naturally occurring heterocyclic compound belongs to the flavanoid group. It showed significant role in pharmaceutical effects [1] including leishmanicidal activity, oviposter stimulant phytoalexins, anti-HIV, vasodilator, antiviral, anti- oxidants, bactericidal, DNA cleavage, ...
International Nuclear Information System (INIS)
Tarasow, E.; Wierciska-Drapao, A.; Jaroszewicz, J.; Siergiejczyk, L.; Orzechowska-Bobkiewicz, A.; Prokopowicz, D.; Walecki, J.
2004-01-01
Purpose : To evaluate proton magnetic resonance spectroscopy ( 1 H MRS) features in order to assess hepatocellular activation in chronic hepatitis C and human immunodeficiency virus/hepatitis C (HIV/HCV) co-infected patients. Material and Methods : Liver in vivo 1 H MR spectra were obtained in 14 patients with hepatitis C virus infection (HCV), 20 HIV/HCV co-infected individuals, and 24 healthy volunteers. Resonances of lipids, glutamine/glutamate (Glx), phosphomonoesters (PME), glycogen/glucose (Glc) were assessed and metabolite ratios to total lipids (TL) were calculated. Results : A significant increase in Glx/TL and PME/TL was observed in the HCV group as compared to healthy individuals. Patients with HIV and HCV co-infection had a further increase of all metabolite ratios. Changes in metabolite ratios were due to both the increase in particular metabolite contents and to the decrease in lipid levels. HIV/HCV-infected patients treated with highly active anti-retroviral therapy (HAART) showed elevated PME and Glx levels and significantly decreased TL compared to patients not undergoing anti-retroviral treatment. Conclusions : Our findings suggest clinical usefulness of liver 1 H MR spectroscopy in detecting even slight disturbances in liver metabolism
Detection of anti-HIV-1 IgG antibodies in whole saliva by GACELISA and Western blot assays.
Matee, M I; Lyamuya, E F; Simon, E; Mbena, E C; Kagoma, C; Samaranayake, L P; Scheutz, F
1996-05-01
The present study, based on 158 HIV seropositives and 167 HIV seronegatives, demonstrates that saliva collected with the Omni-SAL device and tested with GACELISA (an IgG antibody capture ELISA) is an effective non-invasive alternative to serum for anti-HIV IgG antibody screening. The study also shows that a conventional serum Western blot kit can be used, with slight modifications, for confirmatory testing of saliva specimens. Collecting saliva with the Omni-SAL device had a very good acceptance rate among Tanzanian subjects, and although this diagnostic method is not yet known by the general public, 65% of the study participants preferred to give saliva instead of blood for HIV testing.
Govindappa, M.; Hemashekhar, B.; Arthikala, Manoj-Kumar; Ravishankar Rai, V.; Ramachandra, Y. L.
2018-06-01
The current research study is to develop an easy and eco-friendly method for the synthesis of AgNPs using aqueous leaf extract of Calophyllum tomentosum (CtAgNPs) and evaluated the extract to know the effects of anti-bacterial, antioxidant, anti-diabetic, anti-inflammatory and anti-tyrosinase activity. Using UV-vis spectrophotometer, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX) characterized the Calophyllum tomentosum mediated silver nanoparticles. The leaf extract of C. tomentosum yielded flavonoids, saponins, tannins, alkaloids, glycosides, phenols, terpenoids and coumarins. AgNPs formation was confirmed by UV-vis spectra at 438 nm. Crystalline structure with a face centered cubic (fcc) of AgNPs was observed in XRD. FTIR had shown that the phytochemicals were responsible for the reduction and capping material of silver nanoparticles. The size and shape of the AgNPs were determined using SEM. From EDX study analysed the strong absorption property of AgNPs. The CtAgNPs have showed significant antibacterial activity on multi drug resistance bacteria. The CtAgNPs had shown strong antioxidant (DPPH, H2O2 scavenging, nitric oxide scavenging power, reducing power) activities. The CtAgNPs had strongly inhibited the α-glucosidase and DPPIV compared to α-amylase. The CtAgNPs exhibited strong anti-inflammatory activity (albumin denaturation, membrane stabilization, heat haemolytic, protein inhibitory, lipoxygenase, xanthine oxidase) and tyrosinase inhibitory activity. To our best knowledge, this is the first attempt on the synthesis of silver nanoparticles using Calophyllum tomentosum leaves extract. Hence, to validate our results the in vivo studies at molecular level are needed to develop an antioxidant, anti-diabetic and anti-inflammatory agent.
Expression of affordable microbicides to combat the spread of HIV pandemic
CSIR Research Space (South Africa)
Mawela, K
2010-09-01
Full Text Available activation, normal T expressed and secreted) show anti-HIV activity through their ability to block the HIV coreceptor CCR5 (Figure 1), and a number of N-terminally modified analogues of these proteins with much higher antiviral potency have been developed...
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Hao Ying
Full Text Available Histone deacetylase (HDAC inhibitors present an exciting new approach to activate HIV production from latently infected cells to potentially enhance elimination of these cells and achieve a cure. M344, a novel HDAC inhibitor, shows robust activity in a variety of cancer cells and relatively low toxicity compared to trichostatin A (TSA. However, little is known about the effects and action mechanism of M344 in inducing HIV expression in latently infected cells.Using the Jurkat T cell model of HIV latency, we demonstrate that M344 effectively reactivates HIV-1 gene expression in latently infected cells. Moreover, M344-mediated activation of the latent HIV LTR can be strongly inhibited by a NF-κB inhibitor aspirin. We further show that M344 acts by increasing the acetylation of histone H3 and histone H4 at the nucleosome 1 (nuc-1 site of the HIV-1 long terminal repeat (LTR and by inducing NF-κB p65 nuclear translocation and direct RelA DNA binding at the nuc-1 region of the HIV-1 LTR. We also found that M344 synergized with prostratin to activate the HIV-1 LTR promoter in latently infected cells.These results suggest the potential of M344 in anti-latency therapies and an important role for histone modifications and NF-κB transcription factors in regulating HIV-1 LTR gene expression.
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Elijah M Songok
Full Text Available To identify novel biomarkers for HIV-1 resistance, including pathways that may be critical in anti-HIV-1 vaccine design, we carried out a gene expression analysis on blood samples obtained from HIV-1 highly exposed seronegatives (HESN from a commercial sex worker cohort in Nairobi and compared their profiles to HIV-1 negative controls. Whole blood samples were collected from 43 HIV-1 resistant sex workers and a similar number of controls. Total RNA was extracted and hybridized to the Affymetrix HUG 133 Plus 2.0 micro arrays (Affymetrix, Santa Clara CA. Output data was analysed through ArrayAssist software (Agilent, San Jose CA. More than 2,274 probe sets were differentially expressed in the HESN as compared to the control group (fold change ≥1.3; p value ≤0.0001, FDR <0.05. Unsupervised hierarchical clustering of the differentially expressed genes readily distinguished HESNs from controls. Pathway analysis through the KEGG signaling database revealed a majority of the impacted pathways (13 of 15, 87% had genes that were significantly down regulated. The most down expressed pathways were glycolysis/gluconeogenesis, pentose phosphate, phosphatidyl inositol, natural killer cell cytotoxicity and T-cell receptor signaling. Ribosomal protein synthesis and tight junction genes were up regulated. We infer that the hallmark of HIV-1 resistance is down regulation of genes in key signaling pathways that HIV-1 depends on for infection.
An assay to monitor HIV-1 protease activity for the identification of novel inhibitors in T-cells.
Directory of Open Access Journals (Sweden)
Brett J Hilton
Full Text Available The emergence of resistant HIV strains, together with the severe side-effects of existing drugs and lack of development of effective anti-HIV vaccines highlight the need for novel antivirals, as well as innovative methods to facilitate their discovery. Here, we have developed an assay in T-cells to monitor the proteolytic activity of the HIV-1 protease (PR. The assay is based on the inducible expression of HIV-1 PR fused within the Gal4 DNA-binding and transactivation domains. The fusion protein binds to the Gal4 responsive element and activates the downstream reporter, enhanced green fluorescent protein (eGFP gene only in the presence of an effective PR Inhibitor (PI. Thus, in this assay, eGFP acts as a biosensor of PR activity, making it ideal for flow cytometry based screening. Furthermore, the assay was developed using retroviral technology in T-cells, thus providing an ideal environment for the screening of potential novel PIs in a cell-type that represents the natural milieu of HIV infection. Clones with the highest sensitivity, and robust, reliable and reproducible reporter activity, were selected. The assay is easily adaptable to other PR variants, a multiplex platform, as well as to high-throughput plate reader based assays and will greatly facilitate the search for novel peptide and chemical compound based PIs in T-cells.
Wijesundara, Danushka K; Jackson, Ronald J; Tscharke, David C; Ranasinghe, Charani
2013-09-23
We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL-13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-γ, tumour necorsis factor (TNF)-α and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Rα2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL-4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti-viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection. Copyright © 2013 Elsevier Ltd. All rights reserved.
Krstic, Tamara
2007-01-01
The main objective of this dissertation is to examine attitudes toward shock advertising of western-European and Serbian university students with regard to public health context (anti-smoking and anti-HIV/AIDS campaigns). Although the use of shock advertising is widely adopted in practice, there has not been extensive research with regard to this topic. Public health context is of special interest in this dissertation as there is an urge for social marketing on Serbian market. The results of ...
Gill, Amanda L; Green, Samantha A; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H Clifford; Catalfamo, Marta
2016-10-23
The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.
Energy Technology Data Exchange (ETDEWEB)
Amano, Masayuki; Miguel Salcedo-Gómez, Pedro; Yedidi, Ravikiran S.; Delino, Nicole S.; Nakata, Hirotomo; Venkateswara Rao, Kalapala; Ghosh, Arun K.; Mitsuya, Hiroaki
2017-09-25
We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2'-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1NL4-3 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2ROD. Under the selection condition, where HIV-1NL4-3 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.
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Tarasow, E.; Wierciska-Drapao, A.; Jaroszewicz, J.; Siergiejczyk, L.; Orzechowska-Bobkiewicz, A.; Prokopowicz, D.; Walecki, J. [Medical Academy Hospital, Bialystok (Poland). Dept. of Radiology
2004-12-01
Purpose : To evaluate proton magnetic resonance spectroscopy ({sup 1}H MRS) features in order to assess hepatocellular activation in chronic hepatitis C and human immunodeficiency virus/hepatitis C (HIV/HCV) co-infected patients. Material and Methods : Liver in vivo {sup 1}H MR spectra were obtained in 14 patients with hepatitis C virus infection (HCV), 20 HIV/HCV co-infected individuals, and 24 healthy volunteers. Resonances of lipids, glutamine/glutamate (Glx), phosphomonoesters (PME), glycogen/glucose (Glc) were assessed and metabolite ratios to total lipids (TL) were calculated. Results : A significant increase in Glx/TL and PME/TL was observed in the HCV group as compared to healthy individuals. Patients with HIV and HCV co-infection had a further increase of all metabolite ratios. Changes in metabolite ratios were due to both the increase in particular metabolite contents and to the decrease in lipid levels. HIV/HCV-infected patients treated with highly active anti-retroviral therapy (HAART) showed elevated PME and Glx levels and significantly decreased TL compared to patients not undergoing anti-retroviral treatment. Conclusions : Our findings suggest clinical usefulness of liver {sup 1}H MR spectroscopy in detecting even slight disturbances in liver metabolism.
Pontikis, R; Dollé, V; Guillaumel, J; Dechaux, E; Note, R; Nguyen, C H; Legraverend, M; Bisagni, E; Aubertin, A M; Grierson, D S; Monneret, C
2000-05-18
To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.
Matono, Takashi; Nishijima, Takeshi; Teruya, Katsuji; Morino, Eriko; Takasaki, Jin; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Kaku, Mitsuo; Oka, Shinichi
2017-11-01
Little information exists on the frequency, severity, and timing of first-line anti-tuberculosis drug-related adverse events (TB-AEs) in HIV-tuberculosis coinfected (HIV-TB) patients in the antiretroviral therapy (ART) era. This matched-cohort study included HIV-TB patients as cases and HIV-uninfected tuberculosis (non-HIV-TB) patients as controls. Tuberculosis was culture-confirmed in both groups. Cases were matched to controls in a 1:4 ratio on age, sex, and year of diagnosis. TB-AEs were defined as Grade 2 or higher requiring drug discontinuation/regimen change. From 2003 to 2015, 94 cases and 376 controls were analyzed (95% men, 98% Asians). Standard four-drug combination therapy was initiated in 91% of cases and 89% of controls (p = 0.45). Cases had a higher frequency of TB-AE [51% (48/94) vs. 10% (39/376), p tuberculosis treatment. HIV infection was an independent risk factor for TB-AEs in the multivariate Cox analysis [adjusted HR (aHR): 6.96; 95% confidence interval: 3.93-12.3]. TB-AEs occurred more frequently in HIV-TB than in non-HIV-TB patients, and were more severe. The majority of TB-AEs occurred within 4 weeks of initiating anti-tuberculosis treatment. Because TB-AEs may delay ART initiation, careful monitoring during this period is warranted in coinfected patients.
DEFF Research Database (Denmark)
Mangesho, Peter E; Reynolds, Joanna; Lemnge, Martha
2014-01-01
BACKGROUND: Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning......, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes...
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Navare, Arti T.; Sova, Pavel; Purdy, David E.; Weiss, Jeffrey M. [Department of Microbiology, University of Washington, Seattle, WA (United States); Wolf-Yadlin, Alejandro [Department of Genome Sciences, University of Washington, Seattle, WA (United States); Korth, Marcus J.; Chang, Stewart T.; Proll, Sean C. [Department of Microbiology, University of Washington, Seattle, WA (United States); Jahan, Tahmina A. [Proteomics Resource, UW Medicine at South Lake Union, Seattle, WA (United States); Krasnoselsky, Alexei L.; Palermo, Robert E. [Department of Microbiology, University of Washington, Seattle, WA (United States); Katze, Michael G., E-mail: honey@uw.edu [Department of Microbiology, University of Washington, Seattle, WA (United States); Washington National Primate Research Center, University of Washington, Seattle, WA (United States)
2012-07-20
Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value{<=}0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.
Mao, Zhonghua; Gan, Chunli; Zhu, Jiuxin; Ma, Nan; Wu, Lijun; Wang, Libo; Wang, Xiaobo
2017-06-15
We have successfully established AS model using thoracic aortas vascular ring which evaluated by the morphological changes of blood vessels, the proliferation of VSMC, and the expression of inflammation factors VEGF, CRP, JNK2 and p38. This AS model has the advantages of low cost, convenient and short period of established time. Moreover, we investigated the anti-AS activities of 7 flavonoids Narirutin (1), Naringin (2), Eriodictyol (3), Luteolin (4), Galuteolin (5), Astragalin (6), Kaempferol (7) from flowers of Helichrysum arenarium L. MOENCH by examining the vascular morphology, the inhibition on the expression of inflammation factors CRP, VEGF, JNK2, p38. In addition, we investigated the anti-AS activities of these 7 flavonoids by examining NO secretion of RAW264.7 cells in response to LPS. All above inflammation factors have been proved to be involved in the formation of AS. After comprehensive analysis of all results to discuss the structure-activity relationship, we summarized the conclusions at follow: compounds 1-7 could inhibit the expression of VEGF, CRP, JNK2, p38 and NO at different level, and we evaluated that flavonol aglycone have more significant anti-inflammation than it's glycoside, and the anti-AS activity of flavonols were stronger than flavanones and flavones, which means that 3-group might be the effective group. Eventually, we supposed the main anti-inflammatory mechanism of these compounds was to reduce the expression of CRP, inhibit the kinases activity of JNK2 and p38, and then the MAPK pathway was suppressed, which resulted in the decrease of NO synthesis, VEGF expression and endothelial adhesion factor expression. And eventually, the scar tissue and vascular stenosis formations were prevented. This conclusion suggested flavonoids have the potential of preventing AS formation. Copyright © 2017 Elsevier Ltd. All rights reserved.
Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).
Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B
Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.
Tian, Ye; Du, Deping; Rai, Diwakar; Wang, Liu; Liu, Huiqing; Zhan, Peng; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong
2014-04-01
In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies. Copyright © 2014 Elsevier Ltd. All rights reserved.
Optimization of TB/HIV co-treatment in Ethiopian patients
Degu, Wondwossen Amogne
2015-01-01
Tuberculosis (TB) and HIV infection act with deadly synergy. HIV is the most important risk factor for latent TB reactivation and active TB progression following exposure or reinfection while TB accelerates HIV progression. TB is the most frequent cause of morbidity and mortality in HIV infection. Anti-TB therapy (ATT) must precede initiation of combination Antiretroviral Therapy (cART), TB being the most immediate threat. Undoubtedly cART benefits; however, important clinical ...
Stigma, activism, and well-being among people living with HIV.
Earnshaw, Valerie A; Rosenthal, Lisa; Lang, Shawn M
2016-01-01
Evidence demonstrates that HIV stigma undermines the psychological and physical health of people living with HIV (PLWH). Yet, PLWH describe engaging in HIV activism to challenge stigma, and research suggests that individuals may benefit from activism. We examine associations between experiences of HIV stigma and HIV activism, and test whether HIV activists benefit from greater well-being than non-activists. Participants include 93 PLWH recruited from drop-in centers, housing programs, and other organizations providing services to PLWH in the Northeastern USA between 2012 and 2013 (mean age = 50 years; 56% Black, 20% White, 18% Other; 61% non-Latino(a), 39% Latino(a); 59% male, 38% female, 3% transgender; 82% heterosexual, 15% sexual minority). Participants completed a cross-sectional written survey. Results of regression analyses suggest that PLWH who experienced greater enacted stigma engaged in greater HIV activism. Anticipated, internalized, and perceived public stigma, however, were unrelated to HIV activism. Moreover, results of a multivariate analysis of variance suggest that HIV activists reported greater social network integration, greater social well-being, greater engagement in active coping with discrimination, and greater meaning in life than non-activists. Yet, HIV activists also reported somewhat greater depressive symptoms than non-activists, suggesting that the association between HIV activism and well-being is complex. By differentiating between HIV stigma mechanisms, the current study provides a more nuanced understanding of which experiences of HIV stigma may be associated with HIV activism. It further suggests that engagement in activism may offer benefits to PLWH, while raising the possibility that activists could experience greater depressive symptoms than non-activists. Given the preliminary nature of this study, future research should continue to examine these complex associations between HIV stigma, activism, and well-being among PLWH
Jones, Christopher P; Saadatmand, Jenan; Kleiman, Lawrence; Musier-Forsyth, Karin
2013-02-01
The primer for initiating reverse transcription in human immunodeficiency virus type 1 (HIV-1) is tRNA(Lys3). Host cell tRNA(Lys) is selectively packaged into HIV-1 through a specific interaction between the major tRNA(Lys)-binding protein, human lysyl-tRNA synthetase (hLysRS), and the viral proteins Gag and GagPol. Annealing of the tRNA primer onto the complementary primer-binding site (PBS) in viral RNA is mediated by the nucleocapsid domain of Gag. The mechanism by which tRNA(Lys3) is targeted to the PBS and released from hLysRS prior to annealing is unknown. Here, we show that hLysRS specifically binds to a tRNA anti-codon-like element (TLE) in the HIV-1 genome, which mimics the anti-codon loop of tRNA(Lys) and is located proximal to the PBS. Mutation of the U-rich sequence within the TLE attenuates binding of hLysRS in vitro and reduces the amount of annealed tRNA(Lys3) in virions. Thus, LysRS binds specifically to the TLE, which is part of a larger LysRS binding domain in the viral RNA that includes elements of the Psi packaging signal. Our results suggest that HIV-1 uses molecular mimicry of the anti-codon of tRNA(Lys) to increase the efficiency of tRNA(Lys3) annealing to viral RNA.
Directory of Open Access Journals (Sweden)
David Warrilow
Full Text Available Recent work suggests a role for multiple host factors in facilitating HIV-1 reverse transcription. Previously, we identified a cellular activity which increases the efficiency of HIV-1 reverse transcription in vitro. Here, we describe aspects of the activity which shed light on its function. The cellular factor did not affect synthesis of strong-stop DNA but did improve downstream DNA synthesis. The stimulatory activity was isolated by gel filtration in a single fraction of the exclusion volume. Velocity-gradient purified HIV-1, which was free of detectable RNase activity, showed poor reverse transcription efficiency but was strongly stimulated by partially purified cell proteins. Hence, the cell factor(s did not inactivate an RNase activity that might degrade the viral genomic RNA and block completion of reverse transcription. Instead, the cell factor(s enhanced first strand transfer and synthesis of late reverse transcription suggesting it stabilized the reverse transcription complex. The factor did not affect lysis of HIV-1 by Triton X-100 in the endogenous reverse transcription (ERT system, and ERT reactions with HIV-1 containing capsid mutations, which varied the biochemical stability of viral core structures and impeded reverse transcription in cells, showed no difference in the ability to be stimulated by the cell factor(s suggesting a lack of involvement of the capsid in the in vitro assay. In addition, reverse transcription products were found to be resistant to exogenous DNase I activity when the active fraction was present in the ERT assay. These results indicate that the cell factor(s may improve reverse transcription by facilitating DNA strand transfer and DNA synthesis. It also had a protective function for the reverse transcription products, but it is unclear if this is related to improved DNA synthesis.
HIV-1 Tat and AIDS-associated cancer: targeting the cellular anti-cancer barrier?
Directory of Open Access Journals (Sweden)
Daniel René
2008-05-01
Full Text Available Abstract The acquired immunodeficiency syndrome (AIDS is accompanied by a significant increase in the incidence of neoplasms. Several causative agents have been proposed for this phenomenon. These include immunodeficiency and oncogenic DNA viruses and the HIV-1 protein Tat. Cancer in general is closely linked to genomic instability and DNA repair mechanisms. The latter maintains genomic stability and serves as a cellular anti-cancer barrier. Defects in DNA repair pathway are associated with carcinogenesis. This review focuses on newly discovered connections of the HIV-1 protein Tat, as well as cellular co-factors of Tat, to double-strand break DNA repair. We propose that the Tat-induced DNA repair deficiencies may play a significant role in the development of AIDS-associated cancer.
Formation of stable and functional HIV-1 nucleoprotein complexes in vitro.
Tanchou, V; Gabus, C; Rogemond, V; Darlix, J L
1995-10-06
HIV genomic RNA resides within the nucleocapsid, in the interior of the virus, which serves to protect the RNA against nuclease degradation and to promote its reverse transcription. To investigate the role of nucleocapsid protein (NCp7) in the stability and replication of genomic RNA within the nucleocapsid, we used NCp7, reverse transcriptase (RT) and RNAs representing the 5' and 3' regions of the genome to reconstitute functional HIV-1 nucleocapsids. The nucleoprotein complexes generated in vitro were found to be stable, which, according to biochemical and genetic data, probably results from the tight binding of NCp7 molecules to the RNA and strong NCp7/NCp7 interactions. The nucleoprotein complexes efficiently protected viral RNA against RNase degradation and, at the same time, promoted viral DNA synthesis by RT. DNA strand transfer from the 5' to the 3' RNA template was very efficient in nucleoprotein complexes formed in the presence of both RNAs, but not when the RNAs were in separate complexes. These results indicate that the in vitro reconstituted HIV-1 nucleoprotein complexes function like virion nucleocapsids and thus provide a way to study at the molecular level this viral substructure and the synthesis of proviral DNA, and to search for new anti-HIV agents.
The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids.
Directory of Open Access Journals (Sweden)
Robin G Mansour
Full Text Available Tenascin-C (TNC is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.
Kteily-Hawa, Roula N; Islam, Shazia; Loutfy, Mona
2018-04-16
South Asian immigrant women in Canada face unique structural barriers that influence their HIV vulnerability. Using an intersectional and anti-oppressive lens, we explored the role of immigration in bringing about changes in gender roles and the structure of gender relations and their effect on HIV risk among immigrant women as they experienced crisis tendencies in the face of hegemonic masculinity. Informed by Connell's theory of gender, the study entailed in-depth interviews with 12 self-identified South Asian immigrant women living in the Greater Toronto Area, in Ontario, Canada. A thematic analysis yielded four themes: power relations, emotional relations, gendered division of labour and social norms. Our findings revealed interdependencies between immigration and each of structural, individual and normative factors (the themes) as they pertain to crisis tendencies when patriarchy is disrupted. Given the rapid increase in global immigration, the connections between transnationalism and hegemony, and the established link between immigration and HIV, future research should extend this work to other immigrant communities.
Yamaguchi, Koushi; Honda, Mitsuo; Ikigai, Hajime; Hara, Yukihiko; Shimamura, Tadakatsu
2002-01-01
Epigallocatechin gallate (EGCg), the major tea catechin, is known as a potent anti-bacterial agent. In addition, anti-tumor promoting, anti-inflammatory, anti-oxidative and antiviral activities have been reported. In the present study, we investigated possible anti-human immunodeficiency virus type-1 (HIV-1) activity of EGCg and its mechanisms of action in the viral life cycle. EGCg impinges on each step of the HIV life cycle. Thus, destruction of the viral particles, viral attachment to cells, post-adsorption entry into cells, reverse transcription (RT), viral production from chronically-infected cells, and the level of expression of viral mRNA, were analyzed using T-lymphoid (H9) and monocytoid (THP-1) cell systems, and antiviral protease activity was measured using a cell-free assay. Inhibitory effects of EGCg on specific binding of the virions to the cellular surfaces and changes in the steady state viral regulation (mRNA expression) due to EGCg were not observed. However, EGCg had a destructive effect on the viral particles, and post-adsorption entry and RT in acutely infected monocytoid cells were significantly inhibited at concentrations of EGCg greater than 1 microM, and protease kinetics were suppressed at a concentration higher than 10 microM in the cell-free study. Viral production by THP-1 cells chronically-infected with HIV-1 was also inhibited in a dose-dependent manner and the inhibitory effect was enhanced by liposome modification of EGCg. As expected, increased viral mRNA production was observed in lipopolysaccharide (LPS)-activated chronically HIV-1-infected cells. This production was significantly inhibited by EGCg treatment of THP-1 cells. In contrast, production of HIV-1 viral mRNA in unstimulated or LPS-stimulated T-lymphoid cells (H9) was not inhibited by EGCg. Anti-HIV viral activity of EGCg may thus result from an interaction with several steps in the HIV-1 life cycle.
International Nuclear Information System (INIS)
Ferir, Geoffrey; Palmer, Kenneth E.; Schols, Dominique
2011-01-01
Griffithsin (GRFT) is possibly the most potent anti-HIV peptide found in natural sources. Due to its potent and broad-spectrum antiviral activity and unique safety profile it has great potential as topical microbicide component. Here, we evaluated various combinations of GRFT against HIV-1 clade B and clade C isolates in primary peripheral blood mononuclear cells (PBMCs) and in CD4 + MT-4 cells. In all combinations tested, GRFT showed synergistic activity profile with tenofovir, maraviroc and enfuvirtide based on the median effect principle with combination indices (CI) varying between 0.34 and 0.79 at the calculated EC 95 level. Furthermore, the different glycosylation patterns on the viral envelope of clade B and clade C gp120 had no observable effect on the synergistic interactions. Overall, we can conclude that the evaluated two-drug combination increases their antiviral potency and supports further clinical investigations in pre-exposure prophylaxis for GRFT combinations in the context of HIV-1 clade C infection.
Synthesis and Anti-HBV Activity of Novel 3′-N-phenylsulfonyl Docetaxel Analogs
Directory of Open Access Journals (Sweden)
Xun Sun
2013-08-01
Full Text Available Nine new 3′-N-phenylsulfonyl docetaxel analogs were synthesized in good yields from the key intermediate N-phenylsulfonyl oxazolidine via a six-step route. These analogs were tested for anti-hepatitis B virus (HBV activity in vitro. Compounds 3e, 3g and 3j showed more potent inhibitory activity against HBeAg secretion than the positive control lamivudine. Further extensive SAR and mechanistic studies will be reported in due course.
Smart nanoparticles as targeting platforms for HIV infections
Adhikary, Rishi Rajat; More, Prachi; Banerjee, Rinti
2015-04-01
While Human Immunodeficiency Virus (HIV) infections are reducing in incidence with the advent of Highly Active Anti-retroviral Therapy (HAART), there remain a number of challenges including the existence of reservoirs, drug resistance and anatomical barriers to antiretroviral therapy. To overcome these, smart nanoparticles with stimuli responsive release are proposed for delivery of anti-retroviral agents. The paper highlights the strategic similarities between the design of smart antiretroviral nanocarriers and those optimized for cancer chemotherapy. This includes the development of nanoparticles capable of passive and active targeting as well as those that are responsive to various internal and external triggers. For antiretroviral therapy, the relevant triggers for stimuli responsive release of drugs include semen, enzymes, endosomal escape, temperature and magnetic field. Deriving from the experience of cancer chemotherapy, additional potential triggers are light and ultrasound which remain hitherto unexplored in HIV therapy. In addition, the roles of nanomicrobicides (nanogels) and virus mimetic nanoparticles are discussed from the point of view of prevention of HIV transmission. The challenges associated with translation of smart nanoparticles for HIV infections to realize the Millennium Development Goal of combating HIV infections are discussed.
Synthesis, characterization, in vitro anti-proliferative and hemolytic activity of hydroxyapatite
Palanivelu, R.; Ruban Kumar, A.
2014-06-01
Hydroxyapatite (Ca10(PO4)6(OH)2, HAP) nanoparticles are widely used in several biomedical applications due to its compositional similarities to bone mineral, excellent biocompatibility and bioactivity, osteoconductivity. In this present investigation, HAP nanoparticles synthesized by precipitation technique using calcium nitrate and di-ammonium phosphate. The crystalline nature and the functional group analysis are confirmed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and Fourier transform Raman spectroscopy (FT-Raman) respectively. The morphological observations are ascertained from field emission electron scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). In vitro anti-proliferative and hemolytic activities are carried out on the synthesized HAP samples and the studies reveals that HAP have mild activity against erythrocytes.
Landa, P. (Přemysl); Skálová, L.; Boušová, I.; Kutil, Z. (Zsófia); Langhansová, L. (Lenka); Lou, J.D.; Vaněk, T. (Tomáš)
2014-01-01
The aim of this study was to evaluate in vitro anti-proliferative (tested on MCF-7, MDA-MB-231, and MCF-10A cell lines) and anti-inflammatory (evaluated as inhibition of prostaglandin E2 synthesis catalyzed by cyclooxygenase-2) effect of various extracts from Vaccinium bracteatum leaves and fruits. The highest anti-proliferative effect possessed leaf dichloromethane extract with IC50 values ranging from 93 to 198 mug/mL. In the case of cyclooxygenase-2 inhibition, n-hexane, dichloromethane, a...
SHORT COMMUNICATION SYNTHESIS AND ANTI ...
African Journals Online (AJOL)
THIADIAZOL DERIVATIVES OF MEFENAMIC ACID ... acid derivatives were synthesized and confirmed by spectroscopic data. ... evaluations indicate that these new compounds showed potent anti-inflammatory activities compare to .... intermediate compound (A) ,this intermediate has a good characteristics like carbonyl.
Dorr, Patrick; Westby, Mike; Dobbs, Susan; Griffin, Paul; Irvine, Becky; Macartney, Malcolm; Mori, Julie; Rickett, Graham; Smith-Burchnell, Caroline; Napier, Carolyn; Webster, Rob; Armour, Duncan; Price, David; Stammen, Blanda; Wood, Anthony
2005-01-01
Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades a...
Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark
2014-01-01
Background Root bark of mulberry (Morus alba L.) has been used in herbal medicine as anti-phlogistic, liver protective, kidney protective, hypotensive, diuretic, anti-cough and analgesic agent. However, the anti-cancer activity and the potential anti-cancer mechanisms of mulberry root bark have not been elucidated. We performed in vitro study to investigate whether mulberry root bark extract (MRBE) shows anti-inflammatory and anti-cancer activity. Methods In anti-inflammatory activity, NO was measured using the griess method. iNOS and proteins regulating NF-κB and ERK1/2 signaling were analyzed by Western blot. In anti-cancer activity, cell growth was measured by MTT assay. Cleaved PARP, ATF3 and cyclin D1 were analyzed by Western blot. Results In anti-inflammatory effect, MRBE blocked NO production via suppressing iNOS over-expression in LPS-stimulated RAW264.7 cells. In addition, MRBE inhibited NF-κB activation through p65 nuclear translocation via blocking IκB-α degradation and ERK1/2 activation via its hyper-phosphorylation. In anti-cancer activity, MRBE deos-dependently induced cell growth arrest and apoptosis in human colorectal cancer cells, SW480. MRBE treatment to SW480 cells activated ATF3 expression and down-regulated cyclin D1 level. We also observed that MRBE-induced ATF3 expression was dependent on ROS and GSK3β. Moreover, MRBE-induced cyclin D1 down-regulation was mediated from cyclin D1 proteasomal degradation, which was dependent on ROS. Conclusions These findings suggest that mulberry root bark exerts anti-inflammatory and anti-cancer activity. PMID:24962785
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Nikhila Gokhale
2017-11-01
Full Text Available The paper describes the facile synthesis of new N-cyclopropyl-1-methyl-1H-indole-2-carboxamide derivatives bearing substituted 2-amino pyrimidine moiety at position-3 of the indole ring. All the intermediate and title compounds were characterized adeptly by 1H NMR, 13C NMR, ESI–MS and elemental analyses. These compounds were evaluated for their in vitro anticancer activity against HeLa, HepG2 and MCF-7 cells. Three among 22 molecules, showed more than 70% growth inhibition against all three tested cancer cells. The nature of the substituent group on the pyrimidine ring (R2 affected significantly the anti-proliferative activity of the molecules. The anti-microbial evaluation of the title molecules revealed the significance of fluoro/chloro groups (R2 in enhancing their inhibition activity. Eight molecules which contain fluoro/chloro groups showed potent anti-microbial activity. In addition, the active molecules displayed negligible toxicity to benign Vero cells.
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Mazyar Etemadzade
2016-11-01
Full Text Available Objective: To evaluate the effect of novel sonochemical silver nanorods on HIV and herpes simplex virus type 1 (HSV-1 viruses in human cervical cancer HeLa cells. Methods: The formation of silver nanorods conjugated with sodium 2-mercaptoethane sulfonate (Ag-MES was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and thermal gravimetric analysis. The antiviral activity of this Ag-MES was examined against HIV and HSV-1 virus replication. Results: The characterizations of Ag-MES and physiochemical structure were determined by scanning electron microscopy, Fourier transform infrared spectroscopy and thermal gravimetric analysis. Approximately entire viral replication was inhibited by Ag-MES at 10 µmol/mL concentration. About 90% of HSV virions failed to replicate in the present of this concentration of nanorods. However, HIV showed more sensitivity to Ag-MES than HSV-1. Conclusions: According to the obtained data, the synthesized sonochemical silver nanorod in this study is a promising candidate for further drug discovery investigation.
Fatores associados à submissão ao teste rápido anti-HIV na assistência ao parto
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Maria Inês Couto de Oliveira
Full Text Available Resumo Os testes rápidos anti-HIV vêm sendo empregados nas maternidades com vistas à prevenção da transmissão vertical. O objetivo do estudo foi analisar os fatores associados à submissão ao teste rápido anti-HIV (desfecho. Estudo transversal, conduzido em 2009, em 15 hospitais do SUS do Rio de Janeiro/RJ, mediante entrevista a amostra representativa de 835 parturientes internadas e consulta a prontuários. Razões de prevalência ajustadas foram obtidas por regressão de Poisson, segundo modelo hierarquizado, permanecendo no modelo final as variáveis associadas ao desfecho (p ≤ 0,05. Segundo os prontuários (SP, 79,6% das mães foram submetidas ao teste rápido anti-HIV e, segundo as entrevistas (SE, 55,7%. No nível distal, a ausência de companheiro (SP, ter ≥ 6 moradores na residência (SP e a cor da pele não branca (SE se associaram a uma maior prevalência do desfecho. No nível intermediário, não dispor de sorologia negativa para o HIV do pré-natal (SP e SE se associou a uma maior prevalência do desfecho, bem como a realização de pré-natal na rede básica (SP e a não realização de pré-natal (SE. No nível proximal, o parto em hospital não certificado como amigo da criança se associou a uma maior prevalência do desfecho (SP e SE.
HEATING AND ULTRAVIOLET LIGHT ACTIVATE ANTI-STRESS GENE FUNCTIONS IN HUMANS
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Victor Fadeevitch Semenkov
2015-07-01
Full Text Available All types of cell stress are accompanied by the activation of anti-stress genes that can suppress ROS synthesis. We hypothesized that different environmental factors would affect organisms through the activation of anti-stress genes by autologous serum (AS proteins, followed by the synthesis of molecules that increase cell resistance to oxidative stress. The goal of this work was to study the influence of AS on ROS production by peripheral blood neutrophils isolated from donors in different age groups. Neutrophils were isolated from 59 donors (38-94 years old. AS was heated at 100˚C for 30 sec. or irradiated by ultraviolet light (UV at 200-280 nm and 8 W for 10 min. Neutrophils were exposed to heat shock at 42˚C for 1 min. (short-term heating stress or 43˚C for 10 min., followed by the determination of the chemiluminescence reaction induced by zymosan. AS can increase or decrease ROS production by neutrophils depending on the structure of the proteins in the serum; these structures can be changed by heating or UV treatment and the temperature of their interaction (4˚C or 37˚C. We propose that the effect of environmental factors on AS proteins can cause an adverse increase in oxidative stress levels due to the functional reduction of anti-stress genes. We found a negative correlation between the quantity of intracellular Hsp70 and levels of intracellular ROS production following 10 minutes of heat shock at 43°C. Short-term heating stress (1 minute at 42°C was followed by a prominent reduction in ROS production. This effect may be a result of the impact of the hormone adrenaline on the functions of anti-stress genes. Indeed, the same effect was observed after treatment of the neutrophils with adrenaline at concentrations of 10-4 M and 10-5 M. In contrast, dexamethasone from the other stress hormone group did not evoke the same effect at the same concentrations.
Wrasidlo, Wolf; Crews, Leslie A; Tsigelny, Igor F; Stocking, Emily; Kouznetsova, Valentina L; Price, Diana; Paulino, Amy; Gonzales, Tania; Overk, Cassia R; Patrick, Christina; Rockenstein, Edward; Masliah, Eliezer
2014-12-01
Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier. We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders. © 2014 The British Pharmacological Society.
Isaakidis, Petros; Varghese, Bhanumati; Mansoor, Homa; Cox, Helen S.; Ladomirska, Joanna; Saranchuk, Peter; Da Silva, Esdras; Khan, Samsuddin; Paryani, Roma; Udwadia, Zarir; Migliori, Giovanni Battista; Sotgiu, Giovanni; Reid, Tony
2012-01-01
Background Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings. Methods Médecins Sans Frontières (MSF) is supporting a community-based treatment program for drug-resistant tuberculosis in HIV-infected patients in a slum setting in Mumbai, India since 2007. Patients are being treated for both diseases and the management of AE is done on an outpatient basis whenever possible. Prospective data were analysed to determine the occurrence and nature of AE. Results Between May 2007 and September 2011, 67 HIV/MDR-TB co-infected patients were being treated with anti-TB treatment and ART; 43.3% were female, median age was 35.5 years (Interquartile Range: 30.5–42) and the median duration of anti-TB treatment was 10 months (range 0.5–30). Overall, AE were common in this cohort: 71%, 63% and 40% of patients experienced one or more mild, moderate or severe AE, respectively. However, they were rarely life-threatening or debilitating. AE occurring most frequently included gastrointestinal symptoms (45% of patients), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%) and hypokalaemia (23%). Eleven patients were hospitalized for AE and one or more suspect drugs had to be permanently discontinued in 27 (40%). No AE led to indefinite suspension of an entire MDR-TB or ART regimen. Conclusions AE occurred frequently in this Mumbai HIV/MDR-TB cohort but not more frequently than in non-HIV patients on similar anti-TB treatment. Most AE can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe AE in the management of co-infected patients are justified, however, they should not cause delays
Pillay, Viness; Mashingaidze, Felix; Choonara, Yahya E; Du Toit, Lisa C; Buchmann, Eckhart; Maharaj, Vinesh; Ndesendo, Valence M K; Kumar, Pradeep
2012-06-01
The past decade has seen several effective anti-HIV-1 agent discoveries, yet microbicides continue to disappoint clinically. Our review expounds the view that unsatisfactory microbicide failures may be a result of inefficient delivery systems employed. We hereby propose a thorough scientific qualitative and quantitative investigation of important aspects involved in HIV-1 transmission as a prerequisite for microbicide delivery. Intravaginal targeting of HIV-1 increases the chances of microbicide success, wherein vaginal microenvironmental factors including pH should be maintained at HIV-1 prohibitive acidic levels simultaneously to ward off other sexually transmitted diseases, which compromise vaginal epithelial barrier properties. Furthermore, choice of receptors to target both on HIV-1 and on target cells is vital in deterring transmission. Appropriate modeling of virus-target cell interactions as well as targeting early stages of the HIV-1 infection accompanied by computation and delivery of appropriate microbicide quantities could revolutionize microbicide research, ultimately delivering a female-controlled HIV-1 prevention modality appropriately. Copyright © 2012 Wiley Periodicals, Inc.
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Gayle Restall
2017-05-01
Full Text Available Background: Occupational therapy can contribute to the health and well-being of people with human immunodeficiency virus (HIV who are experiencing health consequences of living long term with this disease. However, there are no comprehensive rehabilitation service delivery models to guide this emerging area of practice. The purpose of this study was to obtain critical feedback about a service delivery model to address the activity and social participation needs of people living with HIV. Method: We developed a service delivery model from a synthesis of the literature. Using a qualitative research design, we conducted individual and focus group interviews with 35 informants from diverse backgrounds and involvement in HIV-related research, service provision, and policymaking to provide critical feedback about the model. The interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative methods. Results: The informants identified the strengths and limitations of the model and supports and barriers to its implementation. They highlighted the importance of principle-based services, increasing resources for service navigation, building capacity of rehabilitation services to address the needs of people with HIV, and increasing research and program evaluation targeted to achieving activity and social participation outcomes. Conclusions: The model provides a framework for occupational therapists to design and evaluate services for this population.
Jeong, Hee-Yeong; Choi, Yong-Seok; Lee, Jae-Kang; Lee, Beom-Joon; Kim, Woo-Ki; Kang, Hee
2017-07-10
Until recently, fermentation was the only processing used to improve the functionality of wheat germ. The release of 2,6-dimethoxy-1,4-benzoquinone (DMBQ) from hydroquinone glycosides during the fermentation process is considered a marker of quality control. Here, we treated wheat germ extract with citric acid (CWG) to release DMBQ and examined the anti-inflammatory activity of this extract using a lipopolysaccharide-activated macrophage model. Treatment of wheat germ with citric acid resulted in detectable release of DMBQ but reduced total phenolic and total flavonoid contents compared with untreated wheat germ extract (UWG). CWG inhibited secretion of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-12 and the synthesis of cyclooxygenase-2, while UWG only decreased IL-12 production. CWG and UWG induced high levels of anti-inflammatory IL-10 and heme oxygenase-1. CWG specifically inhibited phosphorylation of NF-κB p65 and p38 kinase at 15 min after LPS stimulation. Our study showed that citric acid treatment enhanced the anti-inflammatory activity of wheat germ extract.
International Nuclear Information System (INIS)
Gomez, Milton; Gil, Juan F.
2011-01-01
Phytochemical study of Calea prunifolia HBK identified two compounds derived from p-hydroxyacetophenone, the 1-(2-hydroxy-5-(1-methoxyethyl)phenyl)-3-methylbut-2.en-1-one showed a satisfactory anti-inflammatory activity (58.33%), when considering that this is a natural product. Although the two derived compounds are structurally similar, the anti-inflammatory activity of 1-(2-hydroxy-5-methoxyphenyl)-3-methylbut-2-en-1-one was not significant (2.08%). The test was conducted in a model of inflammation induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the ear of mice. The positive control was tested with indomethacin and the negative control was done only with vehicle. These results allow the identification of a pharmacophore group that through molecular modeling studies and organic synthesis can result in compounds with improved anti-inflammatory activity. (author)
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Gomez, Milton; Gil, Juan F., E-mail: miltongoba@uniquindio.edu.co [Grupo de Busqueda de Principios Bioactivos, Programa de Quimica, Universidad del Quindio, Armenia (Colombia)
2011-09-15
Phytochemical study of Calea prunifolia HBK identified two compounds derived from p-hydroxyacetophenone, the 1-(2-hydroxy-5-(1-methoxyethyl)phenyl)-3-methylbut-2.en-1-one showed a satisfactory anti-inflammatory activity (58.33%), when considering that this is a natural product. Although the two derived compounds are structurally similar, the anti-inflammatory activity of 1-(2-hydroxy-5-methoxyphenyl)-3-methylbut-2-en-1-one was not significant (2.08%). The test was conducted in a model of inflammation induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in the ear of mice. The positive control was tested with indomethacin and the negative control was done only with vehicle. These results allow the identification of a pharmacophore group that through molecular modeling studies and organic synthesis can result in compounds with improved anti-inflammatory activity. (author)
In vitro modeling of HIV proviral activity in microglia.
Campbell, Lee A; Richie, Christopher T; Zhang, Yajun; Heathward, Emily J; Coke, Lamarque M; Park, Emily Y; Harvey, Brandon K
2017-12-01
Microglia, the resident macrophages of the brain, play a key role in the pathogenesis of HIV-associated neurocognitive disorders (HAND) due to their productive infection by HIV. This results in the release of neurotoxic viral proteins and pro-inflammatory compounds which negatively affect the functionality of surrounding neurons. Because models of HIV infection within the brain are limited, we aimed to create a novel microglia cell line with an integrated HIV provirus capable of recreating several hallmarks of HIV infection. We utilized clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology and integrated a modified HIV provirus into CHME-5 immortalized microglia to create HIV-NanoLuc CHME-5. In the modified provirus, the Gag-Pol region is replaced with the coding region for NanoLuciferase (NanoLuc), which allows for the rapid assay of HIV long terminal repeat activity using a luminescent substrate, while still containing the necessary genetic material to produce established neurotoxic viral proteins (e.g. tat, nef, gp120). We confirmed that HIV-NanoLuc CHME-5 microglia express NanoLuc, along with the HIV viral protein Nef. We subsequently exposed these cells to a battery of experiments to modulate the activity of the provirus. Proviral activity was enhanced by treating the cells with pro-inflammatory factors lipopolysaccharide (LPS) and tumor necrosis factor alpha and by overexpressing the viral regulatory protein Tat. Conversely, genetic modification of the toll-like receptor-4 gene by CRISPR/Cas9 reduced LPS-mediated proviral activation, and pharmacological application of NF-κB inhibitor sulfasalazine similarly diminished proviral activity. Overall, these data suggest that HIV-NanoLuc CHME-5 may be a useful tool in the study of HIV-mediated neuropathology and proviral regulation. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
The organization of HIV and other health activities within urban religious congregations.
Palar, Kartika; Mendel, Peter; Derose, Kathryn Pitkin
2013-10-01
Most religious congregations in the USA are involved with some type of social service activity, including health activities. However, relatively few formally engage with people with HIV, and many have reported barriers to introducing HIV prevention activities. We conducted a qualitative case study of HIV involvement among 14 urban congregations in Los Angeles County in 2007. In-depth qualitative interviews of lay leaders and clergy were analyzed for themes related to HIV and other health activities, including types of health issues addressed, types of activities conducted, how activities were organized, and the relationship between HIV and other health activities. We identified three primary models representing how congregations organized HIV and other health activities: (1) embedded (n = 7), where HIV activities were contained within other health activities; (2) parallel (n = 5), where HIV and other health activities occurred side by side and were organizationally distinct; (3) overlap (n = 2), where HIV and non-HIV health efforts were conducted by distinct groups, but shared some members and organization. We discuss implications of each model for initiating and sustaining HIV activities within urban congregations over time.
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Luis Corral-Gudino
2016-09-01
Full Text Available We report a case of paradoxical deterioration. A male patient diagnosed with pleural tuberculosis, but who was not infected with human immunodeficiency virus (HIV, experienced clinical deterioration 3 weeks after the initiation of anti-tuberculous treatment. After other diagnoses were ruled out, a paradoxical response to treatment was established and the patient was started on systemic corticosteroids. Paradoxical response to treatment should be considered in patients with clinical deterioration after they start on anti-tuberculous treatment.
HIV-1 Reservoir Association with Immune Activation
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Alejandro Vallejo
2015-09-01
Full Text Available In this issue of EBioMedicine, Ruggiero and colleagues describe immune activation biomarkers associated with the size of the HIV reservoir in a carefully designed cross-sectional study. The cohort consists of a homogeneous sample of HIV-1-infected patients with long-term plasma HIV-1 RNA suppression under antiretroviral treatment (ART. It is crucial to explore the potential utility of biomarkers that are easier (less labor intensive, less expensive to measure than integrated HIV DNA load, in order to quickly and accurately quantify cellular reservoirs of HIV.
Synthesis and Anti-inflammatory Activity of Some Novel Pyrazole Derivatives of Gallic Acid
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S. Arunkumar
2009-01-01
Full Text Available In the present study, a new series of [5-substituted-3-(phenylamino-1H-pyrazol-1yl] (3,4,5-trihydroxyphenyl-methanone (4a-j have been synthesized. 3, 4, 5-Trihydroxy benzohydrazide (1 was synthesized from propyl gallate and hydrazine hydrate in presence of ethanol. Chalcones (2a-j were synthesized from acetanilide and various aromatic aldehydes in presence of ethanol and sodium hydroxide solution. By refluxing the compound (1 and compounds (2a-j in presence of ethanol yielded [5-substituted-3-(phenylamino-4.5-dihydropyrazol-1yl] (3,4,5-trihydroxy phenyl-methanone (3a-j. The final compounds [5-substituted-3-(phenylamino-1H-pyrazol-1yl] (3,4,5-trihydroxyphenyl-methanone (4a-j were synthesized by treating compounds (3a-j with bromine water. The synthesized compounds have been characterized by IR, 1HNMR and Mass spectral data. The compounds were evaluated for in vivo anti-inflammatory activity by carrageenan induced paw edema test. In general all compounds were found to exhibit good anti-inflammatory activity.
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Mikx Frans HM
2006-08-01
Full Text Available Abstract Background The aim of the study was to compare the prevalence and types of HIV-related oral lesions between children and adult Tanzanian patients on HAART with those not on HAART and to relate the occurrence of the lesions with anti-HIV drug regimen, clinical stage of HIV disease and CD4+ cell count. Methods Participants were 532 HIV infected patients, 51 children and 481 adults, 165 males and 367 females. Children were aged 2–17 years and adults 18 and 67 years. Participants were recruited consecutively at the Muhimbili National Hospital (MNH HIV clinic from October 2004 to September 2005. Investigations included; interviews, physical examinations, HIV testing and enumeration of CD4+ T cells. Results A total of 237 HIV-associated oral lesions were observed in 210 (39.5% patients. Oral candidiasis was the commonest (23.5%, followed by mucosal hyperpigmentation (4.7%. There was a significant difference in the occurrence of oral candidiasis (χ2 = 4.31; df = 1; p = 0.03 and parotid enlargement (χ2 = 36.5; df = 1; p = 0.04 between children and adults. Adult patients who were on HAART had a significantly lower risk of; oral lesions (OR = 0.32; 95% CI = 0.22 – 0.47; p = 0.005, oral candidiasis (OR = 0.28; 95% CI = 0.18 – 0.44; p = 0.003 and oral hairy leukoplakia (OR = 0.18; 95% CI = 0.04 – 0.85; p = 0.03. There was no significant reduction in occurrence of oral lesions in children on HAART (OR = 0.35; 95% CI = 0.11–1.14; p = 0.15. There was also a significant association between the presence of oral lesions and CD4+ cell count 3 (χ2 = 52.4; df = 2; p = 0.006 and with WHO clinical stage (χ2 = 121; df = 3; p = 0.008. Oral lesions were also associated with tobacco smoking (χ2 = 8.17; df = 2; p = 0.04. Conclusion Adult patients receiving HAART had a significantly lower prevalence of oral lesions, particularly oral candidiasis and oral hairy leukoplakia. There was no significant change in occurrence of oral lesions in children
ANTI-MICROBIAL AND ANTI-AMOEBIC ACTIVITY SOME AZOMETHINES - POTENTIAL TEXTILE DYESTUFFS
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DJORDJEVIC Dragan
2016-05-01
Full Text Available In this paper, new synthesized three azomethine derivatives applied in dyeing textiles checking the anti-microbial properties of active components, at the same time [1-3]. The emphasis is thrown on the verification of anti-microbial properties that are important for obtaining textile with significantly improved performance. All compounds were characterized and evaluated for their anti-microbial activity against 7 pathogenic bacteria, 1 parasitic protozoan and 1 fungus. It estimated anti-bacterial activity in vitro against the following microorganisms Staphylococcus aureus, Bacillus anthracis, Streptococcus faecalis, Enterobacter sp., Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Candida albicans. The anti-amoebic activity in vitro was evaluated against the HM1: IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. The synthesized azomethines, showed very good substantivity for wool fibers, gave fine coloring, with good degree of exhaustion after dyeing. The combination of extended synthetic analogues of natural molecules leads to discovery of chemical entities which might be excellent anti-microbial and anti-amoebic compounds as depicted in our results. Being highly the effects this compound can be explored in future as an option for decreasing pathogenic potential of infecting from different sources. Azomethines containing hydrazone (dyestuff 1 and phenylhydrazone (dyestuff 2 as moiety show average yield and moderate inhibition activity while azomethines containing thiosemicarbazone (dyestuff 3 as moiety show higher yield and greater inhibition activity towards gram-negative and gram-positive bacteria as well as a fungus.
Mustapha, Jelili Olaide; Emeribe, Anthony Uchenna; Nasir, Idris Abdullahi
2017-01-01
Dengue and malaria are infections, of great public health concern, especially in sub-Saharan Africa where the burden of HIV infection is high. This study was conducted to determine the seroprevalence of dengue virus IgG antibodies and dengue/malaria coinfection among febrile HIV-infected patients attending the University of Abuja Teaching Hospital, Gwagwalada, Abuja. In this cross-sectional study, blood samples from 178 consenting HIV-infected patients receiving antiretroviral therapy were collected and tested for plasmodiasis and anti-Dengue virus IgG using malaria microscopy and ELISA, respectively. Interviewer-based questionnaires were used to assess subjects' sociodemographic variables and dengue risk factors. Of the 178 screened participants, 44.4% were seropositive for dengue virus IgG antibody, whereas 29.2% were positive for Plasmodium falciparum. About 44.2% were positive for both dengue virus and P. falciparum . There was a statistical association between anti-dengue IgG and occupation ( p =0.03) but not with age, residential area, educational level and patients' gender ( p >0.05). Seroprevalence of anti-dengue specific IgG was relatively higher in participants who adopted protective measures. There was a statistical association between seroprevalence of anti-dengue IgG and adoption of preventive measures ( p <0.05). The high prevalence of malaria and dengue virus IgG indicates the need to strengthen vector control and dengue surveillance programs.
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Ali Moghadam
Full Text Available In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents.
Profiles of HIV-infected anti-retroviral therapy naïve children from Mumbai, India.
Paranjpe, Supriya Mayur; Sarkate, Purva Pankaj; Ingole, Nayana Avinash; Raut, Shweta Sadanand; Mehta, Preeti Rajeev
2016-11-01
This study aimed to investigate the demographic profiles of human immunodifficiency virus (HIV) infected anti-retroviral therapy (ART) naïve children in our hospital and their relations to the clinical, immunological and nutritional status. A cross-sectional study was conducted in an Integrated Counselling and Testing Center (ICTC) at a tertiary care hospital in Mumbai. ART naïve HIV positive children were enrolled in the study. The demographic profiles, clinical features, immunological (CD4%/CD4 count) and nutritional status of these children were recorded. The agreement between clinical, immunological and nutritional staging was determined using Cohen's kappa test. In 192 HIV-infected ART naive children enrolled with a median age of 9 years (range 3 months-14 years), 97.4% acquired infection through vertical transmission. The most common clinical presentation was fever (39.6 %), followed by generalized lymphadenopathy (32.3%), cough (22.4%) and diarrhoea (9.9%). Tuberculosis was seen in 22.9% of the children. The agreement was fair between clinical and immunological staging, and slight between nutritional, immunological and clinical staging. Perinatal transmission is the most common mode of acquiring HIV infection in children. The Prevention of Parent to Child Transmission (PPTCT) program should be strengthened for lowering the transmission rate by providing extended ART to mothers during pregnancy and breast-feeding. Tuberculosis remains a major concern in HIV-infected children. The poor correlation between WHO clinical and immunological staging emphasizes the importance of making CD4 facilities available in HIV prevalent areas. Malnutrition cannot be used as a surrogate marker for predicting stage or severity as it is common at all stages of HIV disease.
Directory of Open Access Journals (Sweden)
Lacour Nedra
2008-07-01
Full Text Available Abstract HIV expressed in genital secretions provides the inoculum from which transmitting variants are selected, both in sexual transmission and mother-to-infant transmission during partuition. Characterization of HIV levels and genotypes found in vaginal secretions and the impact of anti-retroviral therapy (ART on this virus can provide valuable insight for the prevention of HIV transmission. Vaginal HIV was evaluated in a cohort of 43 women attending a New Orleans HIV outpatient clinic. Predominant vaginal genotypes were characterized as R5- or X4-like by heteroduplex tracking analyses of the envelope V3 region. Most women (67.4% shed R5-like genotypes in vaginal secretions which was associated with elevated plasma HIV levels (≥ 10,000 copies HIV-RNA/mL and absence of ART. Because R5-like genotypes are more frequently associated with transmission, these observations suggest that the majority of women shedding HIV in genital secretions present a transmission risk. The levels of vaginal virus were similar between both groups, but shedding of X4-like genotypes was associated with lower plasma viral loads and the use of ART, suggesting that ART use may impact the genotypes of virus found in the female genital compartment.
HIV Infection Status as a Predictor of Hepatitis C Virus RNA Testing in Primary Care
Yartel, Anthony K.; Morgan, Rebecca L.; Rein, David B.; Brown, Kimberly Ann; Kil, Natalie B.; Massoud, Omar I.; Fallon, Michael B.; Smith, Bryce D.
2015-01-01
Introduction Receipt of hepatitis C virus (HCV) RNA testing following a positive HCV antibody (anti-HCV+) test result to establish current infection is a quality indicator for HCV-related care. This study examines HIV infection status as a predictor of HCV RNA test receipt after an anti-HCV+ result in the primary care setting. Methods Electronic medical records of anti-HCV+ patients from a multisite retrospective study of patients aged ≥18 years who utilized one or more primary care outpatient services during 2005–2010 were analyzed in 2014. A multivariable logistic regression model examined the independent relationships between patient characteristics and receipt of HCV RNA testing. Results Among 1,115 anti-HCV+ patients, 133 (11.9%) were also HIV-positive. Of these, 77.4% (n=103) underwent HCV RNA testing to determine current infection status. By contrast, 66.7% (n=654/980) of anti-HCV+ patients who were HIV-negative received HCV RNA testing. Following multivariable adjustment, the odds of receiving HCV RNA testing were higher among anti-HCV+ patients who were also HIV-positive (AOR=1.9, 95% CI=1.2, 3.0), compared with their HIV-negative counterparts. Elevated alanine aminotransferase level was also associated with receipt of HCV RNA testing (AOR=1.9, 95% CI=1.4, 2.4). Black race was associated with decreased odds of receiving HCV RNA testing (AOR=0.7, 95% CI=0.5, 1.0). Conclusions HIV infection status is independently associated with the likelihood of receiving HCV RNA testing following an anti-HCV+ result. One quarter of anti-HCV+ patients who were also HIV-positive and one third of their HIV-negative counterparts, respectively, did not receive testing to establish active HCV infection, which is imperative for appropriate care and treatment. PMID:25896194
International Nuclear Information System (INIS)
Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi; Rhim, Hyangshuk; Bae, Yong Soo; Choi, Soo Young; Park, Jinseu
2014-01-01
HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction
Energy Technology Data Exchange (ETDEWEB)
Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Rhim, Hyangshuk [Department of Biomedical Sciences, Department of Medical Life Sciences, College of Medicine, the Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Bae, Yong Soo [Department of Biological Science, College of Natural Sciences, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Choi, Soo Young [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Park, Jinseu, E-mail: jinpark@hallym.ac.kr [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)
2014-10-01
HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.
Bharathi, Devaraj; Vasantharaj, Seerangaraj; Bhuvaneshwari, V.
2018-05-01
The present study describes the antibacterial, anti-biofilm and photo catalytic activity of silver nanoparticles synthesized using Cordia dichotoma fruits (Cd-AgNPs) for the first time. The phyto-synthesized Cd-AgNPs were characterized by UV-Visible spectroscopy, Field emission-scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), Energy dispersive x-ray spectrometer (EDX), Fourier transform infrared spectroscopy (FT-IR), and x-ray diffraction (XRD). FE-SEM and TEM observation showed that the average size of 2–60 nm with spherical shape of Cd-AgNPs and the presence of phyto-compounds which are responsible for capping and reduction were studied by FT-IR. XRD studies revealed the face-centered cubic structure of Cd-AgNPs. The synthesized Cd-AgNPs showed significant antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, assayed using agar well diffusion method. Phyto-synthesized Cd-AgNPs exhibited more than 90% inhibition of biofilm activity formed by S. aureus and E. coli. Furthermore, photocatalytic degradation of crystal violet (CV) under UV light irradiation using Cd-AgNPs was performed. Synthesized Cd-AgNPs exhibited ∼85% degradation activity for CV. Collectively, our findings suggest that C.dichotoma is a green source for the eco-friendly synthesis of Cd-AgNPs, which further can be used as a novel biocidal agent against bacterial pathogens and a potent photo catalytic agent.
Directory of Open Access Journals (Sweden)
Roberta Maria de Oliveira Silva
2008-12-01
Full Text Available O estudo teve por objetivo conhecer e analisar o significado da realização do teste anti-HIV no pré-natal para as gestantes. Trata-se de uma pesquisa com abordagem qualitativa e foi realizada em um Hospital Escola e em uma Maternidade do município do Rio de Janeiro. Como recurso técnico-metodológico utilizou-se o discurso do sujeito coletivo (DSC. Após a análise dos discursos verificamos que para as gestantes a realização do teste significa a possibilidade de prevenir a transmissão vertical do HIV e como parte da assistência pré-natal. O pré-natal foi considerado pelas gestantes uma excelente oportunidade para a realização do teste anti HIV, para o conhecimento da condição sorológica e início precoce do tratamento. Conclui-se que o teste, para a maioria das gestantes, representa a possibilidade de proteger o filho do HIV, além de fazer parte da construção do papel materno a partir de um cuidado concreto com a saúde do bebê.El estudio que tenía para que el objetivo sepa y analice el significado de la realización del anti-VIH de la prueba en el prenatal para las mujeres embarazadas. Uno está sobre una investigación con acercamiento cualitativo y fue ejecutado en una escuela del hospital y una maternidad de la ciudad de Rio de Janeiro. Como recurso técnico-metodológico el discurso del ciudadano colectivo fue utilizado (DSC. Después de que el análisis de los discursos, nosotros verificamos que para las mujeres embarazadas la realización de la prueba significa la posibilidad para prevenir la transmisión vertical del VIH y como parte de la ayuda prenatal. El prenatal era considerado por las mujeres embarazadas una ocasión excelente para la realización del anti VIH de la prueba, para el conocimiento de la condición sorological y del principio precoz del tratamiento. Se concluye que la prueba, para la mayoría de las mujeres embarazadas, representa la posibilidad para proteger al hijo del VIH, más allá de ser
Coinfecting viruses as determinants of HIV disease.
Lisco, Andrea; Vanpouille, Christophe; Margolis, Leonid
2009-02-01
The human body constitutes a balanced ecosystem of its own cells together with various microbes ("host-microbe ecosystem"). The transmission of HIV-1 and the progression of HIV disease in such an ecosystem are accompanied by de novo infection by other microbes or by activation of microbes that were present in the host in homeostatic equilibrium before HIV-1 infection. In recent years, data have accumulated on the interactions of these coinfecting microbes-viruses in particular-with HIV. Coinfecting viruses generate negative and positive signals that suppress or upregulate HIV-1. We suggest that the signals generated by these viruses may largely affect HIV transmission, pathogenesis, and evolution. The study of the mechanisms of HIV interaction with coinfecting viruses may indicate strategies to suppress positive signals, enhance negative signals, and lead to the development of new and original anti-HIV therapies.
Targeting CXCR4 in HIV Cell-Entry Inhibition
DEFF Research Database (Denmark)
Steen, Anne; Schwartz, T W; Rosenkilde, M M
2010-01-01
CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately half of the patients - from R5 HIV-1 (CCR5 utilizing) strains to X4 HIV-1 (CXCR4 utilizing) strains. Treatment of HIV......-infected individuals with CXCR4 antagonists delays the onset of AIDS by preventing the CCR5 to CXCR4 coreceptor switch. In addition to the endogenous CXCR4 and CCR5 ligands, other chemokines, for example the human herpesvirus 8 encoded CC-chemokine, vCCL2, and modifications hereof, have proven efficient HIV-1 cell...... no oral bioavailability. The hunt for orally active small-molecule CXCR4 antagonists led to the development of monocyclam-based compounds, and recently to the non-cyclam antagonist AMD070, which is orally active and currently in Phase II clinical trial as anti-HIV treatment. Current review provides...
Current treatment of HIV/hepatitis B virus coinfection.
Iser, David M; Sasadeusz, Joseph J
2008-05-01
Coinfection with HIV and hepatitis B virus (HBV) has become a significant global health problem. Liver disease is now one of the leading causes of morbidity and mortality in individuals with HIV, particularly those with viral hepatitis. There are a number of agents available with dual activity against HIV and HBV, and effective treatment depends on understanding the potential advantages and pitfalls in using these agents. There are a number of unresolved issues in the management of HIV/HBV coinfection. These include the role of liver biopsy, the significance of normal aminotransferase levels, serum HBV DNA threshold for treatment, treatment end-points, and the treatment of HBV when HIV does not yet require treatment. Treatment of HBV should be considered in individuals with HIV/HBV coinfection with evidence of significant fibrosis (>/=F2), or with elevated serum HBV DNA levels (>2000 IU/mL). Sustained suppression of serum HBV DNA to below the level of detection by the most sensitive available assay should be the goal of therapy, and, at present, treatment of HBV in HIV/HBV coinfection is lifelong. If antiretroviral therapy is required, then two agents with anti-HBV activity should be incorporated into the regimen. If antiretroviral therapy is not required, then the options are pegylated interferon, adefovir or the early introduction of antiretroviral therapy. Close monitoring is necessary to detect treatment failure or hepatic flares, such as immune reconstitution disease. Further studies of newer anti-HBV agents in individuals HIV/HBV coinfection may advance treatment of this important condition.
Anti-HIV therapy with AZT prodrugs: AZT phosphonate derivatives, current state and prospects.
Khandazhinskaya, Anastasiya; Matyugina, Elena; Shirokova, Elena
2010-06-01
AIDS, a disease caused by human immunodeficiency virus, was called 'plague of the twentieth century'. 3'-Azido-3'-deoxythymidine (AZT), the first compound approved for the treatment of HIV, is still a mandatory component of treatment schemes. However, its toxicity stimulated a search for new agents. This review presents the history and current state of the design of AZT prodrugs based on its phosphonate derivatives. Although every effort was made to include as many AZT structures bearing phosphonate residues and demonstrate the variety they offer, we also concentrated on the studies performed in our laboratory. Special attention was also paid to AZT 5'-H-phosphonate (phosphazide, Nikavir) approved in the Russian Federation as a drug for the prevention and treatment of HIV infection. The prodrug strategy applied to AZT phosphonate derivatives enriched chemistry, biology and medicine not only with new knowledge, methods and structures, but also with a new anti-HIV drug Nikavir. Currently, study of another phosphonate, AZT 5'-aminocarbonylphosphonate, is underway. Slow release of AZT following oral administration and penetration into cells, decreased toxicity and the lack of cumulative properties make the compounds of this group promising as extended-release forms of AZT.
Systemic Immune Activation and HIV Shedding in the Female Genital Tract.
Spencer, LaShonda Y; Christiansen, Shawna; Wang, Chia-Hao H; Mack, Wendy J; Young, Mary; Strickler, Howard D; Anastos, Kathryn; Minkoff, Howard; Cohen, Mardge; Geenblatt, Ruth M; Karim, Roksana; Operskalski, Eva; Frederick, Toni; Homans, James D; Landay, Alan; Kovacs, Andrea
2016-02-01
Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38(+)DR(+) and CD38(-)DR(-)) on CD4(+) and CD8(+) T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. In the univariate model, higher levels of CD4(+) and CD8(+) T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8(+) T cells (CD38(-)DR(-)) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02). The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV
Tang, Jing; Vernekar, Sanjeev Kumar V; Chen, Yue-Lei; Miller, Lena; Huber, Andrew D; Myshakina, Nataliya; Sarafianos, Stefan G; Parniak, Michael A; Wang, Zhengqiang
2017-06-16
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Li, Yang; Wu, Yanbin; Yan, Aixia
2017-07-01
HIV-1 integrase (IN) is a promising target for anti-AIDS therapy, and LEDGF/p75 is proved to enhance the HIV-1 integrase strand transfer activity in vitro. Blocking the interaction between IN and LEDGF/p75 is an effective way to inhibit HIV replication infection. In this work, 274 LEDGF/p75-IN inhibitors were collected as the dataset. Support Vector Machine (SVM), Decision Tree (DT), Function Tree (FT) and Random Forest (RF) were applied to build several computational models for predicting whether a compound is an active or weakly active LEDGF/p75-IN inhibitor. Each compound is represented by MACCS fingerprints and CORINA Symphony descriptors. The prediction accuracies for the test sets of all the models are over 70 %. The best model Model 3B built by FT obtained a prediction accuracy and a Matthews Correlation Coefficient (MCC) of 81.08 % and 0.62 on test set, respectively. We found that the hydrogen bond and hydrophobic interactions are important for the bioactivity of an inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Ragno, Rino; Artico, Marino; De Martino, Gabriella; La Regina, Giuseppe; Coluccia, Antonio; Di Pasquali, Alessandra; Silvestri, Romano
2005-01-13
Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.
Anti-inflammatory and anti-oxidant activities of Secamone afzelii ...
African Journals Online (AJOL)
. This study re-ports the anti-inflammatory and antioxidant properties of S. afzelii. The anti-inflammatory activity was determined by the carrageenan-induced paw oedema method in 7 day old chicks and antioxi-dant property by the 2 ...
Mangasuli, Sumitra N; Hosamani, Kallappa M; Devarajegowda, Hirihalli C; Kurjogi, Mahantesh M; Joshi, Shrinivas D
2018-02-25
A series of novel coumarin-theophylline hybrids were synthesized and examined for their anti-tubercular activity in vitro against Mycobacterium tuberculosis H 37 Rv, anti-microbial activity in vitro against gram-positive bacteria (Staphylococcus aureus) and gram-negative bacterias (Escherichia coli, Salmonella typhi) as well as fungi (Candida albicans). The compound (3a) has shown excellent anti-tubercular activity with MIC of 0.12 μg/mL. Electron donating compounds (3a, 3f) have displayed significant anti-microbial activity. The compounds have also been precisely elucidated using single crystal X-ray diffraction techniques. Molecular docking study has been performed against 4DQU enzyme of Mycobacterium tuberculosis showed good binding interactions and is in agreement with the in vitro results. Copyright © 2018. Published by Elsevier Masson SAS.
Pachulska-Wieczorek, Katarzyna; Stefaniak, Agnieszka K; Purzycka, Katarzyna J
2014-07-03
The nucleocapsid domain of Gag and mature nucleocapsid protein (NC) act as nucleic acid chaperones and facilitate folding of nucleic acids at critical steps of retroviral replication cycle. The basic N-terminus of HIV-1 NC protein was shown most important for the chaperone activity. The HIV-2 NC (NCp8) and HIV-1 NC (NCp7) proteins possess two highly conserved zinc fingers, flanked by basic residues. However, the NCp8 N-terminal domain is significantly shorter and contains less positively charged residues. This study characterizes previously unknown, nucleic acid chaperone activity of the HIV-2 NC protein. We have comparatively investigated the in vitro nucleic acid chaperone properties of the HIV-2 and HIV-1 NC proteins. Using substrates derived from the HIV-1 and HIV-2 genomes, we determined the ability of both proteins to chaperone nucleic acid aggregation, annealing and strand exchange in duplex structures. Both NC proteins displayed comparable, high annealing activity of HIV-1 TAR DNA and its complementary nucleic acid. Interesting differences between the two NC proteins were discovered when longer HIV substrates, particularly those derived from the HIV-2 genome, were used in chaperone assays. In contrast to NCp7, NCp8 weakly facilitates annealing of HIV-2 TAR RNA to its complementary TAR (-) DNA. NCp8 is also unable to efficiently stimulate tRNALys3 annealing to its respective HIV-2 PBS motif. Using truncated NCp8 peptide, we demonstrated that despite the fact that the N-terminus of NCp8 differs from that of NCp7, this domain is essential for NCp8 activity. Our data demonstrate that the HIV-2 NC protein displays reduced nucleic acid chaperone activity compared to that of HIV-1 NC. We found that NCp8 activity is limited by substrate length and stability to a greater degree than that of NCp7. This is especially interesting in light of the fact that the HIV-2 5'UTR is more structured than that of HIV-1. The reduced chaperone activity observed with NCp8 may
Jain, Mamta K; Parekh, Nimisha K; Hester, Jill; Lee, William M
2006-12-01
Discerning drug hepatotoxicity from viral hepatitis flares remains an ongoing problem unique to patients coinfected with HIV and hepatitis B (HBV). We present three such coinfected patients who have been on two anti-HBV agents, lamivudine and tenofovir disoproxil fumarate simultaneously, as part of highly active antiretroviral therapy (HAART). All three developed significant aminotransferase elevations 6-12 weeks after initiation of HAART despite being on two active HBV drugs. Two of the three patients were initially thought to have drug-related hepatotoxicity from HIV medications. It seems more likely that all three patients demonstrated hepatitis B reactivation of differing severity as the result of varying degrees of immune recovery. Distinguishing clearly between drug-related hepatotoxicity and hepatitis reactivation may be difficult but is important as their clinical management differs.
International Nuclear Information System (INIS)
Pessoa-Mahana, David; Nunez, Andres; Espinosa, Christian; Mella-Raipn, Jaime; Pessoa-Mahana, Hernan
2010-01-01
The synthesis of a series of substituted arylpiperazines linked to a 2-(pyridin-3-yl)-1H-benzo[d]imidazole scaffold through an alkylic linker is reported. The novel 1-(2-(4-arylpiperazin-1-yl)alkyl)-2-(pyridin-3-yl)-1H-benzimidazole derivatives are structurally related to the anti-HIV-1 drug Delavirdine and belong to the bis(heteroaryl)piperazines family (BHAPs), a well known HIV-1 reverse transcriptase inhibitors group. (author)
Innate immune recognition and activation during HIV infection
Directory of Open Access Journals (Sweden)
Larsen Carsten S
2010-06-01
Full Text Available Abstract The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis.
O’Rourke, Aubrie
2016-02-04
The sponge Stylissa carteri is known to produce a number of secondary metabolites displaying anti-fouling, anti-inflammatory, and anti-cancer activity. However, the anti-viral potential of metabolites produced by S. carteri has not been extensively explored. In this study, an S. carteri extract was HPLC fractionated and a cell based assay was used to evaluate the effects of HPLC fractions on parameters of Human Immunodeficiency Virus (HIV-1) infection and cell viability. Candidate HIV-1 inhibitory fractions were then analyzed for the presence of potential HIV-1 inhibitory compounds by mass spectrometry, leading to the identification of three previously characterized compounds, i.e., debromohymenialdisine (DBH), hymenialdisine (HD), and oroidin. Commercially available purified versions of these molecules were re-tested to assess their antiviral potential in greater detail. Specifically, DBH and HD exhibit a 30%–40% inhibition of HIV-1 at 3.1 μM and 13 μM, respectively; however, both exhibited cytotoxicity. Conversely, oroidin displayed a 50% inhibition of viral replication at 50 μM with no associated toxicity. Additional experimentation using a biochemical assay revealed that oroidin inhibited the activity of the HIV-1 Reverse Transcriptase up to 90% at 25 μM. Taken together, the chemical search space was narrowed and previously isolated compounds with an unexplored anti-viral potential were found. Our results support exploration of marine natural products for anti-viral drug discovery.
Synthesis, in vitro anti-inflammatory activity and molecular docking ...
Indian Academy of Sciences (India)
alkyl and heterocyclic alkyl moieties were synthesized, characterized and subsequently evaluated for ... Docking studies with these compounds against cyclooxygenase-2 receptor ...... thiadiazole derivatives as possible anti-tubercular agents.
Nakamura, H; Motoyoshi, S; Imazu, C; Ishii, K; Yokoyama, Y; Seto, Y; Kadokawa, T; Shimizu, M
1982-08-01
Anti-inflammatory, analgesic, and anti-pyretic activities of orally administered etofenamate, the diethylene glycol ester of flufenamic acid, were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice and ultra-violet light-induced erythema in guinea pigs, etofenamate produced a dose related inhibition at doses of 40--320 mg/kg and 5--20 mg/kg, respectively. In rats, felt-pellet-induced granuloma formation and adjuvant-induced arthritis were significantly inhibited by repeated administration of etofenamate at doses of 20 mg/kg/day for 5 days and 40 mg/kg/day for 21 days, respectively. Etofenamate showed an inhibitory activity on the squeak response caused by flexing and extending the silver nitrate-induced arthritic joint in rats; and it produced a dose related anti-writhing activity at doses of 50--300 mg/kg and 10--80 mg/kg in mice and rats, respectively, in the acetic acid-induced writhing test. Etofenamate showed a significant anti-pyretic activity at doses of 0.2 mg/kg or more. These potencies of etofenamate were 0.5 to 1.6 times those of flufenamic acid. In particular, the anti-erythema, anti-arthritis, and anti-pyretic activities of etofenamate were approximately equivalent to or superior to those of flufenamic acid. From these results, it was suggested that etofenamate given orally, like other non-steroidal anti-inflammatory drugs, showed anti-inflammatory, analgesic, and anti-pyretic activities in experimental animals.
Directory of Open Access Journals (Sweden)
Ying Pan
2013-01-01
Full Text Available Alzheimer’s disease (AD pathogenesis involves an imbalance between free radical formation and destruction. In order to obtain a novel preclinical anti-AD drug candidate, we synthesized a series of novel hydroxyl chalcone analogs which possessed anti-free radical activity, and screened their effects on scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH and OH free radicals in vitro. Compound C7, 4,2'-dihydroxy-3,5-dimethoxychalcone was found to have potent activity in these anti-free radical activity tests. Further research revealed that C7 could elevate glutathione peroxidase (GSH-PX and super oxide dismutase (SOD levels and lower malonaldehyde (MDA level in vivo in the Alzheimer’s model. The indication of C7’s effect on AD needs further study.
DEFF Research Database (Denmark)
Wong, E. B.; Xulu, B.; Prakadan, S.
2016-01-01
Tuberculosis remains the leading cause of death in HIV-positive people. A better understanding of the impact of HIV on lung immunity may lead to novel immunotherapeutic interventions. MAIT cells are tissue-homing donor-unrestricted T cells with broad anti-microbial activity. HIV infection causes ...... to determine the mechanisms underlying the altered phenotypes of lung-resident MAITs and whether these can be targeted to improve anti-microbial lung immunity in people living with HIV....
Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity.
Lan, Junjie; Huang, Lan; Lou, Huayong; Chen, Chao; Liu, Tangjingjun; Hu, Shengcao; Yao, Yao; Song, Junrong; Luo, Jun; Liu, Yazhou; Xia, Bin; Xia, Lei; Zeng, Xueyi; Ben-David, Yaacov; Pan, Weidong
2018-01-01
Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9). Compound 4g showed strongest cytotoxic effect against PC3 cells with IC 50 value of 0.64 μM, which was 12-fold, 31-fold and 26-fold lower than the parental tetrandrine, 5-fluorouracil and cisplatin, respectively. Preliminary structure-activity relationship study indicated that urea subsititution was the key pharmacophore for the enhancement of their antitumor activities. Induction of apoprosis by 4g was associated with the activation of pro-apoptotic protein BAX and inhibition of antiapoptosis proteins survivin as well as Bcl-2. Moreover, activation of caspases led to increase cleavage of PARP, which further accelerates apoptotic cell death. These results reveal that the compound 4g may be used as a potential anticancer drug candidate. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Discovery of drugs that possess activity against feline leukemia virus.
Greggs, Willie M; Clouser, Christine L; Patterson, Steven E; Mansky, Louis M
2012-04-01
Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use.
Docking Studies and Anti-inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids
Directory of Open Access Journals (Sweden)
Ivan O. Juranic
2008-03-01
Full Text Available The article describes a two-step synthesis of diastereomeric 3-hydroxy-2-methyl-3-(4-biphenylylbutanoic acids. In the first step an intermediate α-bromo propanoicacid 1-ethoxyethyl ester was synthesized. The second step is a new modified Reformatskyreaction in presence of Zn in tetrahydrofuran (THF at –5 to 10 °C between the previouslysynthesized intermediate and 4-acetylbiphenyl. Synthesis of the other studied β-hydroxy-β-arylpropanoic acids has already been reported. These β-hydroxy-β-arylpropanoic acidsbelong to the arylpropanoic acid class of compounds, structurally similar to the NSAIDssuch as ibuprofen. The anti-inflammatory activity and gastric tolerability of thesynthesized compounds were evaluated. Molecular docking experiments were carried outto identify potential COX-2 inhibitors among the β-hydroxy-β-aryl-alkanoic acids class.The results indicate that all compounds possess significant anti-inflammatory activity afteroral administration and that the compounds 2-(9-(9-hydroxy-fluorenyl-2-methylpropanoic acid (5 and 3-hydroxy-3,3-diphenyl-propanoic acid (3 possess thestrongest anti-inflammatory activity, comparable to that of ibuprofen, a standard NSAID,and that none of tested substances or ibuprofen produced any significant gastric lesions.
International Nuclear Information System (INIS)
Muhammad, N.; Ali, S.; Shahzadi, S.; Khan, A.N.
2008-01-01
Oxovanadium(IV) complexes with four different non-steroidal anti-inflammatory drugs have been synthesized. These complexes were characterized by different analytical techniques such as CHN, IR, UV-Vis spectroscopy, and mass spectrometry. The IR data show the bidentate nature of the ligands and reveal hexacoordinate geometry in the solid state. The complexes were tested for their biological activity against six different bacterial strains and plant pathogens, and all complexes showed good biological activity with few exceptions [ru
Chiozzini, Chiara; Arenaccio, Claudia; Olivetta, Eleonora; Anticoli, Simona; Manfredi, Francesco; Ferrantelli, Flavia; d'Ettorre, Gabriella; Schietroma, Ivan; Andreotti, Mauro; Federico, Maurizio
2017-09-01
Intact HIV-1 and exosomes can be internalized by dendritic cells (DCs) through a common pathway leading to their transmission to CD4 + T lymphocytes by means of mechanisms defined as trans-infection and trans-dissemination, respectively. We previously reported that exosomes from HIV-1-infected cells activate both uninfected quiescent CD4 + T lymphocytes, which become permissive to HIV-1, and latently infected cells, with release of HIV-1 particles. However, nothing is known about the effects of trans-dissemination of exosomes produced by HIV-1-infected cells on uninfected or latently HIV-1-infected CD4 + T lymphocytes. Here, we report that trans-dissemination of exosomes from HIV-1-infected cells induces cell activation in resting CD4 + T lymphocytes, which appears stronger with mature than immature DCs. Using purified preparations of both HIV-1 and exosomes, we observed that mDC-mediated trans-dissemination of exosomes from HIV-1-infected cells to resting CD4 + T lymphocytes induces efficient trans-infection and HIV-1 expression in target cells. Most relevant, when both mDCs and CD4 + T lymphocytes were isolated from combination anti-retroviral therapy (ART)-treated HIV-1-infected patients, trans-dissemination of exosomes from HIV-1-infected cells led to HIV-1 reactivation from the viral reservoir. In sum, our data suggest a role of exosome trans-dissemination in both HIV-1 spread in the infected host and reactivation of the HIV-1 reservoir.
Korolevskaya, Larisa B; Shmagel, Konstantin V; Shmagel, Nadezhda G; Saidakova, Evgeniya V
2016-03-01
Currently, immune activation is proven to be the basis for the HIV infection pathogenesis and a strong predictor of the disease progression. Among the causes of systemic immune activation the virus and its products, related infectious agents, pro-inflammatory cytokines, and regulatory CD4+ T cells' decrease are considered. Recently microbial translocation (bacterial products yield into the bloodstream as a result of the gastrointestinal tract mucosal barrier integrity damage) became the most popular hypothesis. Previously, we have found an association between immune complexes present in the bloodstream of HIV infected patients and the T cell activation. On this basis, we propose a significantly modified hypothesis of immune activation in HIV infection. It is based on the immune complexes' participation in the immunocompetent cells' activation. Immune complexes are continuously formed in the chronic phase of the infection. Together with TLR-ligands (viral antigens, bacterial products coming from the damaged gut) present in the bloodstream they interact with macrophages. As a result macrophages are transformed into the type II activated forms. These macrophages block IL-12 production and start synthesizing IL-10. High level of this cytokine slows down the development of the full-scale Th1-response. The anti-viral reactions are shifted towards the serogenesis. Newly synthesized antibodies' binding to viral antigens leads to continuous formation of the immune complexes capable of interacting with antigen-presenting cells. Copyright © 2016 Elsevier Ltd. All rights reserved.
A novel strategy for efficient production of anti-V3 human scFvs against HIV-1 clade C
Directory of Open Access Journals (Sweden)
Kumar Rajesh
2012-11-01
Full Text Available Abstract Background Production of human monoclonal antibodies that exhibit broadly neutralizing activity is needed for preventing HIV-1 infection, however only a few such antibodies have been generated till date. Isolation of antibodies by the hybridoma technology is a cumbersome process with fewer yields. Further, the loss of unstable or slowly growing clones which may have unique binding specificities often occurs during cloning and propagation and the strongly positive clones are often lost. This has been avoided by the process described in this paper, wherein, by combining the strategy of EBV transformation and recombinant DNA technology, we constructed human single chain variable fragments (scFvs against the third variable region (V3 of the clade C HIV-1 envelope. Results An antigen specific phage library of 7000 clones was constructed from the enriched V3- positive antibody secreting EBV transformed cells. By ligation of the digested scFv DNA into phagemid vector and bio panning against the HIV-1 consensus C and B V3 peptides followed by random selection of 40 clones, we identified 15 clones that showed V3 reactivity in phage ELISA. DNA fingerprinting analysis and sequencing showed that 13 out of the 15 clones were distinct. Expression of the positive clones was tested by SDS-PAGE and Western blot. All the 13 anti-V3 scFvs showed cross-reactivity against both the clade C and B V3 peptides and did not show any reactivity against other unrelated peptides in ELISA. Preliminary neutralization assays indicated varying degrees of neutralization of clade C and B viruses. EBV transformation, followed by antigen selection of lines to identify specific binders, enabled the selection of phage from un-cloned lines for scFv generation, thus avoiding the problems of hybridoma technology. Moreover, as the clones were pretested for antigen binding, a comparatively small library sufficed for the selection of a considerable number of unique antigen binding
Heterosexual transmission of HIV in Greece.
Roumelioutou-Karayannis, A; Nestoridou, K; Mandalaki, T; Stefanou, T; Papaevangelou, G
1988-06-01
To provide further evidence for the heterosexual transmission of the acquired immunodeficiency syndrome (AIDS) in Greece we examined 53 Greek female steady heterosexual partners of 53 anti-HIV-positive men. Human immunodeficiency virus (HIV) transmission was estimated by the detection of anti-HIV antibodies. Our results showed that 27.8% (5 of 18) of the female partners of bisexuals, 33.3% (2 of 6) of intravenous drug abusers (IVDA), and 100% (4 of 4) of those who had lived for a long time in Africa were found anti-HIV positive. In contrast, only 4% (1 of 25) of the studied sexual partners of hemophiliac carriers were found to be HIV seropositive. The use of condoms seemed to be the most important factor in reducing HIV transmission. According to our results the duration of sexual relationships and the practice of anal intercourse did not increase the possibility of seroconversion. These results confirm the heterosexual transmission of HIV. However, further studies should be conducted to evaluate the relative role of various risk factors and the overall importance of heterosexual spread of HIV infections.
Vasavi, Halkare Suryanarayana; Arun, Ananthapadmanabha Bhagwath; Rekha, Punchapady-Devasya
2014-05-01
Psidium guajava L., which has been used traditionally as a medicinal plant, was explored for anti-quorum sensing (QS) activity. The anti-QS activity of the flavonoid (FL) fraction of P. guajava leaves was determined using a biosensor bioassay with Chromobacterium violaceum CV026. Detailed investigation of the effects of the FL-fraction on QS-regulated violacein production in C. violaceum ATCC12472 and pyocyanin production, proteolytic, elastolytic activities, swarming motility and biofilm formation in Pseudomonas aeruginosa PAO1 was performed using standard methods. Possible mechanisms of QS-inhibition were studied by assessing violacein production in response to N-acyl homoserine lactone (AHL) synthesis in the presence of the FL-fraction in C. violaceum ATCC31532 and by evaluating the induction of violacein in the mutant C. violaceum CV026 by AHL extracted from the culture supernatants of C. violaceum 31532. Active compounds in the FL-fraction were identified by liquid chromatography-mass spectrometry (LC-MS). Inhibition of violacein production by the FL-fraction in a C. violaceum CV026 biosensor bioassay indicated possible anti-QS activity. The FL-fraction showed concentration-dependent decreases in violacein production in C. violaceum 12472 and inhibited pyocyanin production, proteolytic and elastolytic activities, swarming motility and biofilm formation in P. aeruginosa PAO1. Interestingly, the FL-fraction did not inhibit AHL synthesis; AHL extracted from cultures of C. violaceum 31532 grown in the presence of the FL-fraction induced violacein in the mutant C. violaceum CV026. LC-MS analysis revealed the presence of quercetin and quercetin-3-O-arabinoside in the FL-fraction. Both quercetin and quercetin-3-O-arabinoside inhibited violacein production in C. violaceum 12472, at 50 and 100 μg/mL, respectively. Results of this study provide scope for further research to exploit these active molecules as anti-QS agents. © 2014 The Societies and Wiley Publishing
Biological activities (anti-inflammatory and anti-oxidant) of fractions ...
African Journals Online (AJOL)
Biological activities (anti-inflammatory and anti-oxidant) of fractions and methanolic extract of Philonotis hastate (Duby Wijk & MargaDant). ... The fractions and methanolic extract exhibited moderate antioxidant potentials with various models. The flavonoid contents of the methanol extract and fractions ranged between 1.70 ...
Jin, Weihua; Liu, Ge; Zhong, Weihong; Sun, Chaomin; Zhang, Quanbin
2017-12-01
Monthly variations of polysaccharides from Sargassum thunbergii and their anti-complement and anti-tumour activities were investigated. It was observed that an increase in fucose and total sugar contents occurred during the growth period (from early April to mid-June), accompanied by a decrease in molar ratios of other monosaccharides to fucose. The highest yields were obtained from early July to early September, which was in accordance with the significant increase in molar ratio of glucose to fucose and decrease in molar ratio of other monosaccharides to fucose. And the above results suggested that S. Thunbergii synthesized large amount of laminaran, the storage substance of brown algae, during the senescence period. However, sulfate contents were relatively stable in the life cycle of S. thunbergii. These results suggested that S. thunbergii synthesized complex sulfated heteropolysacchairdes during inactive period, while during other periods, it synthesized more sulfated galactofucan. All polysaccharides showed anti-complement activity, suggesting that the harvesting time did not influence the anti-complement activities. In the anti-tumour assay in vitro, the polysaccharides taken during the senescence period had much lower anti-tumour activity, suggesting that fucoidan, but not laminaran, determined the anti-tumour activities. Therefore, polysaccharides from S. thunbergii might have great potential in anti-complement and anti-tumour application. Copyright © 2017 Elsevier B.V. All rights reserved.
Boons, Eline; Li, Guangdi; Vanstreels, Els; Vercruysse, Thomas; Pannecouque, Christophe; Vandamme, Anne-Mieke; Daelemans, Dirk
2014-12-01
The HIV Rev protein mediates the transport of partially and unspliced HIV mRNA from the nucleus to the cytoplasm. Rev multimerizes on a secondary stem-loop structure present in the viral intron-containing mRNA species and recruits the cellular karyopherin CRM1 to export viral mRNAs from the nucleus to the cytoplasm. Previously we have identified a single-domain intrabody (Nb(190)), derived from a llama heavy-chain antibody, which efficiently inhibits Rev multimerization and suppresses the production of infectious virus. We recently mapped the epitope of this nanobody and demonstrated that Rev residues K20 and Y23 are crucial for interaction while residues V16, H53 and L60 are important to a lesser extent. Here, we generated cell lines stably expressing Nb(190) and assessed the capacity of these cell lines to suppress the replication of different HIV-1 subtypes. These cells stably expressing the single-domain antibody are protected from virus-induced cytopathogenic effect even in the context of high multiplicity of infection. In addition, the replication of different subtypes of group M and one strain of group O is significantly suppressed in these cell lines. Next, we analysed the natural variations of Rev amino acids in sequence samples from HIV-1 infected patients worldwide and assessed the effect of Nb(190) on the most prevalent polymorphisms occurring at the key epitope positions (K20 and Y23) in Rev. We found that Nb(190) was able to suppress the function of these Rev variants except for the K20N mutant, which was present in only 0.7% of HIV-1 sequence populations (n = 4632). Cells stably expressing the single-domain intrabody Nb(190) are protected against virus-induced cytopathogenic effect and display a selective survival advantage upon infection. In addition, Nb(190) suppresses the replication of a wide range of different HIV-1 subtypes. Large-scale sequence analysis reveals that the Nb(190) epitope positions in Rev are well conserved across major HIV-1
Solomon, Ajantha; Ghneim, Khader; Ahlers, Jeffrey; Cameron, Mark J.; Smith, Miranda Z.; Spelman, Tim; McMahon, James; Velayudham, Pushparaj; Brown, Gregor; Roney, Janine; Watson, Jo; Prince, Miles H.; Hoy, Jennifer F.; Chomont, Nicolas; Fromentin, Rémi; Procopio, Francesco A.; Zeidan, Joumana; Palmer, Sarah; Odevall, Lina; Johnstone, Ricky W.; Martin, Ben P.; Sinclair, Elizabeth; Deeks, Steven G.; Hazuda, Daria J.; Cameron, Paul U.; Sékaly, Rafick-Pierre; Lewin, Sharon R.
2014-01-01
Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. Trial Registration ClinicalTrials.gov NCT01365065 PMID:25393648
Directory of Open Access Journals (Sweden)
Julian H Elliott
2014-10-01
Full Text Available Human immunodeficiency virus (HIV persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART. The primary endpoint was change in cell associated unspliced (CA-US HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065. Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90% with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1. CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.ClinicalTrials.gov NCT01365065.
Nguyen, Marie; Pean, Polidy; Lopalco, Lucia; Nouhin, Janin; Phoung, Viseth; Ly, Nary; Vermisse, Pierre; Henin, Yvette; Barré-Sinoussi, Françoise; Burastero, Samuele E; Reynes, Jean-Marc; Carcelain, Guislaine; Pancino, Gianfranco
2006-08-01
To study biological factors related to protection against HIV-1 infection in Cambodia, we recruited 48 partners of HIV-1-infected patients who remained uninfected (exposed uninfected individuals, EUs) despite unprotected sexual intercourse for more than 1 year and 49 unexposed controls (UCs). HIV-1-specific antibodies (IgA anti-gp41 and IgG anti-CD4-gp120 complex), T-cell responses, and cellular factors that may be involved in protection (peripheral blood mononuclear cell [PBMC] resistance to HIV-1 infection and beta-chemokine production) were evaluated. Anti-HIV-1 antibodies were higher in EUs than those in UCs (P = 0.01 and P = 0.04 for anti-gp41 and anti-CD4-gp120, respectively). We observed a decreased susceptibility to a primary Cambodian isolate, HIV-1KH019, in EU PBMCs as compared with UC PBMCs (P = 0.03). A weak T-cell response to one pool of HIV-1 Gag peptides was found by ELISpot in 1 of 19 EUs. Whereas T-cell specific immunity was not associated to protection, our results suggest that HIV-specific humoral immunity and reduced cell susceptibility to infection may contribute to protection against HIV-1 infection in Cambodian EUs.
Alcolea Palafox, M.; Kattan, D.; Afseth, N. K.
2018-04-01
A theoretical and experimental vibrational study of the anti-HIV d4T (stavudine or Zerit) nucleoside analogue was carried out. The predicted spectra in the three most stable conformers in the biological active anti-form of the isolated state were compared. Comparison of the conformers with those of the natural nucleoside thymidine was carried out. The calculated spectra were scaled by using different scaling procedures and three DFT methods. The TLSE procedure leads to the lowest error and is thus recommended for scaling. With the population of these conformers the IR gas-phase spectra were predicted. The crystal unit cell of the different polymorphism forms of d4T were simulated through dimer forms by using DFT methods. The scaled spectra of these dimer forms were compared. The FT-IR spectrum was recorded in the solid state in the 400-4000 cm-1 range. The respective vibrational bands were analyzed and assigned to different normal modes of vibration by comparison with the scaled vibrational values of the different dimer forms. Through this comparison, the polymorphous form of the solid state sample was identified. The study indicates that d4T exist only in the ketonic form in the solid state. The results obtained were in agreement with those determined in related anti-HIV nucleoside analogues.
Dezzutti, Charlene S; Yandura, Sarah; Wang, Lin; Moncla, Bernard; Teeple, Elizabeth A; Devlin, Brid; Nuttall, Jeremy; Brown, Elizabeth R; Rohan, Lisa C
2015-11-01
Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission. 0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety. The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm(2)/min(1/2)), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm(2)/min(1/2)). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe. The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.
Lee, Kwang Sik; Kim, Bo Yeon; Yoon, Hyung Joo; Choi, Yong Soo; Jin, Byung Rae
2016-10-01
Bee venom contains a variety of peptide constituents that have various biological, toxicological, and pharmacological actions. However, the biological actions of secapin, a venom peptide in bee venom, remain largely unknown. Here, we provide the evidence that Asiatic honeybee (Apis cerana) secapin (AcSecapin-1) exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial activities. The recombinant mature AcSecapin-1 peptide was expressed in baculovirus-infected insect cells. AcSecapin-1 functions as a serine protease inhibitor-like peptide that has inhibitory effects against plasmin, elastases, microbial serine proteases, trypsin, and chymotrypsin. Consistent with these functions, AcSecapin-1 inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products, thus indicating the role of AcSecapin-1 as an anti-fibrinolytic agent. AcSecapin-1 also inhibited both human neutrophil and porcine pancreatic elastases. Furthermore, AcSecapin-1 bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi and gram-positive and gram-negative bacteria. Taken together, our data demonstrated that the bee venom peptide secapin has multifunctional roles as an anti-fibrinolytic agent during fibrinolysis and an anti-microbial agent in the innate immune response. Copyright © 2016 Elsevier Ltd. All rights reserved.
Anti-cancer activities of Ganoderma lucidum: active ingredients and pathways
Directory of Open Access Journals (Sweden)
Chi H.J. Kao
2013-02-01
Full Text Available ABSTRACTGanoderma lucidum, commonly referred to as Lingzhi, has been used in Asia for health promotion for centuries. The anti-cancer effects of G. lucidum have been demonstrated in both in vitro and in vivo studies. In addition, the observed anti-cancer activities of Ganoderma have prompted its usage by cancer patients alongside chemotherapy.The main two bioactive components of G. lucidum can be broadly grouped into triterpenes and polysaccharides. Despite triterpenes and polysaccharides being widely known as the major active ingredients, the different biological pathways by which they exert their anti-cancer effect remain poorly defined. Therefore, understanding the mechanisms of action may lead to more widespread use of Ganoderma as an anti-cancer agent.The aim of this paper is to summarise the various bioactive mechanisms that have been proposed for the anti-cancer properties of triterpenes and polysaccharides extracted from G. lucidum. A literature search of published papers on NCBI with keywords “Ganoderma” and “cancer” was performed. Among those, studies which specifically examined the anti-cancer activities of Ganoderma triterpenes and polysaccharides were selected to be included in this paper.We have found five potential mechanisms which are associated with the anti-cancer activities of Ganoderma triterpenes and three potential mechanisms for Ganoderma polysaccharides. In addition, G. lucidum has been used in combination with known anti-cancer agents to improve the anti-cancer efficacies. This suggests Ganoderma’s bioactive pathways may compliment that of anti-cancer agents. In this paper we present several potential anti-cancer mechanisms of Ganoderma triterpenes and polysaccharides which can be used for the development of Ganoderma as an anti-cancer agent.
Kremb, Stephan
2014-08-21
In recent years, marine algae have emerged as a rich and promising source of molecules with potent activities against various human pathogens. The widely distributed brown alga Lobophora variegata that is often associated with tropical coral reefs exerts strong antibacterial and antiprotozoal effects, but so far has not been associated with specific anti-viral activities. This study investigated potential HIV-1 inhibitory activity of L. variegata collected from different geographical regions, using a cell-based full replication HIV-1 reporter assay. Aqueous L. variegata extracts showed strong inhibitory effects on several HIV-1 strains, including drug-resistant and primary HIV-1 isolates, and protected even primary cells (PBMC) from HIV-1-infection. Anti-viral potency was related to ecological factors and showed clear differences depending on light exposition or epiphyte growth. Assays addressing early events of the HIV-1 replication cycle indicated that L. variegata extracts inhibited entry of HIV-1 into cells at a pre-fusion step possibly by impeding mobility of virus particles. Further characterization of the aqueous extract demonstrated that even high doses had only moderate effects on viability of cultured and primary cells (PBMCs). Imaging-based techniques revealed extract effects on the plasma membrane and actin filaments as well as induction of apoptosis at concentrations exceeding EC50 of anti-HIV-1 activity by more than 400 fold. In summary, we show for the first time that L. variegata extracts inhibit HIV-1 entry, thereby suggesting this alga as promising source for the development of novel HIV-1 inhibitors.
Rawson, Jonathan M.; Heineman, Richard H.; Beach, Lauren B.; Martin, Jessica L.; Schnettler, Erica K.; Dapp, Michael J.; Patterson, Steven E.; Mansky, Louis M.
2013-01-01
The nucleoside analog 5,6-dihydro-5-aza-2’-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C ...
AIDS in the Third World: how to stop the HIV infection?
De Clercq, E
2007-01-01
Of the 38.6 million people living with HIV/AIDS globally, almost 25 million (65%) live in sub-Saharan Africa. Preventive strategies and measures fall short, often simply because they are not available or are largely male-controlled. A preventive HIV vaccine is still far away; hence the drive to develop alternative prevention technologies, such as microbicides and oral pre-exposure prophylaxis, that could be female controlled. There are, at present, twenty-two anti-HIV drugs which have been formally licensed for clinical use in the treatment of HIV infections (AIDS): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir and enfuvirtide. These compounds, in combination, form the basis of HAART (highly active antiretroviral therapy), which has led to the development of a single daily pill existing of the combination of tenofovir disoproxil fumarate, emtricitabine and efavirenz, which has to be taken orally once daily for the treatment of AIDS. Beyond development of new drugs and clinical evaluation of existing medications, several companies within the pharmaceutical industry have established innovative policies that provide HIV medications at affordable prices in the least-developed countries. Reduced pricing is not alone a solution, and thus companies are actively working in partnership with the World Health Organization and other multinational groups to address roadblocks such as complex registration and procurement systems. Even in this period of successful anti-HIV therapy via HAART, a growing number of patients is cycling through the various remaining therapeutic options and are increasingly becoming dependent of the availability of newly developed anti-HIV agents. It is of concern that existing and future therapies will have to be effective against newly evolving
Arzanol, a Potent mPGES-1 Inhibitor: Novel Anti-Inflammatory Agent
Directory of Open Access Journals (Sweden)
Pankaj S. Kothavade
2013-01-01
Full Text Available Arzanol is a novel phloroglucinol α-pyrone, isolated from a Mediterranean plant Helichrysum italicum (Roth Don ssp. microphyllum which belongs to the family Asteraceae. Arzanol has been reported to possess a variety of pharmacological activities. However, anti-inflammatory, anti-HIV, and antioxidant activities have been studied in some detail. Arzanol has been reported to inhibit inflammatory transcription factor NFκB activation, HIV replication in T cells, releases of IL-1β, IL-6, IL-8, and TNF-α, and biosynthesis of PGE2 by potentially inhibiting mPGES-1 enzyme. Diversity of mechanisms of actions of arzanol may be useful in treatment of disease involving these inflammatory mediators such as autoimmune diseases and cancer. This review presents comprehensive information on the chemistry, structure-activity relationship, and pharmacological activities of arzanol. In addition this review discusses recent developments and the scope for future research in these aspects.
Arzanol, a Potent mPGES-1 Inhibitor: Novel Anti-Inflammatory Agent
Kothavade, Pankaj S.; Nagmoti, Dnyaneshwar M.; Bulani, Vipin D.; Juvekar, Archana R.
2013-01-01
Arzanol is a novel phloroglucinol α-pyrone, isolated from a Mediterranean plant Helichrysum italicum (Roth) Don ssp. microphyllum which belongs to the family Asteraceae. Arzanol has been reported to possess a variety of pharmacological activities. However, anti-inflammatory, anti-HIV, and antioxidant activities have been studied in some detail. Arzanol has been reported to inhibit inflammatory transcription factor NFκB activation, HIV replication in T cells, releases of IL-1β, IL-6, IL-8, and TNF-α, and biosynthesis of PGE2 by potentially inhibiting mPGES-1 enzyme. Diversity of mechanisms of actions of arzanol may be useful in treatment of disease involving these inflammatory mediators such as autoimmune diseases and cancer. This review presents comprehensive information on the chemistry, structure-activity relationship, and pharmacological activities of arzanol. In addition this review discusses recent developments and the scope for future research in these aspects. PMID:24198734
Inhibition of HIV-1 by curcumin A, a novel curcumin analog
Kumari, Namita; Kulkarni, Amol A; Lin, Xionghao; McLean, Charlee; Ammosova, Tatiana; Ivanov, Andrey; Hipolito, Maria; Nekhai, Sergei; Nwulia, Evaristus
2015-01-01
Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities. PMID:26366056
DEFF Research Database (Denmark)
Worm, Signe Westring; Sabin, Caroline; Weber, Rainer
2010-01-01
BACKGROUND. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. METHODS. Poisson regression models were adjusted for cardiovascular risk...... factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients......% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. CONCLUSIONS. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI...
International Nuclear Information System (INIS)
Yadav, Anjana; Pati, Shibani; Nyugen, Anhthu; Barabitskaja, Oxana; Mondal, Prosanta; Anderson, Michael; Gallo, Robert C.; Huso, David L.; Reid, William
2006-01-01
Impaired CD4+ T cell responses, resulting in dysregulated T-helper 1 (Th1) effector and memory responses, are a common result of HIV-1 infection. These defects are often preceded by decreased expression and function of the α/β T cell receptor (TCR)-CD3 complex and of co-stimulatory molecules including CD28, resulting in altered T cell proliferation, cytokine secretion and cell survival. We have previously shown that HIV Tg rats have defective development of T cell effector function and generation of specific effector/memory T cell subsets. Here we identify abnormalities in activated HIV-1 Tg rat CD4+ T cells that include decreased pY505 dephosphorylation of Lck (required for Lck activation), decreased CD28 function, reduced expression of the anti-apoptotic molecule Bcl-xL, decreased secretion of the mitogenic lympokine interleukin-2 (IL-2) and increased activation induced apoptosis. These events likely lead to defects in antigen-specific signaling and may help explain the disruption of Th1 responses and the generation of specific effector/memory subsets in transgenic CD4+ T cells
It's Not Just the Pills: A Qualitative Meta-Synthesis of HIV Antiretroviral Adherence Research.
Barroso, Julie; Leblanc, Natalie M; Flores, Dalmacio
Antiretroviral therapy (ART) improves the health and longevity of people living with HIV infection (PLWH) and also prevents transmission of the virus. Yet, lack of adherence to ART regimens has been a persistent problem, even with simpler regimens. Guidelines that deal with ART adherence are based almost solely on quantitative studies; this focus ignores the context and complexity of patients' lives. Guidelines are also focused on the individual. We argue that the solution is to include the broader communities in which patients live, and to deal with systemic disparities that persist worldwide; this can be done in part through demedicalizing HIV care for healthy PLWH. We present findings from a qualitative meta-synthesis of 127 studies conducted around the world on the last two pillars of the HIV treatment cascade: starting and remaining on ART until optimal viral suppression is achieved. We use Maslow's hierarchy of needs to frame our findings. Copyright © 2017 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved.
IN-VITRO EVALUATION OF ANTI-TRICHOMONAL ACTIVITIES OF ...
African Journals Online (AJOL)
infective, has shown anti-malarial and antitrypanocidal activities. Therefore using bioactivity guided fractionation, anti-trichomonal activity of E. uniflora leaf was investigated. Anti-trichomonal activities of leaf methanol extract and its fractions against ...
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Alessandra Pontillo
2016-11-01
Conclusions: These results suggest that the actual selection of HIV+ individual for immunotherapy, based on clinical features, did not ensure the same DC product, and that less “activated/exhausted” DC could positively affect the outcome of immunotherapy.
International Nuclear Information System (INIS)
Poeschla, Eric
2013-01-01
Central initiation of plus strand synthesis is a conserved feature of lentiviruses and certain other retroelements. This complication of the standard reverse transcription mechanism produces a transient “central DNA flap” in the viral cDNA, which has been proposed to mediate its subsequent nuclear import. This model has assumed that the important feature is the flapped DNA structure itself rather than the process that produces it. Recently, an alternative kinetic model was proposed. It posits that central plus strand synthesis functions to accelerate conversion to the double-stranded state, thereby helping HIV-1 to evade single-strand DNA-targeting antiviral restrictions such as APOBEC3 proteins, and perhaps to avoid innate immune sensor mechanisms. The model is consistent with evidence that lentiviruses must often synthesize their cDNAs when dNTP concentrations are limiting and with data linking reverse transcription and uncoating. There may be additional kinetic advantages for the artificial genomes of lentiviral gene therapy vectors. - Highlights: • Two main functional models for HIV central plus strand synthesis have been proposed. • In one, a transient central DNA flap in the viral cDNA mediates HIV-1 nuclear import. • In the other, multiple kinetic consequences are emphasized. • One is defense against APOBEC3G, which deaminates single-stranded DNA. • Future questions pertain to antiviral restriction, uncoating and nuclear import
Latest animal models for anti-HIV drug discovery.
Sliva, Katja
2015-02-01
HIV research is limited by the fact that lentiviruses are highly species specific. The need for appropriate models to promote research has led to the development of many elaborate surrogate animal models. This review looks at the history of animal models for HIV research. Although natural animal lentivirus infections and chimeric viruses such as chimera between HIV and simian immunodeficiency virus and simian-tropic HIV are briefly discussed, the main focus is on small animal models, including the complex design of the 'humanized' mouse. The review also traces the historic evolution and milestones as well as depicting current models and future prospects for HIV research. HIV research is a complex and challenging task that is highly manpower-, money- and time-consuming. Besides factors such as hypervariability and latency, the lack of appropriate animal models that exhibit and recapitulate the entire infectious process of HIV, is one of the reasons behind the failure to eliminate the lentivirus from the human population. This obstacle has led to the exploitation and further development of many sophisticated surrogate animal models for HIV research. While there is no animal model that perfectly mirrors and mimics HIV infections in humans, there are a variety of host species and viruses that complement each other. Combining the insights from each model, and critically comparing the results obtained with data from human clinical trials should help expand our understanding of HIV pathogenesis and drive future drug development.
Tsvetkov, Vladimir B; Serbin, Alexander V
2014-06-01
In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.
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Dina Tsukrov
2016-09-01
Full Text Available Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT, a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infect-ed cells. Since gp41 expression by infected cells is likely down-regulated in patients on an-tiretroviral therapy (ART, we evaluated the ability of RIT to kill ART-treated infected cells us-ing both in vitro models and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal anti-body to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. conjugated to the human monoclonal antibody 2556, which binds to HIV gp41. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: ten on ART and five ART-naive. We found that 213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral load in vitro than either therapy alone, indicating that gp41 expression under ART was sufficient to allow 213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that 213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART, and supports continued development of 213Bi
Shindo, Keisuke; Takaori-Kondo, Akifumi; Kobayashi, Masayuki; Abudu, Aierken; Fukunaga, Keiko; Uchiyama, Takashi
2003-11-07
Human immunodeficiency virus, type 1 (HIV-1) Vif protein plays an essential role in the regulation of the infectivity of HIV-1 virion. Vif functions to counteract an anti-HIV-1 cellular factor in non-permissive cells, CEM15/Apobec-3G, which shares a cytidine deaminase motif. CEM15/Apobec-3G deaminates dC to dU in the minus strand DNA of HIV-1, resulting in G to A hypermutation in the plus strand DNA. In this study, we have done the mutagenesis analysis on two cytidine deaminase motifs in CEM15/Apobec-3G and examined their antiviral functions as well as the DNA editing activity. Point mutations in the C-terminal active site such as E259Q and C291A almost completely abrogated the antiviral function, while those in the N-terminal active site such as E67Q and C100A retained this activity to a lesser extent as compared with that of the wild type. The DNA editing activities of E67Q and E259Q mutants were both retained but impaired to the same extent. This indicates that the enzymatic activity of this protein is essential but not a sole determinant of the antiviral activity. Furthermore, all the deletion mutants tested in this study lost the antiviral activity because of the loss of the activity for dimerization, suggesting that the entire protein structure is necessary for the antiviral function.
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Yu. L. Shepeta
2016-04-01
Full Text Available Aim. The study of anti-inflammatory activity of novel 4H-1,2,4-triazole-3-thiol derivatives is one of the most priority direction of pharmacological investigation of mentioned heterocyclic system. Methods and results. Based on the heterocyclization reaction of N-substituted thiosemicarbazides in alkaline medium the synthesis of novel non-condensed derivatives with 4H-1,2,4-triazole and 2-(2,6-dichlorophenylaminobenzyl fragments was carried out. Further chemical modification of synthesized 5-[2-(2,6-dichlorophenylaminobenzyl]-4H-1,2,4-triazole-3-thioles was performed via S-alkylation reactions with N-aryl(thiophene-2-ylsubstituted 2-chloroacetamides and 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-ylethanones. Structure of synthesized compounds was confirmed by the elemental analysis and 1H NMR spectral data. Conclusions. The research of anti-inflammatory activity has been conducted on the carrageenan-induced edema of the rat’s extremities model. The results allow to identify highly active compounds 2-{5-[2-(2,6-dichloro-phenylamino-benzyl]-4-ethyl-4Н-[1,2,4]triazol-3-ylsulfanyl}-N-(4-chlorophenylacetamide (compound 3b and 2-{5-[2-(2,6-dichloro-phenylamino-benzyl]-4-ethyl-4Н-[1,2,4]triazol-3-ylsulfanyl}-1-[5-(4-methoxy-phenyl-3-(naphthalen-2-yl-4,5-dihydro-pyrazol-1-yl]-ethanone (compound 5c with evident antiexudative effect comparable with the same effect of diclofenac sodium.
Lapadat-Tapolsky, M; Gabus, C; Rau, M; Darlix, J L
1997-05-02
Retroviral nucleocapsid (NC) protein is an integral part of the virion nucleocapsid where it coats the dimeric RNA genome. Due to its nucleic acid binding and annealing activities, NC protein directs the annealing of the tRNA primer to the primer binding site and greatly facilitates minus strand DNA elongation and transfer while protecting the nucleic acids against nuclease degradation. To understand the role of NCp7 in viral DNA synthesis, we examined the influence of NCp7 on self-primed versus primer-specific reverse transcription. The results show that HIV-1 NCp7 can extensively inhibit self-primed reverse transcription of viral and cellular RNAs while promoting primer-specific synthesis of proviral DNA. The role of NCp7 vis-a-vis the presence of mutations in the viral DNA during minus strand elongation was examined. NCp7 maximized the annealing between a cDNA(-) primer containing one to five consecutive errors and an RNA representing the 3' end of the genome. The ability of reverse transcriptase (RT) in the presence of NCp7 to subsequently extend the mutated primers depended upon the position of the mismatch within the primer:template complex. When the mutations were at the polymerisation site, primer extension by RT in the presence of NCp7 was very high, about 40% for one mismatch and 3% for five consecutive mismatches. Mutations within the DNA primer or at its 5' end had little effect on the extension of viral DNA by RT. Taken together these results indicate that NCp7 plays major roles in proviral DNA synthesis within the virion core due to its ability to promote prime-specific proviral DNA synthesis while concurrently inhibiting non-specific reverse transcription of viral and cellular RNAs. Moreover, the observation that NCp7 enhances the incorporation of mutations during minus strand DNA elongation favours the notion that NCp7 is a factor contributing to the high mutation rate of HIV-1.
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Patrícia Constante Jaime
2004-03-01
Full Text Available OBJETIVO: Avaliar o estado nutricional de indivíduos portadores do HIV/AIDS em uso de terapia anti-retroviral de alta potência, segundo sexo e número de linfócitos T CD4.+. MATERIAL E MÉTODOS: Estudo transversal envolvendo 223 indivíduos (171 homens e 52 mulheres tratados com inibidores de protease, com idade entre 20 e 59 anos, recrutados em um serviço de referência em tratamento de HIV/AIDS do município de São Paulo. Os dados antropométricos utilizados foram peso, estatura e circunferência da cintura (CC. O índice de massa corporal (IMC foi calculado como a razão entre peso (kg e estatura ao quadrado (m², de acordo com o critério de classificação proposto pela Organização Mundial de Saúde. Os pacientes foram divididos em três categorias por número de linfócitos T CD4.+: 350 (cel/mm³. RESULTADOS: A prevalência de sobrepeso na população foi de 30,5%, e de obesidade abdominal de 12,6%. As mulheres apresentaram prevalência maior de sobrepeso (36,5% e de obesidade abdominal (32,7% quando comparadas aos homens (28,7% e 6,4% respectivamente. A prevalência de baixo peso foi maior nas mulheres (7,7% do que nos homens (2,3%. Ausência de associação significativa entre sobrepeso, obesidade abdominal e número de linfócitos T CD4.+ foi observada tanto nos homens como nas mulheres. CONCLUSÃO: As mulheres apresentaram prevalências maiores de baixo peso, sobrepeso e obesidade abdominal em relação aos homens. A obesidade é o desvio do estado nutricional mais importante, superando a desnutrição, nesta população de indivíduos portadores do HIV/AIDS em uso de terapia anti-retroviral de alta potência.OBJECTIVE: To evaluate the nutritional status of HIV/AIDS patients treated with highly active antiretroviral therapy, according to gender and T CD4 + lymphocyte count. MATERIAL AND METHODS: This was a cross-sectional study, including 223 individuals (171 men and 52 women treated with protease inhibitors, aged between 20 and
Buckley, Niall; Huber, Ashley; Lo, Yungtai; Castle, Philip E.; Kemal, Kimdar; Burk, Robert D.; Strickler, Howard D.; Einstein, Mark H.; Young, Mary; Anastos, Kathryn; Herold, Betsy C.
2015-01-01
Problem High-risk human papillomavirus (HR-HPV) is prevalent in HIV-infected women and may be associated with mucosal changes that promote HIV replication. Method of Study Innate immune molecules, antimicrobial activity, HIV RNA, and HPV DNA genotypes were measured in a cross-sectional study of 128 HIV-infected women categorized into HPV-16 (n=8), other HR-HPV (n=41), and non-HR-HPV controls (n=79). Results Compared to controls, HR-HPV groups had higher plasma viral loads (p=0.004), lower CD4 cells (p=0.02), more genital tract HIV RNA (p=0.03), greater number of different HPV types (p<0.001), higher cervicovaginal lavage (CVL) IL-1α (p=0.03) and human beta defensin 2 (HBD2) (p=0.049), and less anti-HIVBal activity (p=0.03). HPV-16 remained significantly associated with higher HBD2 (p=0.03), higher IL-1α (p=0.009), and lower anti-HIVBaL activity (p=0.03) compared to controls after adjusting for plasma viral load and CD4 T cell count. Conclusion HR-HPV is associated with mucosal changes in HIV-infected women that could adversely impact genital tract health. PMID:26685115
International Nuclear Information System (INIS)
Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.
2011-01-01
Highlights: → Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. → Cell type-dependent synergy between MPA and anti-proliferative agents. → The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. → The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.
[Synthesis and biological activity of 2,3-secotriterpene acid mono- and diamides].
Tolmacheva, I A; Igosheva, E V; Vikharev, Iu B; Grishko, V V; Savinova, O V; Boreko, E I; Eremin, V F
2013-01-01
Four types of amide (C3; C28; C3-C28) conjugates based on 2,3-seco-18alphaH-oleanane and 2,3-secolupane mono- and dicarboxylic acids were synthesized. The range of diamide derivatives was supplemented with C3-C3' and C28-C28' dicondensed amides with two A-secotriterpene backbones educed by reacting monocarboxylic A-secoacids with biogenic amino acid lysine. Compounds with inhibitory action against herpes virus reproduction (EC50 8.7 and 4.1 McM) were found among the synthesized mono- and diamide derivatives containing an ethyl-beta-alaninate fragment. It has been ascertained that diamide with ethyl-beta-alaninate fragment combines anti-herpes virus properties and anti-HIV activity (EC50 5.1 McM). For active compounds, the maximum non-toxic concentration (MNTC)/EC50 ratios ranges from 9.7 to 40.8. The synthesized amide conjugates do not exhibit any marked cytotoxic effects against human tumor cell lines rabdomiosarcoma RD TE32, A549 lung carcinoma and melanoma MS.
Costi, Roberta; Métifiot, Mathieu; Esposito, Francesca; Cuzzucoli Crucitti, Giuliana; Pescatori, Luca; Messore, Antonella; Scipione, Luigi; Tortorella, Silvano; Zinzula, Luca; Novellino, Ettore; Pommier, Yves; Tramontano, Enzo; Marchand, Christophe; Di Santo, Roberto
2013-11-14
The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.
Gringeri, A; Santagostino, E; Mannucci, P M; Siracusano, L; Marinoni, A; Criscuolo, M; Carcagno, M; Fall, L S; M'Bika, J P; Bizzini, B
1995-05-01
A randomized, placebo-controlled trial was designed to evaluate safety and immunogenicity of an anti-cytokine vaccine in high risk HIV-positive patients. This strategy was aimed to modulate the impaired cytokine regulation in AIDS. Twelve asymptomatic patients on antiretroviral therapy for at least 1 year and with CD4 cell counts between 100-300/mm3 were randomized to receive adjuvanted formol-inactivated interferon alpha-2a (IFN alpha) and continue the current antiretroviral treatment, whatever it was, or to receive the adjuvant alone and the current antiretroviral treatment. All patients received 4 i.m. injections monthly, followed by booster injections every 3 months. Clinical status, immunology and virology were monitored. Immune response to vaccination was evaluated in term of antibody detection (ELISA) and serum anti-IFN alpha neutralizing capacity. Only local discomfort and transient fever were reported. All vaccines except one showed increased levels of anti-IFN alpha Abs and developed serum IFN alpha neutralizing capacity. Viral load did not increase in vaccinees while it remained unchanged or even increased in placebo-treated patients. None of them showed HIV-related symptoms and all had their CD4 cell counts stabilized over 18 months, whereas 2 placebo-treated patients developed full-blow AIDS. In conclusion, anti-IFN alpha vaccine was safe and immunogenic. Stable clinical and immunological status over 18 months was observed in vaccinees coupled to increased serum IFN alpha neutralizing capacity.
Mitchell, Elizabeth O; Stewart, Greg; Bajzik, Olivier; Ferret, Mathieu; Bentsen, Christopher; Shriver, M Kathleen
2013-12-01
A multisite study was conducted to evaluate the performance of the Bio-Rad 4th generation GS HIV Combo Ag/Ab EIA versus Abbott 4th generation ARCHITECT HIV Ag/Ab Combo. The performance of two 3rd generation EIAs, Ortho Diagnostics Anti-HIV 1+2 EIA and Siemens HIV 1/O/2 was also evaluated. Study objective was comparison of analytical HIV-1 p24 antigen detection, sensitivity in HIV-1 seroconversion panels, specificity in blood donors and two HIV false reactive panels. Analytical sensitivity was evaluated with International HIV-1 p24 antigen standards, the AFFSAPS (pg/mL) and WHO 90/636 (IU/mL) standards; sensitivity in acute infection was compared on 55 seroconversion samples, and specificity was evaluated on 1000 negative blood donors and two false reactive panels. GS HIV Combo Ag/Ab demonstrated better analytical HIV antigen sensitivity compared to ARCHITECT HIV Ag/Ab Combo: 0.41 IU/mL versus 1.2 IU/mL (WHO) and 12.7 pg/mL versus 20.1 pg/mL (AFSSAPS); GS HIV Combo Ag/Ab EIA also demonstrated slightly better specificity compared to ARCHITECT HIV Ag/Ab Combo (100% versus 99.7%). The 4th generation HIV Combo tests detected seroconversion 7-11 days earlier than the 3rd generation HIV antibody only EIAs. Both 4th generation immunoassays demonstrated excellent performance in sensitivity, with the reduction of the serological window period (7-11 days earlier detection than the 3rd generation HIV tests). However, GS HIV Combo Ag/Ab demonstrated improved HIV antigen analytical sensitivity and slightly better specificity when compared to ARCHITECT HIV Ag/Ab Combo assay, with higher positive predictive values (PPV) for low prevalence populations. Copyright © 2013 Elsevier B.V. All rights reserved.
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Dorsey Grant
2009-11-01
Full Text Available Abstract Background HIV infection increases the risk of placental malaria, which is associated with poor maternal and infant outcomes. Recommendations in Uganda are for HIV-infected pregnant women to receive daily trimethoprim-sulphamethoxazole (TS and HIV-uninfected women to receive intermittent sulphadoxine-pyrimethamine (SP. TS decreases the risk of malaria in HIV-infected adults and children but has not been evaluated among pregnant women. Methods This was a cross sectional study comparing the prevalence of placental malaria between HIV-infected women prescribed TS and HIV-uninfected women prescribed intermittent preventive therapy with sulphadoxine-pyrimethamine (IPT-SP in a high malaria transmission area in Uganda. Placental blood was evaluated for malaria using smear and PCR. Results Placentas were obtained from 150 HIV-infected women on TS and 336 HIV-uninfected women on IPT-SP. The proportion of HIV-infected and HIV-uninfected women with placental malaria was 19% vs. 26% for those positive by PCR and 6% vs. 9% for those positive by smear, respectively. Among all infants, smear+ placental malaria was most predictive of low birth weight (LBW. Primigravidae were at higher risk than multigravidae of having placental malaria among HIV-uninfected, but not HIV-infected, women. Adjusting for gravidity, age, and season at the time of delivery, HIV-infected women on TS were not at increased risk for placental malaria compared to HIV-uninfected women on IPT-SP, regardless of the definition used. Conclusion Prevalence of placental malaria was similar in HIV-infected women on TS and HIV-uninfected women on IPT-SP. Nonetheless, while nearly all of the women in this study were prescribed anti-folates, the overall risk of placental malaria and LBW was unacceptably high. The population attributable risk of placental malaria on LBW was substantial, suggesting that future interventions that further diminish the risk of placental malaria may have a
Silvestri, Romano; Artico, Marino
2005-01-01
Indolyl aryl sulfones (IASs) are a potent class of NNRTIs developed from L-737,126, a lead agent discovered by Merck AG. IAS derivatives are endowed with inhibitory activities against wt HIV-1 in the low nanomolar concentration range. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of the aryl sulfonyl moiety furnished IAS derivatives such as 5-chloro- or 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide, which showed very potent and selective anti-HIV-1 activity against some mutants carrying NNRTI resistant mutations at positions 103 and 181 of the reverse transcriptase. IAS derivatives bearing 2-hydroxyethylcarboxyamide or 2-hydroxyethylcarboxyhydrazide groups at position 2 of the indole nucleus were more active than L-737,126 against the K103N-Y181C double mutant. A great improvement of antiviral activity against wt HIV-1 and resistant mutants was obtained by coupling 1-3 simple amino acids, such as glycine and alanine, in sequence, with the 3-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-carbonyl moiety. The transformation of the chain terminus into amide or hydrazide, produced short peptides with high selectivity and potent activity against wt HIV-1, and the viral mutants Y181C, K103N-Y181C and EFV(R). IAS having two halogen atoms at the indole showed potent inhibitory activity against the Y181C and the EFV(R) resistant mutant strains. In particular, the introduction of a fluorine atom at position 4 of the indole ring notably contributed to improve the antiviral activities against both wt and the related resistant mutants. 5-Nitro-IASs were highly active against wt HIV-1 and exhibited low cytotoxicity. Experimental data highlighted the class IAS derivatives as promising candidates for clinical trials.
Abdel-Motal, U M; Harbison, C; Han, T; Pudney, J; Anderson, D J; Zhu, Q; Westmoreland, S; Marasco, W A
2014-09-01
Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.
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Beth S Zha
Full Text Available HIV protease inhibitors (PI are core components of Highly Active Antiretroviral Therapy (HAART, the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/- mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.
Adrenaline-induced mobilization of T cells in HIV-infected patients
DEFF Research Database (Denmark)
Søndergaard, S R; Cozzi-Lepri, A; Ullum, H
2000-01-01
The present study aimed to investigate lymphocyte mobilization from peripheral cell reservoirs in HIV-infected patients. Nine HIV-infected patients on stable highly active anti-retroviral therapy (HAART), eight treatment-naive HIV-infected patients and eight HIV- controls received a 1-h adrenaline...... infusion. The adrenaline infusion induced a three-fold increase in the concentration of lymphocytes in all three groups. All HIV-infected patients mobilized significantly higher numbers of CD8+ cells but less CD4+ cells. All subjects mobilized CD45RA+CD62L+ and CD8+CD28+ cells to a lesser extent than CD45......RO+CD45RA- and CD8+CD28-cells. Furthermore, high numbers of CD8+CD38+ cells were mobilized only in the HIV-infected patients. It was therefore predominantly T cells with an activated phenotype which were mobilized after adrenaline stimulation. It is concluded that the HIV-associated immune defect...
Effects of highly active antiretroviral therapy on the survival of HIV ...
African Journals Online (AJOL)
Recent improvements in access to Anti-Retroviral Therapy (ART) have radically reduced hospitalizations and deaths associated with HIV infection in both developed countries and sub-Saharan Africa. Not much is known about survival of patients on ART in slums. The objective of this study was to identify factors associated ...
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Getnet Yimer
Full Text Available BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI in HIV and tuberculosis (TB co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353 were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001, higher plasma efavirenz level (p = 0.009, efavirenz/8-hydroxyefavirenz ratio (p = 0.036, baseline AST (p = 0.022, ALT (p = 0.014, lower hemoglobin (p = 0.008, and serum albumin (p = 0.007, NAT2 slow-acetylator genotype (p = 0.039 and ABCB1 3435TT genotype (p = 0.001. CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification
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Marie-Lise Gougeon
2017-02-01
Conclusion: We report that brain injury in chronically HIV-infected patients on stable HAART is strongly associated with persistent CNS inflammation, which is correlated with increased levels of HMGB1 and anti-HMGB1 IgG in the CSF. Moreover, we identified circulating anti-HMGB1 IgG as a very early biomarker of neurological impairment in patients without HAND. These results might have important implication for the identification of patients who are at high risk of developing neurological disorders.
Anti-inflammatory and neuropharmacological activities of ...
African Journals Online (AJOL)
The crude methanolic extracts of leaves of Caesalpinia pulcherrima were evaluated for its anti-inflammatory and neuropharmacological activities. When given orally to rats at dose of 200 and 400 mg/kg, the extract showed a significant (P<0.001) anti-inflammatory activity against carrageenin induced paw edema in rats ...
Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon
Akiyama, Hisashi; Ramirez, Nora-Guadalupe Pina; Gibson, Gregory; Kline, Christopher; Watkins, Simon; Ambrose, Zandrea
2017-01-01
ABSTRACT A hallmark of human immunodeficiency virus type 1 (HIV-1) infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4+ T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gag and CD169, suggesting productive infection of CD169+ myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+ T cells was robustly decreased, initiation of infection in trans via coculture with CD169+ IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state. IMPORTANCE HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN
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Bridgette Janine Connell
Full Text Available Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS as well as to an antibody (mAb 17b directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.
Sondergaard, J.N.; Vinner, L.; Brix, S.
2014-01-01
Plasmacytoid dendritic cells (pDCs) play a vital role in activation of anti-HIV-1 immunity, and suppression of pDCs might mitigate immune responses against HIV-1. HIV-1 gp120 high-mannose has been attributed immunosuppressive roles in human myeloid DCs, but no receptors for high-mannose have so far
Anti-oxidant and anti-inflammatory activity of leaf extracts and fractions of Mangifera indica.
Mohan, C G; Deepak, M; Viswanatha, G L; Savinay, G; Hanumantharaju, V; Rajendra, C E; Halemani, Praveen D
2013-04-13
To evaluate the anti-oxidant and anti-inflammatory activity of leaf extracts and fractions of Mangifera indica in in vitro conditions. In vitro DPPH radical scavenging activity and lipoxygenase (LOX) inhibition assays were used to evaluate the anti-oxidant and anti-inflammatory activities respectively. Methanolic extract (MEMI), successive water extract (SWMI) and ethyl acetate fraction (EMEMI), n-butanol fraction (BMEMI) and water soluble fraction (WMEMI) of methanolic extract were evaluated along with respective reference standards. In in vitro DPPH radical scavenging activity, the MEMI, EMEMI and BMEMI have offered significant antioxidant activity with IC(50) values of 13.37, 3.55 and 14.19 μg/mL respectively. Gallic acid, a reference standard showed significant antioxidant activity with IC(50) value of 1.88 and found to be more potent compared to all the extracts and fractions. In in vitro LOX inhibition assay, the MEMI, EMEMI and BMEMI have showed significant inhibition of LOX enzyme activity with IC(50) values of 96.71, 63.21 and 107.44 μg/mL respectively. While, reference drug Indomethacin also offered significant inhibition against LOX enzyme activity with IC(50) of 57.75. Furthermore, MEMI was found to more potent than SWMI and among the fractions EMEMI was found to possess more potent antioxidant and anti-inflammatory activity. These findings suggest that the MEMI and EMEMI possess potent anti-oxidant and anti-inflammatory activities in in vitro conditions. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.
Anti-Inflammatory Activity of Sanghuangporus sanghuang Mycelium
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Wang-Ching Lin
2017-02-01
Full Text Available Acute lung injury (ALI is characterized by inflammation of the lung tissue and oxidative injury caused by excessive accumulation of reactive oxygen species. Studies have suggested that anti-inflammatory or antioxidant agents could be used for the treatment of ALI with a good outcome. Therefore, our study aimed to test whether the mycelium extract of Sanghuangporus sanghuang (SS-1, believed to exhibit antioxidant and anti-inflammatory properties, could be used against the excessive inflammatory response associated with lipopolysaccharides (LPS-induced ALI in mice and to investigate its possible mechanism of action. The experimental results showed that the administration of SS-1 could inhibit LPS-induced inflammation. SS-1 could reduce the number of inflammatory cells, inhibit myeloperoxidase (MPO activity, regulate the TLR4/PI3K/Akt/mTOR pathway and the signal transduction of NF-κB and MAPK pathways in the lung tissue, and inhibit high mobility group box-1 protein 1 (HNGB1 activity in BALF. In addition, SS-1 could affect the synthesis of antioxidant enzymes Heme oxygenase 1 (HO-1 and Thioredoxin-1 (Trx-1 in the lung tissue and regulate signal transduction in the KRAB-associated protein-1 (KAP1/nuclear factor erythroid-2-related factor Nrf2/Kelch Like ECH associated Protein 1 (Keap1 pathway. Histological results showed that administration of SS-1 prior to induction could inhibit the large-scale LPS-induced neutrophil infiltration of the lung tissue. Therefore, based on all experimental results, we propose that SS-1 exhibits a protective effect against LPS-induced ALI in mice. The mycelium of S. sanghuang can potentially be used for the treatment or prevention of inflammation-related diseases.
Kappus, R P; Berger, S; Thomas, C A; Ottmann, O G; Ganser, A; Stille, W; Shah, P M
1992-07-01
Clinical observations show that the HIV infection is often associated with affections of the skin. In order to examine the involvement of the epidermal immune system in the HIV infection, we determined accessory cell function of epidermal cells from HIV-1-infected patients. For this we measured the proliferative response of enriched CD(4+)-T-lymphocytes from HIV-infected patients and noninfected controls to stimulation with anti-CD3 and IL-2 in the presence of epidermal cells; the enhancement of the response is dependent on the presence of functionally intact accessory cells. The capacity of epidermal cells to increase the anti-CD3-stimulated T-cell proliferative response was significantly enhanced in HIV patients (CDC III/IVA) as compared with noninfected donors. It is discussed, whether the increased activity of epidermal cells from HIV-infected patients may be responsible for several of the dermal lesions in the course of an HIV infection as due to an enhanced production and release of epidermal cell-derived cytokines.
Alterations in HIV-1 LTR promoter activity during AIDS progression
International Nuclear Information System (INIS)
Hiebenthal-Millow, Kirsten; Greenough, Thomas C.; Bretttler, Doreen B.; Schindler, Michael; Wildum, Steffen; Sullivan, John L.; Kirchhoff, Frank
2003-01-01
HIV-1 variants evolving in AIDS patients frequently show increased replicative capacity compared to those present during early asymptomatic infection. It is known that late stage HIV-1 variants often show an expanded coreceptor tropism and altered Nef function. In the present study we investigated whether enhanced HIV-1 LTR promoter activity might also evolve during disease progression. Our results demonstrate increased LTR promoter activity after AIDS progression in 3 of 12 HIV-1-infected individuals studied. Further analysis revealed that multiple alterations in the U3 core-enhancer and in the transactivation-response (TAR) region seem to be responsible for the enhanced functional activity. Our findings show that in a subset of HIV-1-infected individuals enhanced LTR transcription contributes to the increased replicative potential of late stage virus isolates and might accelerate disease progression
Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma
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Eline Boons
2015-09-01
Full Text Available Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1 mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.
Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound
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Irene Sola
2015-03-01
Full Text Available We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer’s disease (AD. Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.
Zhang, Yan; Wu, Liying; Ma, Zhongsu; Cheng, Jia; Liu, Jingbo
2015-12-23
Corn silk is a well-known ingredient frequently used in traditional Chinese herbal medicines. This study was designed to evaluate the anti-diabetic, anti-oxidant and anti-hyperlipidemic activities of crude flavonoids extracted from corn silk (CSFs) on streptozotocin (STZ)-induced diabetic mice. The results revealed that treatment with 300 mg/kg or 500 mg/kg of CSFs significantly reduced the body weight loss, water consumption, and especially the blood glucose (BG) concentration of diabetic mice, which indicated their potential anti-diabetic activities. Serum total superoxide dismutase (SOD) and malondialdehyde (MDA) assays were also performed to evaluate the anti-oxidant effects. Besides, several serum lipid values including total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C) were reduced and the high density lipoprotein cholesterol level (HDL-C) was increased. The anti-diabetic, anti-oxidant and anti-hyperlipidemic effect of the CSFs suggest a potential therapeutic treatment for diabetic conditions.
Dendrimers as Potential Therapeutic Tools in HIV Inhibition
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Xiangbo Li
2013-07-01
Full Text Available The present treatments for HIV transfection include chemical agents and gene therapies. Although many chemical drugs, peptides and genes have been developed for HIV inhibition, a variety of non-ignorable drawbacks limited the efficiency of these materials. In this review, we discuss the application of dendrimers as both therapeutic agents and non-viral vectors of chemical agents and genes for HIV treatment. On the one hand, dendrimers with functional end groups combine with the gp120 of HIV and CD4 molecule of host cell to suppress the attachment of HIV to the host cell. Some of the dendrimers are capable of intruding into the cell and interfere with the later stages of HIV replication as well. On the other hand, dendrimers are also able to transfer chemical drugs and genes into the host cells, which conspicuously increase the anti-HIV activity of these materials. Dendrimers as therapeutic tools provide a potential treatment for HIV infection.
Profile of HIV-1 RNA viral load among HIV-TB co-infected patients in ...
African Journals Online (AJOL)
Profile of HIV-1 RNA viral load among HIV-TB co-infected patients in a tertiary health facility in Maiduguri, Northeastern Nigeria. ... This study aims to estimate the HIV-1 RNA viral load and impact of anti TB therapy (ATT) ... HOW TO USE AJOL.
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GUILHERME FREIRE GARCIA
2000-08-01
/1/1997 to 1/31/1998. The clinical history was directed to the presence of risk factors for AIDS or TB, previous treatments or abandoned treatments for TB, and TB clinical forms. Patients with AIDS defining illnesses, except for TB, and with previous anti-HIV tests were excluded. All patients had an ELISA anti-HIV serology, and when positive, a Western-Blot test was performed to confirm the previous result. X-square test and Fisher test were used for statistical analysis. Results: Sixty-five patients were divided into group I (positive serology for HIV, n = 6 and group II (negative serology for HIV, n = 59. There were no statistical differences between the groups comparing the risk factors for AIDS and TB, previous treatments or abandoned treatments for TB, or TB clinical forms. Conclusions: The high prevalence of TB/HIV co-infection (9.2% reinforces that: 1 the clinical history was not able to detect a significant number of patients with TB/HIV co-infection and that: 2 anti-HIV serology should be performed in all patients with active TB forms.
Adeoye-Agboola, D I; Evans, H; Hewson, D; Pappas, Y
2016-07-01
To critically review, appraise and evaluate quality of evidence on HIV disclosure among people living with HIV/AIDS (PLWHA) in Nigeria, and to identify a possible gap in knowledge on HIV/AIDS and disclosure. A systematic review using narrative synthesis and meta-analysis. MedLine, PsycINFO, PubMed Central, Scopus and CINAHL were searched. Data were extracted with the use of spread sheet. An analysis of heterogeneity was performed for the disclosure rate and the presence of a supportive reaction from partners. A meta-analysis was performed for the disclosure rates to sexual partners, with data available for all ten studies. Ten studies met the inclusion criteria. The outcomes show that HIV disclosure of sero-positive status is most common between spouses or sexual partners than disclosure to relatives/family members, friends, pastor/Imam or work colleagues/employers. The participants in most of these studies are women, and amongst the most influential factors on disclosure are gender, anticipated outcome, marital status and knowledge of partners' status. Some studies reported non-disclosure as a way of limiting stigma. Almost all of the studies highlighted that there is fear of stigma and social exclusion associated with disclosure. This review discusses the overall experience of HIV disclosure on the management of the disease and barriers to disclosure. We found that PLWHA in Nigeria disclosed to at least one person within their social networks. Stigma is still a major consideration for PLWHA who experience a range of misconceptions around HIV transmission. The findings of this study may inform local policies and plans for improving the PLWHA quality of life. Targeted policies to increase disclosure of sero-positive status and reduce stigma may facilitate disease prevention. The methodological rigour of the included studies was appraised low. Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
Purinergic Receptors: Key Mediators of HIV-1 infection and inflammation
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Talia H Swartz
2015-11-01
Full Text Available Human immunodeficiency virus (HIV-1 causes a chronic infection that afflicts more than 38 million individuals worldwide. While the infection can be suppressed with potent anti-retroviral therapies, individuals infected with HIV have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV pathogenesis to this inflammation has yet to be identified. Purinergic receptors are known to mediate inflammation and have been shown to be required for HIV-1 infection at the level of HIV-1 membrane fusion. Here we review the literature on the role of purinergic receptors in HIV-1 infection and associated inflammation and describe a role for these receptors as potential therapeutic targets.
He, Yan; Luo, Yan; Ding, Yi-ling; Zheng, Yu-huang; Li, Jing; Huang, Jian; Li, Jie-min
2011-10-01
To identify the effect of highly active anti-retroviral therapy (HAART) on prevention of mother to child transmission (PMTCT) of HIV and on infant growth and development. A total of 16 HIV-infected women or pregnant women selected in this study received HAART before or 18 - 24 weeks after pregnancy. The treatment included taking Zidovudine (AZT) 0.3 g each time, twice a day, Lamivudine (3TC) 0.3 g each time, once a day and Nevirapine (NVP) 0.2 g each time, twice a day or Efavirenz (EFV) 0.6 g each time, once a day, as well as labor intervention and artificial feeding. The growth index for 17 infants from HIV-infected mothers (experimental group) and 16 normal infants (control group) were observed for 18 months. Neonatal hemoglobin (Hb), liver and kidney function, serum iron and calcium were detected at neonatal period and at 12(th) month, respectively. All the pregnant women were in good conditions and had tolerance with HAART. The birth weight, length and Apgar score of the newborns in the experimental group were (3.5 ± 0.9) kg, (54.2 ± 3.8) cm and 7 - 10 scores respectively, however those in the control group were (3.6 ± 0.8) kg, (55.6 ± 3.6) cm and 8 - 10 scores (t(weight) = 1.01, t(length) = 6.98, P > 0.05). Weight and length of infants in experimental group were (9.36 ± 1.8) kg and (76.3 ± 2.7) cm at 12(th) month, while those in control group were (9.86 ± 2.5) kg and (76.8 ± 2.9) cm (t(weight) = 0.83, t(length) = 1.00, P > 0.05). The level of Hb in experimental group was (126.2 ± 16.7) g/L, and was (148.6 ± 20.5) g/L in control group (t = -5.89, P = 0.11). At 12(th) month, the levels of Hb and the total bilirubin (TB) were (125.9 ± 19.8) g/L and (11.7 ± 3.5) µmol/L in experimental group; and those in the control group were (130.1 ± 18.7) g/L and (13.2 ± 3.7) µmol/L (t(Hb) = -3.82, t(TB) = -2.14, P > 0.05). Serum iron and calcium were (25.4 ± 5.7) µmol/L and (26.4 ± 7.2) µmol/L at neonatal period and were (2.3 ± 0.6) mol/L and (2.8 ± 0
Castro-Aceituno, Verónica; Abbai, Ragavendran; Moon, Seong Soo; Ahn, Sungeun; Mathiyalagan, Ramya; Kim, Yu-Jin; Kim, Yeon-Ju; Yang, Deok Chun
2017-09-01
Pleuropterus multiflorus (Hasuo) is a widely used medicinal plant in Korea and China for treating amnesia, isnomia, heart throbbing etc. With the constructive idea of promoting the wide-spread usage of P. multiflorus, we propose its indirect usage in the form of biologically active silver (Pm-AgNPs) and gold nanoparticles (Pm-AuNPs). The synthesized nanoparticles were predominantly spherical, crystalline with the Z-average hydrodynamic diameter of 274.8nm and 104.8nm respectively. Also, proteins and phenols were identified as the major players involved in their synthesis and stability. Further, Pm-AgNPs at 25μg/mL were significantly cytotoxic to lung cancer cells, whereas, Pm-AuNPs were not cytotoxic to both normal keratinocyte and lung cancer cells even at 100μg/mL. In addition, further evaluation of the anti-cancer activity of these new nanoparticles, such as migration and apoptosis, shown that Pm-AgNPs have a potential therapeutic effect on A549 lung cancer cell treatment. To the best of our knowledge, this is the first report dissecting out the ability of the endemic P. multiflorus for the synthesis of bioactive silver and gold nanoparticle which would open up doors for its extensive usage in medicinal field. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
DEFF Research Database (Denmark)
Søndergaard, Jonas Nørskov; Vinner, Lasse; Pedersen, Susanne Brix
2014-01-01
Plasmacytoid dendritic cells (pDCs) play a vital role in activation of anti-HIV-1 immunity, and suppression of pDCs might mitigate immune responses against HIV-1. HIV-1 gp120 high-mannose has been attributed immunosuppressive roles in human myeloid DCs, but no receptors for high-mannose have so far...... or viable HIV-1 particles with various degrees of mannosylation were cultured with pDCs. Activation of pDCs was determined by assaying secretion of IFN-alpha, viability, and upregulation of several pDC-activation markers: CD40, CD86, HLA-DR, CCR7, and PD-L1. The level of activation negatively correlated...
Chen, Yi; Yu, Kun; Tan, Nian-Yuan; Qiu, Ren-Hua; Liu, Wei; Luo, Ning-Lin; Tong, Le; Au, Chak-Tong; Luo, Zi-Qiang; Yin, Shuang-Feng
2014-05-22
Three heterocyclic hypervalent organoantimony chlorides RN(CH2C6H4)2SbCl (2a R = t-Bu, 2b R = Cy, 2c R = Ph) and their chalcogenide derivatives [RN(CH2C6H4)2Sb]2O (3a R = t-Bu, 3b R = Cy, 3c R = Ph) were synthesized and characterized by techniques such as (1)H NMR, (13)C NMR, X-ray diffraction, and elemental analysis. It is found that the anti-proliferative activity detected over these compounds can be attributed to the coordination bond between the antimony and nitrogen atoms of these compounds. Moreover, a preliminary study on mechanistic action suggests that the inhibition effect is ascribable to cell cycle arrest and cell apoptosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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Yan Zhang
2015-12-01
Full Text Available Corn silk is a well-known ingredient frequently used in traditional Chinese herbal medicines. This study was designed to evaluate the anti-diabetic, anti-oxidant and anti-hyperlipidemic activities of crude flavonoids extracted from corn silk (CSFs on streptozotocin (STZ-induced diabetic mice. The results revealed that treatment with 300 mg/kg or 500 mg/kg of CSFs significantly reduced the body weight loss, water consumption, and especially the blood glucose (BG concentration of diabetic mice, which indicated their potential anti-diabetic activities. Serum total superoxide dismutase (SOD and malondialdehyde (MDA assays were also performed to evaluate the anti-oxidant effects. Besides, several serum lipid values including total cholesterol (TC, triacylglycerol (TG, low density lipoprotein cholesterol (LDL-C were reduced and the high density lipoprotein cholesterol level (HDL-C was increased. The anti-diabetic, anti-oxidant and anti-hyperlipidemic effect of the CSFs suggest a potential therapeutic treatment for diabetic conditions.
TOXOPLASMA AND VIRAL ANTIBODIES AMONG HIV PATIENTS AND INMATES IN CENTRAL JAVA, INDONESIA.
Sari, Yulia; Haryati, Sri; Raharjo, Irvan; Prasetyo, Afiono Agung
2015-11-01
In Indonesia, Toxoplasma and its associations with blood-borne viruses have been poorly studied. In order to study the association between anti-Toxoplasma antibodies and blood-borne viral antibodies, blood samples from 497 participants (375 inmates from four prisons in Central Java, Indonesia and 122 HIV patients at a Voluntary Counseling and Testing Clinic in Surakarta, Indonesia) were tested for serological markers of Toxoplasma, human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and human T-lymphotropic virus types I and II (HTLV-1/2). Anti-Toxoplasma IgG and IgM positivity rates were 41.6% and 3.6%, respectively. One point two percent of participants was positive for both anti-Toxoplasma IgG and IgM antibodies. Sixteen point five percent, 11.3%, 2.6% and 2.8% of participants were positive for anti- Toxoplasma IgG combined with anti-HCV antibodies, anti-Toxoplasma IgG combined with anti-HIV antibodies, anti-Toxoplasma IgM combined with anti-HIV antibodes and anti-Toxoplasma IgG combined with both anti-HIV and anti-HCV antibodies, respectively. Anti-Toxoplasma IgM seropositivity was associated with anti-HIV (aOR = 4.3; 95% CI: 1.112-16.204, p = 0.034). Anti-Toxoplasma IgG antibodies were associated with anti-HCV (aOR = 2.8; 95% CI: 1.749-4.538, p < 0.001) and history of injection drug use (aOR = 3.1; 95% CI: 1.905-5.093, p < 0.001). In conclusion, we recommend patients with HIV, HCV infection and injection drug users should be screened for Toxoplasma infection in Indonesia.
Gabus, C; Ficheux, D; Rau, M; Keith, G; Sandmeyer, S; Darlix, J L
1998-08-17
Retroviruses, including HIV-1 and the distantly related yeast retroelement Ty3, all encode a nucleoprotein required for virion structure and replication. During an in vitro comparison of HIV-1 and Ty3 nucleoprotein function in RNA dimerization and cDNA synthesis, we discovered a bipartite primer-binding site (PBS) for Ty3 composed of sequences located at opposite ends of the genome. Ty3 cDNA synthesis requires the 3' PBS for primer tRNAiMet annealing to the genomic RNA, and the 5' PBS, in cis or in trans, as the reverse transcription start site. Ty3 RNA alone is unable to dimerize, but formation of dimeric tRNAiMet bound to the PBS was found to direct dimerization of Ty3 RNA-tRNAiMet. Interestingly, HIV-1 nucleocapsid protein NCp7 and Ty3 NCp9 were interchangeable using HIV-1 and Ty3 RNA template-primer systems. Our findings impact on the understanding of non-canonical reverse transcription as well as on the use of Ty3 systems to screen for anti-NCp7 drugs.
Rohazila M., H.; Nazlina, I.; Yaacob W., A.
2014-09-01
A study was carried out to isolate and identify the active compounds from Melastoma malabathricum stem bark that exhibit anti-biofilm and anti-adherence activities against Streptococcus mutans. Purification of the active compounds from the stem bark extract was performed via silica gel chromatography to produce 12 fractions. Further fractionation of fraction 9 by high performance liquid chromatography (HPLC) produced 21 sub fractions. All the sub fractions were subjected to thin layer chromatography (TLC) bioautography as preliminary screening to determine anti bacterial activity. TLC-bioautography showed that sub fraction 18 (SF18) demonstrated large inhibited zone against S. mutans. Gas chromatography mass spectrometry (GCMS) was used to identify the active compounds in SF18. Fraction SF18 revealed 27 compounds such as hexanoic acid, 8-methyl-1-undecene, propanenitrile, and 1-decene. Anti-biofilm and anti-adherence activities were determined using crystal violet and glass surface assays respectively. The concentrations that produced 50% reduction in anti-biofilm and anti-adherence activities were 1.88 mg/ml and 3.75 mg/ml respectively.
Evaluation of a rapid test for HIV antibodies in saliva and blood ...
African Journals Online (AJOL)
Objective. To test whole blood and saliva for HIV antibodies (anti-HIV) using a rapid test strip capillary flow . immunoassay, and to correlate the test strip results with blood specimen results obtained from routine diagnostic antiHIV assays. Design. A prospective pilot study of selected HIV-positive and HIV-negative individuals ...
HIV/AIDS Prevention Activities of Faith-Based Christian ...
African Journals Online (AJOL)
Based on these findings, it was recommended that the faith-based Christian organizations should collaborate with relevant agencies, community based workers and non-formal education providers to improve HIV/AIDS prevention service delivery in the study area. Keywords: Prevention, Activities, HIV/AIDS, Empowerment, ...
Nigella Sativa Concoction induced sustained seroreversion in HIV ...
African Journals Online (AJOL)
African Journal of Traditional, Complementary and Alternative Medicines ... Abstract. Nigella sativa had been documented to possess many therapeutic functions in medicine but the least expected is sero-reversion in HIV infection which is very rare despite extensive therapy with highly active anti-retroviral therapy (HAART).
The politics and anti-politics of social movements
DEFF Research Database (Denmark)
Burchardt, Marian; Patterson, Amy S.; Mubanda Rasmussen, Louise
2013-01-01
's poverty. Religious HIV/AIDS activities must be analysed in a conceptual space between a civil society/politics approach and a service-provider/anti-politics framework. That is, religious mobilisation may at times seek to engage the public realm to shape policies, while at other times it may shun politics...
Khodadadi, Iraj; Abdi, Mohammad; Ahmadi, Abbas; Wahedi, Mohammad Saleh; Menbari, Shahoo; Lahoorpour, Fariba; Rahbari, Rezgar
2011-08-01
To determine adenosine deaminase (ADA) activity as a possible diagnostic marker in HIV and HIV-HBV co-infected patients. Blood samples were collected from 72 healthy, 33 HIV positive and 30 HIV-HBV co-infected subjects. Blood CD4+ cell count was recorded and serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total ADA, and ADA1 and ADA2 isoenzyme activities were determined. Serum ALT, AST, total ADA and ADA2 isoenzyme activities were significantly higher in HIV positive and HIV-HBV co-infected groups compare to the control (pADA activities (R(2)=0.589, pADA was significantly increased in HIV and HIV-HBV co-infections. Therefore, because of its low cost and simplicity to perform, ADA activity might be considered as a useful diagnostic tool among the other markers in these diseases. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Alkaloids from sponge, scaffolds for the inhibition of human immunodeficiency virus (hiv)
O'Rourke, Aubrie
2016-05-06
Anti-viral compounds with low cytotoxicity are identified from screening of products found in Red Sea sponges, including the sponge Stylissa carteri. The identified compounds can be brominated pyrrole-2- aminoimidazole alkaloids and derivatives thereof. Specific examples of identified compounds include oroidin, hymenialdisine, and debromohymenialdisine, as well as derivatives thereof. The compounds also can be useful scaffolds or pharmacores for further chemical modification and derivatization. Selected compounds, particularly oroidin, show selective anti-viral HIV-1 activity coupled with reduced cytotoxicity. The compounds can function as HIV reverse-transcriptase inhibitors, and molecular modeling can be used to confirm inhibition.
Menteşe, E; Yilmaz, F; Ülker, S; Kahveci, B
2015-01-01
In this study, a new series of fluorine containing benzimidazoles (4a-l) and bisbenzimidazoles (6a-c, 8) were synthesized by the reaction of o-phenylenediamines with iminoester hydrochlorides (3a-l, 7) in methanol under microwave irradiation. The structures of these newly synthesized compounds were identified by IR, (1)H-NMR, (13)C-NMR, mass spectroscopy and elemental analysis data. The synthesized compounds were screened for their pancreatic lipase activities. Our results indicate that the compounds 6a, 6b and 6c can serve as an anti-lipase agent. The compounds 6b and 6c inhibited pancreatic lipase activity by 84.03% and 97.49% at a concentration of 3 µg/mL, respectively. © Georg Thieme Verlag KG Stuttgart · New York.
Gopala Krishna, Prashanth; Paduvarahalli Ananthaswamy, Prashanth; Trivedi, Priyanka; Chaturvedi, Vinita; Bhangi Mutta, Nagabhushana; Sannaiah, Ananda; Erra, Amani; Yadavalli, Tejabhiram
2017-06-01
In this study, we report the synthesis, structural and morphological characteristics of zinc oxide (ZnO) nanoparticles using solution combustion synthesis method where lemon juice was used as the fuel. In vitro anti-tubercular activity of the synthesized ZnO nanoparticles and their biocompatibility studies, both in vitro and in vivo were carried out. The synthesized nanoparticles showed inhibition of Mycobacterium tuberculosis H37Ra strain at concentrations as low as 12.5μg/mL. In vitro cytotoxicity study performed with normal mammalian cells (L929, 3T3-L1) showed that ZnO nanoparticles are non-toxic with a Selectivity Index (SI) >10. Cytotoxicity performed on two human cancer cell lines DU-145 and Calu-6 indicated the anti-cancer activity of ZnO nanoparticles at varied concentrations. Results of blood hemolysis indicated the biocompatibility of ZnO nanoparticles. Furthermore, in vivo toxicity studies of ZnO nanoparticles conducted on Swiss albino mice (for 14days as per the OECD 423 guidelines) showed no evident toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.
Directory of Open Access Journals (Sweden)
Rongrong Yang
2014-11-01
Conclusions: HBV co-infection can affect late immunological and virological responses to ART and increase the risk of hepatotoxicity. Mortality due to liver disease was high among HIV/HBV co-infected individuals in this study, despite HBV-active ART. As long as HIV/HBV co-infected persons need anti-HBV therapy, they should be recommended ART that includes agents with activity against both HIV and HBV, regardless of the CD4 cell count level.
Directory of Open Access Journals (Sweden)
Surached Thitimuta
2017-03-01
Full Text Available The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE (Camellia sinensis L.. The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl4-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE’s principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl4-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl4 intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.
Thitimuta, Surached; Pithayanukul, Pimolpan; Nithitanakool, Saruth; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart
2017-03-04
The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) ( Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl₄-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE's principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl₄-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl₄ intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.
Ditmore, Melissa Hope; Allman, Dan
2013-01-01
Introduction Since 2003, US government funding to address the HIV and AIDS pandemic has been subject to an anti-prostitution clause. Simultaneously, the efficacy of some HIV prevention efforts for sex work in areas receiving US government funding has diminished. This article seeks to explain why. Methods This analysis utilizes a case story approach to build a narrative of defining features of organizations in receipt of funding from the President's Emergency Plan for AIDS Relief (PEPFAR) and other US funding sources. For this analysis, multiple cases were compiled within a single narrative. This helps show restrictions imposed by the anti-prostitution clause, any lack of clarity of guidelines for implementation and ways some agencies, decision-making personnel, and staff on the ground contend with these restrictions. Results Responses to PEPFAR's anti-prostitution clause vary widely and have varied over time. Organizational responses have included ending services for sex workers, gradual phase-out of services, cessation of seeking US government HIV funds and increasing isolation of sex workers. Guidance issued in 2010 did not clarify what was permitted. Implementation and enforcement has been dependent in part on the interpretations of this policy by individuals, including US government representatives and organizational staff. Conclusions Different interpretations of the anti-prostitution clause have led to variations in programming, affecting the effectiveness of work with sex workers. The case story approach proved ideal for working with information like this that is highly sensitive and vulnerable to breach of anonymity because the method limits the potential to betray confidences and sources, and limits the potential to jeopardize funding and thereby jeopardize programming. This method enabled us to use specific examples without jeopardizing the organizations and individuals involved while demonstrating unintended consequences of PEPFAR's anti
Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies
Pietsch, E C; Dong, J; Cardoso, R; Zhang, X; Chin, D; Hawkins, R; Dinh, T; Zhou, M; Strake, B; Feng, P-H; Rocca, M; Santos, C Dos; Shan, X; Danet-Desnoyers, G; Shi, F; Kaiser, E; Millar, H J; Fenton, S; Swanson, R; Nemeth, J A; Attar, R M
2017-01-01
CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices. PMID:28234345
Mahalingam, Alamelu; Geonnotti, Anthony R.; Balzarini, Jan; Kiser, Patrick F.
2011-01-01
Lectins derived from plant and microbial sources constitute a vital class of entry inhibitors that target the oligomannose residues on the HIV envelope gp120. Despite their potency and specificity, success of lectin-based entry inhibitors may be impeded by issues in regards to economical production, formulation and potential mitogenicity. Therefore, there exists a gap in the HIV therapeutics pipeline that underscores the need for mass producible, synthetic, broad-spectrum, and biocomptabile inhibitors of HIV entry. Here, we present the development of a polymeric synthetic lectin, based on benzoboroxole (BzB), which exhibits weak affinity (~25 M−1) for non-reducing sugars, similar to those found on the HIV envelope. High molecular weight BzB-functionalized polymers demonstrated antiviral activity that increased with an increase in ligand density and molecular weight of the polymer construct; revealing that polyvalency improves activity. Polymers showed significant increase in activity from 25 to 75 mol% BzB functionalization with EC50 of 15 μM and 15 nM, respectively. A further increase in mole functionalization to 90% resulted in an increase of the EC50 (59 ± 5 nM), likely due to the elongated rigid structure of the polymer chain compelled by electrostatic repulsion between the boronic acid groups. An increase in molecular weight of the polymer at 50 mol% BzB functionalization showed a gradual but significant increase in antiviral activity, with the highest activity seen with the 382 kDa polymer (EC50 of 1.1 ± 0.5 nM in CEM cells and 11 ± 3 nM in TZM-bl cells). Supplementing the polymer backbone with 10 mol% sulfonic acid not only increased the aqueous solubility of the polymers by at least 50-fold, but also demonstrated a synergistic increase in anti-HIV activity (4.0 ± 1.5 nM in TZM-bl cells), possibly due to electrostatic interactions between the negatively charged polymer backbone and the positively charged V3-loop in the gp120. The benzoboroxole
Interleukin Gene Polymorphisms and Susceptibility to HIV Infection
Indian Academy of Sciences (India)
Chrysa
vaccines, and with almost 36.7 million HIV-infected individuals worldwide .... The allelic and genotypic distribution of the IL genes SNPs are presented in .... polymorphism using the genetic model-free bivariate approach produced, as in ... Through its immuno-inhibitory and anti-inflammatory activities and, in particular, by.
Savic, Jelena; Dilber, Sanda; Milenkovic, Marina; Kotur-Stevuljevic, Jelena; Markovic, Bojan; Vladimirov, Sote; Brboric, Jasmina
2017-01-01
Nonsteriodal anti-inflammatory drugs (NSAIDs) are numerous and widely used for more than 60 years, but there is still a strong need for developing novel selective NSAIDs. The need is justified by the fact that nonselective NSAIDs can produce serious gastric side effects and that some of the selective NSAID are withdrawn due to their cardiotoxic side effects. Eight β-hydroxy-β-arylpropanoic acids, which belong to the arylpropanoic acid class of compounds, structurally similar to some nonsteroidal anti-inflammatory drugs (NSAIDs), were docked into 3D catalytic site of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Seven out of those eight acids were synthesized using already published modification of Reformatsky reaction additionally optimized by increasing temperature. Synthesized compounds were tested in vivo in order to elucidate anti-inflammatory activity, gastric tolerability and impact on liver function of rats. Results of docking studies have indicated that all compounds have potential to selectively inhibit COX-2 isoform, but that the compounds containing polar substituents on phenyl ring are better inhibitors. Results of carrageenan-induced rat paw oedema test have shown that all compounds exhibit dose dependence and good gastric tolerability and none of the tested compounds have shown negative effect on liver function compared to ibuprofen. The compound containing polar nitro group in para position has shown the best docking results, anti-inflammatory activity, low hepatotoxicity and good gastric tolerability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
DEFF Research Database (Denmark)
Efsen, Anne Marie W; Schultze, Anna; Post, Frank A
2015-01-01
OBJECTIVES: Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients......% of participants in EE compared with 90-96% in other regions (pmanagement of TB/HIV patients in EE requires...... better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART....
Stigma, HIV and health: a qualitative synthesis
Chambers, Lori A.; Rueda, Sergio; Baker, D. Nico; Wilson, Michael G.; Deutsch, Rachel; Raeifar, Elmira; Rourke, Sean B.; Team, The Stigma Review
2015-01-01
Background HIV-related stigma continues to negatively impact the health and well-being of people living with HIV, with deleterious effects on their care, treatment and quality of life. A growing body of qualitative research has documented the relationship between HIV-related stigma and health. This review aims to synthesize qualitative evidence that explored the intersections of stigma and health for people with HIV. Methods A thematic summary was conducted that was guided by the qualitative ...
The enantioselective total synthesis of (+)-clusianone.
Horeischi, Fiene; Guttroff, Claudia; Plietker, Bernd
2015-02-11
(+)-Clusianone, an exo-type B PPAP with reported anti-HIV and chemoprotective activities, was synthesized in eleven steps with 97% ee starting from acetylacetone. An enantioselective decarboxylative Tsuji-Trost-allylation and a Ru-catalyzed ring-closing metathesis-decarboxylative allylation were used to control both diastereo- and enantioselectivity.
HIV-associated multicentric Castleman’s disease
Directory of Open Access Journals (Sweden)
Fauzia de Fátima Naime
2012-09-01
Full Text Available Multicentric Castleman’s disease (MCD is a rare lymphoproliferative disorder. It is found with higher frequency in patients with HIV infection, with systemic symptoms and poor prognosis. We present the case of a 32-year old man with HIV disease, Kaposi’s sarcoma, lymphadenopathy, fever and hemolytic anemia. A diagnosis of Castleman’s disease is confirmed through biopsy and treatment is often based only on published case reports. Systemic treatments for MCD have included chemotherapy, anti-herpes virus, highly active antiretroviral therapy and, more recently, monoclonal antibodies against both IL6 and CD20.
The synthesis of [3H]-indole-3-carbinol, a natural anti-carcinogen from cruciferous vegetables
International Nuclear Information System (INIS)
Dashwood, R.H.; Uyetake, Lyle; Fong, A.T.; Hendricks, J.D.; Bailey, G.S.
1989-01-01
Indole-3-carbinol is a natural anti-carcinogen found as a glucosinolate in cruciferous vegetables such as cabbage, cauliflower and broccoli. A complete understanding of the mechanisms of anti-carcinogenesis by this dietary inhibitor requires improved insight into the disposition and metabolic fate of indole-3-carbinol in vivo. Such metabolic studies have been hampered by the lack of a commercial source of radiolabelled compound. This provided the main impetus for the work reported here, the synthesis of 5-[ 3 H]-indole-3-carbinol from 5-bromoindole. (author)
Maksimovic-Ivanic, Danijela; Fagone, Paolo; McCubrey, James; Bendtzen, Klaus; Mijatovic, Sanja; Nicoletti, Ferdinando
2017-04-15
The possible use of HIV protease inhibitors (HIV-PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV-related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tumors, KS, lymphoma, fibrosarcoma, multiple myeloma and prostate cancer suggest other mechanisms for the anti-neoplastic activity of PIs. However, a major drawback for the possible adoption of HIV-PIs in the therapy of cancer relies on their relatively weak anticancer potency and important side effects. This has propelled several groups to generate derivatives of HIV-PIs for anticancer use, through modifications such as attachment of different moieties, ligands and transporters, including saquinavir-loaded folic acid conjugated nanoparticles and nitric oxide (NO) derivatives of HIV-PIs. In this article, we discuss the current preclinical and clinical evidences for the potential use of HIV-PIs, and of novel derivatives, such as saquinavir-NO in the treatment of cancer. © 2016 UICC.
Directory of Open Access Journals (Sweden)
Annette J. Theron
2017-11-01
Full Text Available Even after attainment of sustained viral suppression following implementation of highly active antiretroviral therapy, HIV-infected persons continue to experience persistent, low-grade, systemic inflammation. Among other mechanisms, this appears to result from ongoing microbial translocation from a damaged gastrointestinal tract. This HIV-related chronic inflammatory response is paralleled by counteracting, but only partially effective, biological anti-inflammatory processes. Paradoxically, however, this anti-inflammatory response not only exacerbates immunosuppression but also predisposes for development of non-AIDS-related, non-communicable disorders. With respect to the pathogenesis of both sustained immunosuppression and the increased frequency of non-AIDS-related disorders, the anti-inflammatory/profibrotic cytokine, transforming growth factor-β1 (TGF-β1, which remains persistently elevated in both untreated and virally suppressed HIV-infected persons, may provide a common link. In this context, the current review is focused on two different, albeit related, harmful activities of TGF-β1 in HIV infection. First, on the spectrum of anti-inflammatory/immunosuppressive activities of TGF-β1 and the involvement of this cytokine, derived predominantly from T regulatory cells, in driving disease progression in HIV-infected persons via both non-fibrotic and profibrotic mechanisms. Second, the possible involvement of sustained elevations in circulating and tissue TGF-β1 in the pathogenesis of non-AIDS-defining cardiovascular, hepatic, pulmonary and renal disorders, together with a brief comment on potential TGF-β1-targeted therapeutic strategies.
Anti-Inflammatory and Anti-Ulcerogenic Activities of Chantaleela ...
African Journals Online (AJOL)
The analgesic activity of Chantaleela recipe may act via mechanism at peripheral and partly central nervous system. In antipyretic test, Chantaleela recipe significantly decreased rectal temperature of brewer's yeast-induced hyperthermia rats, probably by inhibiting synthesis and/or release of prostaglandin E2 in the ...
DEFF Research Database (Denmark)
Kristensen, Anne B; Lay, William N; Ana-Sosa-Batiz, Fernanda
2016-01-01
to immunize this at-risk group. IMPORTANCE: Infection with HIV is associated with increasing disease severity following influenza infections, and annual influenza vaccinations are recommended for this target group. However, HIV-infected individuals respond relatively poorly to vaccination compared to healthy......This study seeks to assess the ability of seasonal trivalent inactivated influenza vaccine (TIV) to induce nonneutralizing antibodies (Abs) with Fc-mediated functions in HIV-uninfected and HIV-infected subjects. Functional influenza-specific Ab responses were studied in 30 HIV-negative and 27 HIV......-positive subjects immunized against seasonal influenza. All 57 subjects received the 2015 TIV. Fc-mediated antihemagglutinin (anti-HA) Ab activity was measured in plasma before and 4 weeks after vaccination using Fc-receptor-binding assays, NK cell activation assays, and phagocytosis assays. At baseline, the HIV...
Fitz Harris, Lauren F; Toledo, Lauren; Dunbar, Erica; Aquino, Gustavo A; Nesheim, Steven R
2014-01-01
We identified the level and type of program collaboration and service integration (PCSI) among HIV prevention programs in 59 CDC-funded health department jurisdictions. Annual progress reports (APRs) completed by all 59 health departments funded by CDC for HIV prevention activities were reviewed for collaborative and integrated activities reported by HIV programs for calendar year 2009. We identified associations between PCSI activities and funding, AIDS diagnosis rate, and organizational integration. HIV programs collaborated with other health department programs through data-related activities, provider training, and providing funding for sexually transmitted disease (STD) activities in 24 (41%), 31 (53%), and 16 (27%) jurisdictions, respectively. Of the 59 jurisdictions, 57 (97%) reported integrated HIV and STD testing at the same venue, 39 (66%) reported integrated HIV and tuberculosis testing, and 26 (44%) reported integrated HIV and viral hepatitis testing. Forty-five (76%) jurisdictions reported providing integrated education/outreach activities for HIV and at least one other disease. Twenty-six (44%) jurisdictions reported integrated partner services among HIV and STD programs. Overall, the level of PCSI activities was not associated with HIV funding, AIDS diagnoses, or organizational integration. HIV programs in health departments collaborate primarily with STD programs. Key PCSI activities include integrated testing, integrated education/outreach, and training. Future assessments are needed to evaluate PCSI activities and to identify the level of collaboration and integration among prevention programs.
Torres-Gómez, Héctor; Lehmkuhl, Kirstin; Frehland, Bastian; Daniliuc, Constantin; Schepmann, Dirk; Ehrhardt, Christina; Wünsch, Bernhard
2015-08-01
Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti-3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti-3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki=11 μM). However, both propellanamines syn-3 and anti-3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti-3 retain the NMDA antagonistic activity but loose the antiviral activity. Copyright © 2015 Elsevier Ltd. All rights reserved.
Directory of Open Access Journals (Sweden)
Ananidia Rivero
2000-12-01
Full Text Available Se describe un estudio realizado con los hemoclasificadores monoclonales cubanos Hemo CIM anti-A y anti-B producidos por el Centro de Inmunología Molecular (CIM y comercializados por CIMAB S.A, para ser evaluados en pacientes VIH/SIDA. Se analizaron un total de 130 pacientes en el Servicio de Transfusiones del Instituto "Pedro Kourí". Se utilizaron en paralelo los antisueros policlonales de producción nacional (Laboratorios Betera y los reactivos monoclonales comerciales producidos y donados por International Blood Group Reference Laboratory; Bristol, UK. Se demostró que los reactivos Hemo CIM anti-A y Hemo CIM anti-B se comportaron de forma similar a sus homólogos comerciales y policlonales. Al comparar la efectividad de la aglutinación para los 3 reactivos pudimos comprobar que con el reactivo monoclonal, Hemo CIM anti-A y anti-B se obtuvieron los mejores resultados expresados en crucesA study conducted with the Cuban anti-A and anti-B Hemo CIM monoclonal hemoclassifiers produced by the Center of Molecular Immunology (CMI and commercialized by CIMAB S.A. to be evaluated in HIV/AIDS patients is described. 130 patients were analyzed at the Service of Transfusions of "Pedro Kouri" Institute. The polyclonal antisera of national production (Betera Laboratories and the commercial monoclonal reagents produced and donated by the International Blood Group Reference Laboratory; Bristol, UK, were used at the same time. It was proved that the anti-A Hemo CIM and anti-B Hemo CIM reagents behaved similarly to their commercial and polyclonal homologues. On comparing the effectiveness of the agglutination for the 3 reagents, we were able to verify that the best results expressed in crosses were obtained with the anti-A and anti-B Hemo CIM monoclonal reagents
HIV-1 gp41 Fusion Intermediate: A Target for HIV Therapeutics
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Chungen Pan
2010-02-01
Full Text Available Human immunodeficiency virus (HIV-1 infection is initiated by the binding of gp120 envelope glyco-protein to its cell receptor (CD4 and a coreceptor (CXCR4 or CCR5, followed by a series of conformational changes in the gp41 transmembrane subunit. These changes include insertion of fusion peptide into the target cell membrane and association of C-heptad repeat (CHR peptide with the N-heptad repeat (NHR trimer, a pre-hairpin fusion intermediate. A stable six-helix bundle core is then formed, bringing the viral envelope and target cell membrane into close proximity for fusion. Peptides derived from the CHR region, such as T20 and C34, inhibit HIV-1 fusion by interacting with the gp41 fusion intermediate. A number of anti-HIV-1 peptides and small molecule compounds targeting the gp41 NHR-trimer have been identified. By combining HIV fusion/entry inhibitors targeting different sites in the gp41 fusion intermediate, a potent synergistic effect takes place, resulting in a potential new therapeutic strategy for the HIV infection/AIDS. Here, we present an overview of the current development of anti-HIV drugs, particularly those targeting the gp41 fusion intermediate.
Singh, Kislay; Jaiswal, Swadha; Singh, Richa; Fatma, Sana; Prasad, Bhim Bali
2018-07-15
Double layered one-by-one imprinted hollow core-shells@ pencil graphite electrode was fabricated for sequential sensing of anti-HIV drugs. For this, two eccentric layers were developed on the surface of vinylated silica nanospheres to obtain double layered one-by-one imprinted solid core-shells. This yielded hollow core-shells on treatment with hydrofluoric acid. The modified hollow core-shells (single layered dual imprinted) evolved competitive diffusion of probe/analyte molecules. However, the corresponding double layered one-by-one imprinted hollow core-shells (outer layer imprinted with Zidovudine, and inner layer with Lamivudine) were found relatively better owing to their bilateral diffusions into molecular cavities, without any competition. The entire work is based on differential pulse anodic stripping voltammetry at double layered one-by-one imprinted hollow core-shells. This resulted in indirect detection of electro inactive targets with limits of detection as low as 0.91 and 0.12 (aqueous sample), 0.94 and 0.13 (blood serum), and 0.99 and 0.20 ng mL -1 (pharmaceutics) for lamivudine and zidovudine, respectively in anti-HIV drug combination. Copyright © 2018 Elsevier B.V. All rights reserved.
Raltegravir: first in class HIV integrase inhibitor
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Zelalem Temesgen
2008-06-01
Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors
Tubuloreticular inclusions in skin biopsies from patients with HIV infection
DEFF Research Database (Denmark)
Pedersen, C; Horn, T; Junge, Jette
1989-01-01
Skin biopsies obtained from apparently normal skin from 15 HIV infected patients and 6 anti-HIV negative patients were examined by electron microscopy. Tubuloreticular inclusions (TRI) were detected within the cytoplasm of capillary endothelial cells in 5/5 AIDS patients and in 2/5 patients...... of the patients without TRI, interferon activity was below detection level. The occurrence of TRI was not dependent on the presence of free p24 antigen in serum. It is concluded that the occurrence of TRI in entothelial cells of skin capillaries is associated with late stages of HIV infection and this may...
Analgesic, anti-inflammatory and anti-platelet activities of Buddleja crispa.
Bukhari, Ishfaq A; Gilani, Anwar H; Meo, Sultan Ayoub; Saeed, Anjum
2016-02-25
Buddleja crispa Benth (Buddlejaceae) is a dense shrub; several species of genus Buddleja have been used in the management of various health conditions including pain and inflammation. The present study was aimed to investigate the analgesic, anti-inflammatory and anti-platelet properties of B. crispa. Male rats (220-270 gm,) and mice (25-30 gm) were randomly divided into different groups (n = 6). Various doses of plant extract of B. crispa, its fractions and pure compounds isolated from the plant were administered intraperitoneally (i.p). The analgesic, anti-inflammatory and anti-platelet activities were assessed using acetic acid and formalin-induced nociception in mice, carrageenan-induced rat paw edema and arachidonic acid-induced platelets aggregation tests. The intraperitoneal administration of the methanolic extract (50 and 100 mg/kg), hexane fraction (10 and 25 mg/kg i.p) exhibited significant inhibition (P < 0.01) of the acetic acid-induced writhing in mice and attenuated formalin-induced reaction time of animals in second phase of the test. Pure compounds BdI-2, BdI-H3 and BH-3 isolated from B. crispa produced significant (P < 0.01) analgesic activity in acetic acid-induced and formalin tests. The crude extract of B. crispa (50-200 mg/kg i.p.) and its hexane fraction inhibited carrageenan-induced rat paw edema with maximum inhibition of 65 and 71% respectively (P < 0.01). The analgesic and anti-inflammatory effect of the plant extract and isolated pure compounds were comparable to diclofenac sodium. B. crispa plant extract (0.5-2.5 mg/mL) produced significant anti-platelet effect (P < 0.01) with maximum inhibition of 78% at 2.5 mg/ml. The findings from our present study suggest that B. crispa possesses analgesic, anti-inflammatory and anti-platelet properties. B. crispa could serve a potential novel source of compounds effective in pain and inflammatory conditions.
In vitro demonstration of anti-lipogenic activity in serum from obese rats
International Nuclear Information System (INIS)
Harris, R.B.S.; Martin, R.J.
1986-01-01
Studies with parabiosed rats provide evidence for a humoral factor, originating in obese animals, that specifically inhibits adipose lipogenesis. A bioassay was developed that allows serum from obese rats to be tested for this factor in vitro. Adipocytes are isolated from epididymal fat of 250g Sprague-Dawley rats. The cells are preincubated at 37 0 C for 1 or 12 hrs, in TC199 media containing 1.1 mg/ml glucose, 0.1 M Hepes and 2% serum. Following preincubation, the cells are washed 3 times and resuspended in serum-free media. Aliquots of cells are tested for metabolic activity in a subsequent 2 hour radiolabelled incubation in serum-free media with the addition of 0.5 μCi/ml U- 14 C-glucose. Basal, insulin (100 μU/ml) and norepinephrine (0.1 μg/ml) stimulated rates of glucose oxidation and conversion to triglyceride fatty acids are measured. Using serum from ad libitum fed rats as control, preincubation with serum from obese rats (20 days at 2 x normal intake) depressed basal and insulin stimulated glucose oxidation, and basal fatty acid synthesis. Serum from obese parabiotic rats and parabiotic partners of obese rats depressed basal fatty acid synthesis. This assay allows us to test serum for anti-lipogenic activity and may be used to identify the factor responsible for this activity in obese animals
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Monajemi Mahdis
2012-04-01
Full Text Available Abstract The enzyme APOBEC3G (A3G mutates the human immunodeficiency virus (HIV genome by converting deoxycytidine (dC to deoxyuridine (dU on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G’s standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation.
Bhargava, S; Adhikari, N; Amin, S A; Das, K; Gayen, S; Jha, T
2017-12-01
Application of HIV-1 protease inhibitors (as an anti-HIV regimen) may serve as an attractive strategy for anti-HIV drug development. Several investigations suggest that there is a crucial need to develop a novel protease inhibitor with higher potency and reduced toxicity. Monte Carlo optimized QSAR study was performed on 200 hydroxyethylamine derivatives with antiprotease activity. Twenty-one QSAR models with good statistical qualities were developed from three different splits with various combinations of SMILES and GRAPH based descriptors. The best models from different splits were selected on the basis of statistically validated characteristics of the test set and have the following statistical parameters: r 2 = 0.806, Q 2 = 0.788 (split 1); r 2 = 0.842, Q 2 = 0.826 (split 2); r 2 = 0.774, Q 2 = 0.755 (split 3). The structural attributes obtained from the best models were analysed to understand the structural requirements of the selected series for HIV-1 protease inhibitory activity. On the basis of obtained structural attributes, 11 new compounds were designed, out of which five compounds were found to have better activity than the best active compound in the series.
Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics
Debnath, Utsab; Verma, Saroj; Jain, Surabhi; Katti, Setu B.; Prabhakar, Yenamandra S.
2013-07-01
CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors' binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants' isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.
Shan, Liang; Siliciano, Robert F.
2014-01-01
Chronic immune activation is a key factor in HIV-1 disease progression. The translocation of microbial products from the intestinal lumen into the systemic circulation occurs during HIV-1 infection and is associated closely with immune activation; however, it has not been determined conclusively whether microbial translocation drives immune activation or occurs as a consequence of HIV-1 infection. In an important study in this issue of the JCI, Kristoff and colleagues describe the role of microbial translocation in producing immune activation in an animal model of HIV-1 infection, SIV infection of pigtailed macaques. Blocking translocation of intestinal bacterial LPS into the circulation dramatically reduced T cell activation and proliferation, production of proinflammatory cytokines, and plasma SIV RNA levels. This study directly demonstrates that microbial translocation promotes the systemic immune activation associated with HIV-1/SIV infection. PMID:24837427
Inhibition of ecto-ATPase activities impairs HIV-1 infection of macrophages.
Schachter, Julieta; Delgado, Kelly Valcárcel; Barreto-de-Souza, Victor; Bou-Habib, Dumith Chequer; Persechini, Pedro Muanis; Meyer-Fernandes, José Roberto
2015-05-01
Nucleotides and nucleosides are secreted into extracellular media at different concentrations as a consequence of different physiologic and pathological conditions. Ecto-nucleotidases, enzymes present on the surface of most cells, hydrolyze these extracellular nucleotides and reduce the concentration of them, thus affecting the activation of different nucleotide and nucleoside receptors. Also, ecto-nucleotidases are present in a number of microorganisms and play important roles in host-pathogen interactions. Here, we characterized the ecto-ATPase activities present on the surface of HIV-1 particle and human macrophages as well. We found that the kinetic properties of HIV-1 and macrophage ecto-ATPases are similar, suggesting that the enzyme is the same. This ecto-ATPase activity was increased in macrophages infected in vitro with HIV-1. Using three different non-related ecto-ATPase inhibitors-POM-1, ARL67156 and BG0-we showed that the inhibition of these macrophage and viral ecto-ATPase activities impairs HIV-1 infection. In addition, we also found that elevated extracellular concentrations of ATP inhibit HIV-1 production by infected macrophages. Copyright © 2014 Elsevier GmbH. All rights reserved.
Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L.
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McCoy Joe-Ann
2011-04-01
Full Text Available Abstract Background The mint family (Lamiaceae produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L., sage (Salvia spp., peppermint (Mentha × piperita L., hyssop (Hyssopus officinalis L., basil (Ocimum spp. and self-heal (Prunella vulgaris L.. To further characterize the anti-lentiviral activities of Prunella vulgaris, water and ethanol extracts were tested for their ability to inhibit HIV-1 infection. Results Aqueous extracts contained more anti-viral activity than did ethanol extracts, displaying potent antiviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in our virus/cell interaction studies, extract effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that it was targeting of these latter steps that was most important for mediating inhibition of virus infectivity. Conclusions We demonstrate that aqueous P. vulgaris extracts inhibited HIV-1 infectivity. Our studies suggest that inhibition occurs primarily by interference of early, post-virion binding events. The ability of aqueous extracts to inhibit early events within the HIV life cycle suggests that these extracts, or purified constituents responsible for the antiviral activity, are promising microbicides and/or antivirals against HIV-1.
Denegetu, Amenu Wesen; Dolamo, Bethabile Lovely
2014-01-01
Collaborative TB/HIV management is essential to ensure that HIV positive TB patients are identified and treated appropriately, and to prevent tuberculosis (TB) in HIV positive patients. The purpose of this study was to assess HIV case finding among TB patients and Co-trimoxazole Preventive Therapy (CPT) for HIV/TB patients in Addis Ababa. A descriptive cross-sectional, facility-based survey was conducted between June and July 2011. Data was collected by interviewing 834 TB patients from ten health facilities in Addis Ababa. Both descriptive and inferential statistics were used to summarize and analyze findings. The proportion of TB patients who (self reported) were offered for HIV test, tested for HIV and tested HIV positive during their anti-TB treatment follow-up were; 87.4%, 69.4% and 20.2%; respectively. Eighty seven HIV positive patients were identified, who knew their status before diagnosed for the current TB disease, bringing the cumulative prevalence of HIV among TB patients to 24.5%. Hence, the proportion of TB patients who knew their HIV status becomes 79.9%. The study revealed that 43.6% of those newly identified HIV positives during anti-TB treatment follow-up were actually treated with CPT. However, the commutative proportion of HIV positive TB patients who were ever treated with CPT was 54.4%; both those treated before the current TB disease and during anti-TB treatment follow-up. HIV case finding among TB patients and provision of CPT for TB/HIV co-infected patients needs boosting. Hence, routine offering of HIV test and provision of CPT for PLHIV should be strengthened in-line with the national guidelines.
Raja, K.; Saravanakumar, A.; Vijayakumar, R.
2012-11-01
In this paper, aqueous extract of fresh leaves of Prosopis juliflora was used for the synthesis of silver (Ag) nanoparticles. UV-Vis spectroscopy studies were carried out to asses silver nanoparticles formation within 5 min, scanning electron microscopic was used to characterize shape of the Ag nanoparticles, X-ray diffraction analysis confirms the nanoparticles as crystalline silver and facecentered cubic type and Fourier transform infra-red assed that shows biomolecule compounds which are responsible for reduction and capping material of silver nanoparticles. The anti microbial activity of silver nanoparticle was performed using sewage. The approach of plant-mediated synthesis appears to be cost efficient, eco-friendly and easy methods.
Non-adherence to anti-retroviral therapy among HIV infected adults in Mon State of Myanmar
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Win Lei Aye
2017-05-01
Full Text Available Abstract Background The provision of Anti-Retroviral Therapy (ART was started in Myanmar in 2005 in collaboration with the National AIDS Program and the private sector. Successful clinical management of HIV-infected patients is subject to optimal adherence. The aim of the study was to determine the prevalence of adherence to ART and identify factors associated with non-adherence to ART among HIV infected adults registered in a private sector setting in Mon State, Myanmar. Methods This cross-sectional study was conducted with adults living with HIV receiving ART at an HIV outpatient clinic between April and May 2016. A total of three hundred People Living with HIV(PLHIV were interviewed using a pretested and structured questionnaire. The 30 days Visual Analog Scale (VAS adherence instrument was used to assess the level of adherence. Multivariable logistic regression analysis was used to determine factors associated with non-adherence to ART. Results Among 300 patients (male 37.7% and female 62.3%, with a mean age of 41.3 years, standard deviation 8.7, 84% reported ≥95% adherence to ART in the past month. Among 16% of those reporting non-adherence, major reasons for skipping the medication were being busy (23%, being away from home (17.7% and being forgetful (12.3%. In multivariable logistic rgeression, low behavioural skills on ART adherence (OR = 0.31, 95% CI: 0.10-0.94, tobacco use (OR = 3.22, 95% CI:1.28-8.12, having disclosed their HIV status (OR = 0.07, 95% CI: 0.01-0.69, having a partner who was not on ART (OR = 4.25, 95% CI: 1.70-10.64 and among men, having erectile dysfunction (OR = 15.14, 95% CI: 1.41-162.66 were significant associated with ART non-adherence. Conclusion Non-adherence to ART was associated with individual moderating factors and behavioral skills. Priority measures such as addressing risk behaviour and behavioural change communication tailored to individual patients’ lifestyles requires comprehensive
Non-adherence to anti-retroviral therapy among HIV infected adults in Mon State of Myanmar.
Aye, Win Lei; Puckpinyo, Apa; Peltzer, Karl
2017-05-05
The provision of Anti-Retroviral Therapy (ART) was started in Myanmar in 2005 in collaboration with the National AIDS Program and the private sector. Successful clinical management of HIV-infected patients is subject to optimal adherence. The aim of the study was to determine the prevalence of adherence to ART and identify factors associated with non-adherence to ART among HIV infected adults registered in a private sector setting in Mon State, Myanmar. This cross-sectional study was conducted with adults living with HIV receiving ART at an HIV outpatient clinic between April and May 2016. A total of three hundred People Living with HIV(PLHIV) were interviewed using a pretested and structured questionnaire. The 30 days Visual Analog Scale (VAS) adherence instrument was used to assess the level of adherence. Multivariable logistic regression analysis was used to determine factors associated with non-adherence to ART. Among 300 patients (male 37.7% and female 62.3%, with a mean age of 41.3 years, standard deviation 8.7), 84% reported ≥95% adherence to ART in the past month. Among 16% of those reporting non-adherence, major reasons for skipping the medication were being busy (23%), being away from home (17.7%) and being forgetful (12.3%). In multivariable logistic rgeression, low behavioural skills on ART adherence (OR = 0.31, 95% CI: 0.10-0.94), tobacco use (OR = 3.22, 95% CI:1.28-8.12), having disclosed their HIV status (OR = 0.07, 95% CI: 0.01-0.69), having a partner who was not on ART (OR = 4.25, 95% CI: 1.70-10.64) and among men, having erectile dysfunction (OR = 15.14, 95% CI: 1.41-162.66) were significant associated with ART non-adherence. Non-adherence to ART was associated with individual moderating factors and behavioral skills. Priority measures such as addressing risk behaviour and behavioural change communication tailored to individual patients' lifestyles requires comprehensive interventions to improve adherence.
Pantelic, Marija; Boyes, Mark; Cluver, Lucie; Meinck, Franziska
2017-08-21
Internalized HIV stigma is a key risk factor for negative outcomes amongst adolescents living with HIV (ALHIV), including non-adherence to anti-retroviral treatment, loss-to-follow-up and morbidity. This study tested a theoretical model of multi-level risk pathways to internalized HIV stigma among South African ALHIV. From 2013 to 2015, a survey using t otal population sampling of ALHIV who had ever initiated anti-retroviral treatment (ART) in 53 public health facilities in the Eastern Cape, South Africa was conducted. Community-tracing ensured inclusion of ALHIV who were defaulting from ART or lost to follow-up. 90.1% of eligible ALHIV were interviewed ( n = 1060, 55% female, mean age = 13.8, 21% living in rural locations). HIV stigma mechanisms (internalized, enacted, and anticipated), HIV-related disability, violence victimization (physical, emotional, sexual abuse, bullying victimization) were assessed using well-validated self-report measures. Structural equation modelling was used to test a theoretically informed model of risk pathways from HIV-related disability to internalized HIV stigma. The model controlled for age, gender and urban/rural address. Prevalence of internalized HIV stigma was 26.5%. As hypothesized, significant associations between internalized stigma and anticipated stigma, as well as depression were obtained. Unexpectedly, HIV-related disability, victimization, and enacted stigma were not directly associated with internalized stigma. Instead significant pathways were identified via anticipated HIV stigma and depression. The model fitted the data well (RMSEA = .023; CFI = .94; TLI = .95; WRMR = 1.070). These findings highlight the complicated nature of internalized HIV stigma. Whilst it is seemingly a psychological process, indirect pathways suggest multi-level mechanisms leading to internalized HIV stigma. Findings suggest that protection from violence within homes, communities and schools may interrupt risk pathways from HIV
Imperatorin inhibits HIV-1 replication through an Sp1-dependent pathway.
Sancho, Rocío; Márquez, Nieves; Gómez-Gonzalo, Marta; Calzado, Marco A; Bettoni, Giorgio; Coiras, Maria Teresa; Alcamí, José; López-Cabrera, Manuel; Appendino, Giovanni; Muñoz, Eduardo
2004-09-03
Coumarins and structurally related compounds have been recently shown to present anti-human immunodeficiency virus, type 1 (HIV-1) activity. Among them, the dietary furanocoumarin imperatorin is present in citrus fruits, in culinary herbs, and in some medicinal plants. In this study we report that imperatorin inhibits either vesicular stomatitis virus-pseudotyped or gp160-enveloped recombinant HIV-1 infection in several T cell lines and in HeLa cells. These recombinant viruses express luciferase as a marker of viral replication. Imperatorin did not inhibit the reverse transcription nor the integration steps in the viral cell cycle. Using several 5' long terminal repeat-HIV-1 constructs where critical response elements were either deleted or mutated, we found that the transcription factor Sp1 is critical for the inhibitory activity of imperatorin induced by both phorbol 12-myristate 13-acetate and HIV-1 Tat. Moreover in transient transfections imperatorin specifically inhibited phorbol 12-myristate 13-acetate-induced transcriptional activity of the Gal4-Sp1 fusion protein. Since Sp1 is also implicated in cell cycle progression we further studied the effect of imperatorin on cyclin D1 gene transcription and protein expression and in HeLa cell cycle progression. We found that imperatorin strongly inhibited cyclin D1 expression and arrested the cells at the G(1) phase of the cell cycle. These results highlight the potential of Sp1 transcription factor as a target for natural anti-HIV-1 compounds such as furanocoumarins that might have a potential therapeutic role in the management of AIDS.
The design of drugs for HIV and HCV.
De Clercq, Erik
2007-12-01
Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antiviral drugs, and future treatment strategies for chronic HCV might involve combination regimens that are analogous to those currently used for HIV. By considering the drug targets in the different stages of the life cycle of these two viruses, this article presents aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV, and highlights general lessons learned from anti-HIV-drug design that could be applied to HCV.
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J. Dik F. Habbema
2011-10-01
Full Text Available Background: Micronutrient supplementation has been shown to reduce the progression of HIV but does not have an effect on the intestinal barrier or the intestinal microbiota of HIV patients. Studies have suggested that probiotics could potentially complement micronutrients in preserving the immune-function of HIV patients. Objective: Assess the impact of micronutrient supplemented probiotic yogurt on the immune function of HIV patients. Design: We performed a randomized, double blind, controlled trial with CD4 count as primary outcome among HIV patients naïve to anti-retroviral treatment. Secondary outcomes included hematological parameters, incidence of diarrhea and clinical symptoms. A total of 112 HIV patients were randomized to receive a micronutrient fortified yogurt with (n = 55 or without additional probiotic Lactobacillus rhamnosus GR-1 (n = 57 for four weeks. Results: An average decline in CD4 count of −70 cells/μL (95% CI: −154 to −15 was observed in the micronutrient, probiotic group versus a decrease of −63 cells/μL (95% CI: −157 to −30 in the micronutrient control group (p = 0.9. Additional probiotic supplementation was well tolerated and not associated with adverse events. No difference between groups was detected in incidence of diarrhea or clinical symptoms. An improvement of hemoglobin levels was observed for all subjects, based upon a mean difference from baseline of 1.4 g/L (SD = 6 (p = 0.02. Conclusion: The addition of probiotics to a micronutrient fortified yogurt was well tolerated by HIV patients but was not associated with a further increase in CD4 count after one month.
Darlix, J L; Vincent, A; Gabus, C; de Rocquigny, H; Roques, B
1993-08-01
Two DNA strand transfer reactions take place during reverse transcription of the retroviral genome. The first transfer, that of the minus-strand strong stop DNA from the 5' end of the viral RNA to the 3' end, has been studied in vitro with two RNAs mimicking the 5' and 3' regions of the HIV1 genome and with nucleocapsid protein, NCp7, and reverse transcriptase. The results show that NCp7 strongly activates the 5' to 3' DNA strand transfer during reverse transcription while a basic peptide resembling NCp7 is inactive. Activation of the first transfer by several NCp7 derived peptides and the influence of the terminal redundancies (R) present at the 5' and 3' ends of HIV1 RNA were also examined. The first transfer is optimal in the presence of intact NCp7 and necessitates R on both the 5' and 3' RNAs. Sequencing of full length viral DNA products reveals approximately 40% misincorporations at the first nucleotide beyond the transfer point. If such base misincorporations occur during proviral DNA synthesis with possible homologous recombinations it may well contribute to the high level of genetic variability of HIV.
Qadir, Muhammad Imran; Abbas, Khizar; Hamayun, Rahma; Ali, Muhammad
2014-11-01
The objective of the study was to investigate the analgesic, anti-inflammatory and anti-pyretic activity of aqueous ethanolic extracts of Tamarix aphylla. The powdered plant was extracted by the method of cold maceration using aqueous ethanol (70:30) as solvents. Analgesic activity was assessed by Eddy's hot plate method, formalin-induced paw licking and acetic acid-induced writhing in mice. Anti-inflammatory activity was evaluated by carageenan-induced mice paw edema. The anti-pyretic activity was determined by yeast-induced pyrexia in mice. The aqueous ethanolic extract of Tamarix aphylla showed 42% inhibition (pTamarix aphylla exhibit analgesic and antipyretic activity but lacks anti-inflammatory activity.
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Rafiq Nabi
Full Text Available Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV replication in elite controllers (EC remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC and viremic noncontrollers (HN on highly active antiretroviral therapy (HAART. Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1, a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of
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Buchholz Bernd
2009-11-01
Full Text Available Abstract German-Austrian recommendations for HIV1-therapy in pregnancy - Update 2008 Bernd Buchholz (University Medical Centre Mannheim, Pediatric Clinic, Matthias Beichert (Mannheim, Gynecology and Obstetrics Practice, Ulrich Marcus (Robert Koch Institute, Berlin, Thomas Grubert, Andrea Gingelmaier (Gynecology Clinic of the Ludwig Maximilians University of Munich, Dr. med. Annette Haberl (HIV-Department, J. W. Goethe-University Hospital, Frankfurt, Dr. med. Brigitte Schmied (Otto-Wagner Spital, Wien. In Germany during the last years about 200-250 HIV1-infected pregnant women delivered a baby each year, a number that is currently increasing. To determine the HIV-status early in pregnancy voluntary HIV-testing of all pregnant women is recommended in Germany and Austria as part of prenatal care. In those cases, where HIV1-infection was known during pregnancy, since 1995 the rate of vertical transmission of HIV1 was reduced to 1-2%. This low transmission rate has been achieved by the combination of anti-retroviral therapy of pregnant women, caesarean section scheduled before onset of labour, anti-retroviral post exposition prophylaxis in the newborn and refraining from breast-feeding by the HIV1-infected mother. To keep pace with new results in research, approval of new anti-retroviral drugs and changes in the general treatment recommendations for HIV1-infected adults, in 1998, 2001, 2003 and 2005 an interdisciplinary consensus meeting was held. Gynaecologists, infectious disease specialists, paediatricians, pharmacologists, virologists and members of the German AIDS Hilfe (NGO were participating in this conference to update the prevention strategies. A fifth update became necessary in 2008. The updating process was started in January 2008 and was terminated in September 2008. The guidelines provide new recommendations on the indication and the starting point for HIV-therapy in pregnancies without complications, drugs and drug combinations to be
International Nuclear Information System (INIS)
Stankovicova, M.; Bachrata, M.; Sveda, P.; Rauko, P.; Blesova, P.
1995-01-01
Hydrochloride of 5'-chloro-5'-deoxy-cytocytidine (Cl-cC) is an analogue of hydrochloride (cC), a pro-drug of the compound with of the compound with the strong anti-leukemic activity arabinosylcytosine (araC). This paper is devoted to the study of its cytotoxic activity in vitro and to the effect of acid alkaline conditions and temperature on its stability. Cl-cC inhibits not only the growth of L1210 leukemia cells in vitro and the DNA synthesis (IC 50 = 0.09 μmol/dm 3 ) but, at the same time, it has a weak effect on RNA synthesis (IC 50 > 250 μmol/dm 3 ) and no effect on proteosynthesis. In alkaline conditions Cl-cC is transformed to 5'-chloro-araC and 2',5'-anhydro-araC but is more stable in acid solutions. (author)
Avettand-Fenoël, Véronique; Nembot, Georges; Mélard, Adeline; Blanc, Catherine; Lascoux-Combe, Caroline; Slama, Laurence; Allegre, Thierry; Allavena, Clotilde; Yazdanpanah, Yazdan; Duvivier, Claudine; Katlama, Christine; Goujard, Cécile; Seksik, Bao Chau Phung; Leplatois, Anne; Molina, Jean-Michel; Meyer, Laurence; Autran, Brigitte; Rouzioux, Christine
2013-01-01
Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3−CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that
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Charline Bacchus
Full Text Available Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI. We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM] and short-lived (transitional-memory [TTM] and effector-memory cells [TEM] resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells, although 10-fold less (p = 0.0005 than in equally infected TCM (4.5, TTM (4.7 and TEM (4.6 cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells, unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells. The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility
Non-Neutralizing Antibodies Directed against HIV and Their Functions
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Luzia M. Mayr
2017-11-01
Full Text Available B cells produce a plethora of anti-HIV antibodies (Abs but only few of them exhibit neutralizing activity. This was long considered a profound limitation for the enforcement of humoral immune responses against HIV-1 infection, especially since these neutralizing Abs (nAbs are extremely difficult to induce. However, increasing evidence shows that additional non-neutralizing Abs play a significant role in decreasing the viral load, leading to partial and sometimes even total protection. Mechanisms suspected to participate in protection are numerous. They involve the Fc domain of Abs as well as their Fab part, and consequently the induced Ab isotype will be determinant for their functions, as well as the quantity and quality of the Fc-receptors (FcRs expressed on immune cells. Fc-mediated inhibitory functions, such as Ab-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, aggregation, and even immune activation have been proposed. However, as for nAbs, the non-neutralizing activities are limited to a subset of anti-HIV Abs. An improved in-depth characterization of the Abs displaying these functional responses is required for the development of new vaccination strategies, which aim to selectively trigger the B cells able to induce the right functional Ab combinations both at the right place and at the right time. This review summarizes our current knowledge on non-neutralizing functional inhibitory Abs and discusses the potential benefit of inducing them via vaccination. We also provide new insight into the roles of the FcγR-mediated Ab therapeutics in clinical trials for HIV diseases.
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Eliane Maria Fleury Seidl
2007-10-01
Full Text Available O estudo objetivou descrever o comportamento de adesão ao tratamento anti-retroviral em pessoas vivendo com HIV/AIDS e investigar preditores da adesão entre as variáveis escolaridade, presença de efeitos colaterais, interrupção anterior da terapia anti-retroviral (TARV por conta própria, auto-estima, expectativa de auto-eficácia, estratégias de enfrentamento, suporte social e satisfação com a relação profissional de saúde-usuário. Adesão foi medida pelo auto-relato da perda do número de comprimidos/cápsulas dos medicamentos anti-retrovirais na última semana e mês, sendo considerada satisfatória na ocorrência de omissão inferior a 5% do total prescrito. Participaram 101 pessoas, 60,4% homens, idades entre 20 a 71 anos (M = 37,9 anos, 73,3% sintomáticos. A coleta de dados incluiu entrevista e instrumentos auto-aplicáveis. A maioria (n = 73; 72,3% relatou adesão igual ou superior a 95%. Nos resultados da regressão logística, interrupção anterior da TARV e expectativa de auto-eficácia foram preditores significativos da adesão. Faz-se necessária a qualificação da assistência pela constituição de equipes interdisciplinares, para o desenvolvimento de abordagens adequadas às dificuldades médicas e psicossociais de adesão das pessoas vivendo com HIV/AIDS.This study aimed to describe the adherence of persons living with HIV/AIDS to antiretroviral therapy (ART and to investigate adherence predictors among the following: level of schooling, presence of side effects, current or previous interruption of ART by the persons themselves, self-esteem, self-efficacy expectation, coping strategies, social support, and satisfaction with the health professional-patient relationship. Adherence was measured by self-reported number of ART pills/capsules missed during the previous week and previous month, evaluated as satisfactory when less than 5%. 101 HIV+ adults took part in this study, 60.4% males, ranging from 20 to 71 years
Toledo, Thaís Regina; Dejani, Naiara N.; Monnazzi, Luis Gustavo Silva; Kossuga, Miriam H.; Berlinck, Roberto G. S.; Sette, Lara D.; Medeiros, Alexandra I.
2014-01-01
Very little is known about the immunomodulatory potential of secondary metabolites isolated from marine microorganisms. In the present study, we characterized pyrenocine A, which is produced by the marine-derived fungus Penicillium paxilli Ma(G)K and possesses anti-inflammatory activity. Pyrenocine A was able to suppress, both pretreatment and posttreatment, the LPS-induced activation of macrophages via the inhibition of nitrite production and the synthesis of inflammatory cytokines and PGE2. Pyrenocine A also exhibited anti-inflammatory effects on the expression of receptors directly related to cell migration (Mac-1) as well as costimulatory molecules involved in lymphocyte activation (B7.1). Nitrite production was inhibited by pyrenocine A in macrophages stimulated with CpG but not Poly I:C, suggesting that pyrenocine A acts through the MyD88-dependent intracellular signaling pathway. Moreover, pyrenocine A is also able to inhibit the expression of genes related to NFκB-mediated signal transduction on macrophages stimulated by LPS. Our results indicate that pyrenocine A has promissory anti-inflammatory properties and additional experiments are necessary to confirm this finding in vivo model. PMID:24574582
Cortisol patterns are associated with T cell activation in HIV.
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Sarah Patterson
Full Text Available The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.We studied 128 HIV-infected adults who were not on treatment and had a CD4(+ T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+ T cells (r = -0.26, p = 0.006. Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+ T cells (r = -0.17, p = 0.08. A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+ (r = 0.24, p = 0.018 and CD8(+ (r = 0.24, p = 0.017 activation.These data suggest that the hypothalamic-pituitary-adrenal (HPA axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.
Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 Gag-Pol.
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Anna Figueiredo
2006-11-01
Full Text Available Nonnucleoside reverse transcriptase inhibitors (NNRTIs target HIV-1 reverse transcriptase (RT by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation.
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Sergio Corrêa Marques
2015-01-01
Full Text Available Objetivos: identificar e descrever as condutas dos profissionais de saúde na oferta do teste anti-HIV; analisar as práticas dos profissionais a partir dos relatos das usuárias dos serviços da rede básica de saúde. Método: é um estudo descritivo, qualitativo, com 40 mulheres assistidas em 08 Centros Municipais de Saúde. Resultados: a produção discursiva das entrevistas foi submetida ao programa Alceste, constituindo duas categorias de análise. A primeira contempla as abordagens no atendimento individual na rede de CMS do Rio de Janeiro descrevendo os três modos de conduta dos profissionais de saúde durante a oferta de teste anti-HIV. A segunda categoria refere-se às abordagens no atendimento coletivo, onde se observa que as atividades de aconselhamento não ocorrem de maneira uniforme. Conclusão: que os resultados apontam para uma prática que se desvirtua do que vem sendo preconizado pelos Programas oficiais em relação ao Aconselhamento.
The successes and failures of HIV drug discovery.
Hashimoto, Chie; Tanaka, Tomohiro; Narumi, Tetsuo; Nomura, Wataru; Tamamura, Hirokazu
2011-10-01
To date, several anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have been developed and used clinically for the treatment of patients infected with HIV. Recently, novel drugs have been discovered which have different mechanisms of action from those of the above inhibitors, including entry inhibitors and integrase (IN) inhibitors; the clinical use of three of these inhibitors has been approved. Other inhibitors are still in development. This review article summarizes the history of the development of anti-HIV drugs and also focuses on successes in the development of these entry and IN inhibitors, along with looking at exploratory approaches for the development of other inhibitors. Currently used highly active antiretroviral therapy can be subject to a loss of efficacy, due to the emergence of multi-drug resistant (MDR) strains; a change of regimens of the drug combination is required to combat this, along with careful monitoring of the virus and CD4 in the blood, by methods such as cellular tropism testing. In such a situation, entry inhibitors such as CCR5/CXCR4 antagonists, CD4 mimics, fusion inhibitors and IN inhibitors might be optional agents for an expansion of the drug repertoire available to patients at all stages of HIV infection.
Abdel-Mohsen, Mohamed; Kuri-Cervantes, Leticia; Grau-Exposito, Judith; Spivak, Adam M; Nell, Racheal A; Tomescu, Costin; Vadrevu, Surya Kumari; Giron, Leila B; Serra-Peinado, Carla; Genescà, Meritxell; Castellví, Josep; Wu, Guoxin; Del Rio Estrada, Perla M; González-Navarro, Mauricio; Lynn, Kenneth; King, Colin T; Vemula, Sai; Cox, Kara; Wan, Yanmin; Li, Qingsheng; Mounzer, Karam; Kostman, Jay; Frank, Ian; Paiardini, Mirko; Hazuda, Daria; Reyes-Terán, Gustavo; Richman, Douglas; Howell, Bonnie; Tebas, Pablo; Martinez-Picado, Javier; Planelles, Vicente; Buzon, Maria J; Betts, Michael R; Montaner, Luis J
2018-04-18
The persistence of HIV reservoirs, including latently infected, resting CD4 + T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4 + T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4 + T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV + or SIV + subjects, we found that most of the circulating memory CD32 + CD4 + T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a T H 2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4 + T cells in peripheral blood or lymphoid tissue; isolated CD32 + resting CD4 + T cells accounted for less than 3% of the total HIV DNA in CD4 + T cells. Cell-associated HIV DNA and RNA loads in CD4 + T cells positively correlated with the frequency of CD32 + CD69 + CD4 + T cells but not with CD32 expression on resting CD4 + T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4 + T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4 + T cells enriched for transcriptionally active HIV after long-term ART. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
The synthesis of ( sup 3 H)-indole-3-carbinol, a natural anti-carcinogen from cruciferous vegetables
Energy Technology Data Exchange (ETDEWEB)
Dashwood, R H; Uyetake, Lyle; Fong, A T; Hendricks, J D; Bailey, G S [Oregon State Univ., Corvallis, OR (USA). Dept. of Food Science and Technology
1989-08-01
Indole-3-carbinol is a natural anti-carcinogen found as a glucosinolate in cruciferous vegetables such as cabbage, cauliflower and broccoli. A complete understanding of the mechanisms of anti-carcinogenesis by this dietary inhibitor requires improved insight into the disposition and metabolic fate of indole-3-carbinol in vivo. Such metabolic studies have been hampered by the lack of a commercial source of radiolabelled compound. This provided the main impetus for the work reported here, the synthesis of 5-({sup 3}H)-indole-3-carbinol from 5-bromoindole. (author).
Risk Factors of Active Tuberculosis in People Living with HIV/AIDS ...
African Journals Online (AJOL)
BACKGROUND: Determinants of active tuberculosis among People Living with HIV/AIDS (PLHA) are not well elucidated in countries with limited resources. The objective of this study was to assess distal and proximate determinants of active tuberculosis among people living with HIV/AIDS in southwest. Ethiopia.
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Amelia S Knopf
Full Text Available AIDS-related illness is the leading cause of mortality for adolescents in sub-Saharan Africa. Together, Kenya, Tanzania, and Uganda account for 21% of HIV-infected adolescents in sub-Saharan Africa. The United Nations framework for addressing the epidemic among adolescents calls for comprehensive sexual and reproductive health education. These HIV prevention efforts could be informed by a synthesis of existing research about the formal and informal sexual education of adolescents in countries experiencing generalized epidemics. The purpose of this study was to describe the process of sexual learning among East African adolescents living in the context of generalized HIV epidemics.Qualitative metasynthesis, a systematic procedure for integrating the results of multiple qualitative studies addressing a similar phenomenon, was used. Thirty-two research reports met study inclusion criteria. The reports were assessed in a four-step analytic process: appraisal, classification of findings, synthesis of findings, and construction of a framework depicting the process of sexual learning in this population.The framework includes three phases of sexual learning: 1 being primed for sex, 2 making sense of sex, and 3 having sexual experiences. Adolescents were primed for sex through gender norms, cultural practices, and economic structures as well as through conversations and formal instruction. They made sense of sex by acquiring information about sexual intercourse, reproduction and pregnancy, sexually transmitted infections, and relationships and by developing a variety of beliefs and attitudes about these topics. Some adolescents described having sexual experiences that met wants or needs, but many experienced sex that was coerced or violent. Whether sex was wanted, coerced, or violent, adolescents experienced worry about sexually transmitted infections or premarital pregnancy.The three phases of sexual learning interact to shape adolescents' sexual lives
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Núria Climent
Full Text Available Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B in human monocyte-derived dendritic cells (MDDC and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α. MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8(+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8(+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4(+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.
Habashneh, Almeqdad Y; El-Abadelah, Mustafa M; Bardaweel, Sanaa K; Taha, Mutasem O
2017-12-04
Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies. All compounds were virtually nontoxic against normal fibroblast cells. Docking into the oncogenic kinase bcr/abl illustrated the critical importance of (i) p-halogen substituent on the ligand's phenyl ring and (ii) the presence of positive ionizable moiety at the ligand's piperazine fragment for anticancer activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
HAART in HIV/AIDS Treatments: Future Trends.
Lu, Da-Yong; Wu, Hong-Ying; Yarla, Nagendra Sastry; Xu, Bin; Ding, Jian; Lu, Ting-Ren
2018-01-01
AIDS (acquired immune deficient syndrome) is a deadly human viral infectious disease caused by HIV (human immune-deficient virus) infection. Almost every AIDS patient losses his/her life before mid 1990s. AIDS was once the 1st disease killer in US (1993). After one decade hard work, antiviral drug cocktails-high active anti-retroviral therapy (HAART) have been invented for almost all HIV infection treatments. Due to the invention of HAART, 80-90% HIV/AIDS patients still effectively response to HAART for deadly AIDS episode controls and life saving. Yet, this type of HIV therapeutics is incurable. HIV/AIDS patients need to take HAART medications regularly and even life-long. To counteract this therapeutic drawback, more revolutionary efforts (different angles of therapeutic modes/attempts) are urgently needed. In this article, the major progresses and drawbacks of HIV/AIDS chemotherapy (HAART) to HIV/AIDS patients have been discussed. Future trends (updating pathogenesis study, next generations of drug developments, new drug target discovery, different scientific disciplinary and so on) are highlighted. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Ali, Amna Qasem; Teoh, Siang Guan; Salhin, Abdussalam; Eltayeb, Naser Eltaher; Khadeer Ahamed, Mohamed B; Abdul Majid, A M S
2014-05-05
New derivatives of thiosemicarbazone Schiff base with isatin moiety were synthesized L1-L6. The structures of these compounds were characterized based on the spectroscopic techniques. Compound L6 was further characterized by XRD single crystal. The interaction of these compounds with calf thymus (CT-DNA) exhibited high intrinsic binding constant (k(b)=5.03-33.00×10(5) M(-1)) for L1-L3 and L5 and (6.14-9.47×10(4) M(-1)) for L4 and L6 which reflect intercalative activity of these compounds toward CT-DNA. This result was also confirmed by the viscosity data. The electrophoresis studies reveal the higher cleavage activity of L1-L3 than L4-L6. The in vitro anti-proliferative activity of these compounds against human colon cancer cell line (HCT 116) revealed that the synthesized compounds (L3, L6 and L2) exhibited good anticancer potency. Copyright © 2014 Elsevier B.V. All rights reserved.
Immunological Response of Hiv-Infected Children to Highly Active ...
African Journals Online (AJOL)
BACKGROUND: The effectiveness of highly active antiretroviral therapy (HAART) in children has not been well studied specially in developing countries where the burden of HIV is high. This study was aimed to assess the immunologic response of HIV-infected children to HAART at Pediatric ART Clinic Gondar University ...
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Amit Anthwal
2014-01-01
Full Text Available In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5 and colon cancer (HCT116 cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents. Some compounds were found to show higher cytotoxicity against cancer cell lines in comparison to curcumin used as standard.
Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition
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Xiaocong Yu
2016-01-01
Full Text Available Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89 on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells.
Škamperle, Mateja; Seme, Katja; Lunar, Maja M; Maver, Polona J; Tomažič, Janez; Vovko, Tomaž D; Pečavar, Blaž; Matičič, Mojca; Poljak, Mario
2014-01-01
Since the introduction of highly active antiretroviral therapy, chronic hepatitis C has become one of the leading causes of non-AIDS-related morbidity and mortality in patients with HIV infection. Two previous Slovenian nationwide studies published in 2002 and 2009 showed a very low prevalence of hepatitis C virus (HCV) infection among Slovenian HIV-infected individuals (14.5% and 10.7%, respectively). The presence of HCV infection was tested in 579/639 (90.6%) patients that were confirmed as HIV-positive in Slovenia by the end of 2013. Among them, 7.6% (44/579) of HIV-infected individuals were anti-HCV-positive, and 33/44 (75%) anti-HCV-positive patients were also HCV RNA-positive. HCV genotype 1 was most prevalent among HIV-infected patients (68%), followed by genotype 3 (20%), genotype 4 (8%), and genotype 2 (4%). Anti-HCV positivity was significantly higher in those that acquired HIV by the parenteral route (91.8%) than in those that acquired HIV by the sexual route (2.8%). Slovenia remains among the countries with the lowest prevalence of HCV infection in HIV-infected individuals. Because the burden of HIV among men who have sex with men in Slovenia is disproportionately high and increasing rapidly, the current favorable situation could change quickly and should be therefore monitored regularly.
Antioxidant and Anti-Fatigue Activities of Flavonoids from Puerariae ...
African Journals Online (AJOL)
This study evaluated the antioxidant and anti-fatigue activities of flavonoids from Puerariae radix (FPR). In vitro antioxidant activities of FPR were investigated through hydroxyl and superoxide radical scavenging activities. In vivo anti-fatigue activity of FPR was investigated through loaded swimming exercise of mice. Results ...
Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation.
Dang, Eric V; McDonald, Jeffrey G; Russell, David W; Cyster, Jason G
2017-11-16
Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h -/- . Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation. Copyright © 2017 Elsevier Inc. All rights reserved.
In vitro anti-inflammatory and anti-cancer activities of Cuscuta reflexa Roxb.
Suresh, V; Sruthi, V; Padmaja, B; Asha, V V
2011-04-12
To determine anti-inflammatory and anti-cancer activities of Cuscuta reflexa in cell lines (in vitro). Anti-inflammatory activity of the water extract was analysed in vitro using lipopolysaccharide (LPS) induced inflammatory reactions in murine macrophage cell line RAW264.7. The expression of COX-2 and TNF-α genes involved in inflammation was analysed by SQ RT-PCR. EMSA was conducted to analyse the influence of the extract on NF-κB signalling. Anti-cancer activity was analysed on Hep3B cells by MTT assay, DAPI staining, annexin V staining and SQ-RT PCR analysis of BAX, Bcl-2, p53 and survivin. The extract down regulated LPS induced over expression of TNF-α and COX-2 in RAW264.7 cells; blocked NF-κB binding to its motifs and induced apoptosis in Hep3B cells as evidenced from MTT, DAPI staining and annexin V staining assays. The extract up regulated pro-apoptotic factors BAX and p53, and down regulated anti-apoptotic factors Bcl-2 and survivin. The study showed that Cuscuta reflexa inhibits LPS induced inflammatory responses in RAW264.7 cells through interplay of TNF-α, COX-2 and NF-κB signalling. It induced apoptosis in Hep3B cells through the up regulation of p53, BAX and down regulation of Bcl-2 and survivin. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Neutralization epitopes on HIV pseudotyped with HTLV-I: Conservation of carbohydrate Epitopes
DEFF Research Database (Denmark)
Sørensen, A M; Nielsen, C; Arendrup, M
1994-01-01
One mechanism for expanding the cellular tropism of human immunodeficiency virus (HIV) in vitro is through formation of phenotypically mixed particles (pseudotypes) with human T lymphotropic virus type I (HTLV-I). In this study we found that pseudotypes allow penetration of HIV particles into CD4......-negative cells, previously nonsusceptible to HIV infection. The infection of CD4-negative cells with pseudotypes could be blocked with anti-HTLV-I serum but failed to be significantly inhibited with anti-HIV serum or a V3-neutralizing anti-gp120 monoclonal antibody. This may represent a possibility...... by cell-free pseudotypes in CD4-negative cells. We suggest that although viral cofactors might expand the tropism of HIV in vivo, HIV and HTLV-I seem to induce common carbohydrate neutralization epitopes....
Neutralization epitopes on HIV pseudotyped with HTLV-I: conservation of carbohydrate epitopes
DEFF Research Database (Denmark)
Sørensen, A M; Nielsen, C; Arendrup, M
1994-01-01
One mechanism for expanding the cellular tropism of human immunodeficiency virus (HIV) in vitro is through formation of phenotypically mixed particles (pseudotypes) with human T lymphotropic virus type I (HTLV-I). In this study we found that pseudotypes allow penetration of HIV particles into CD4......-negative cells, previously nonsusceptible to HIV infection. The infection of CD4-negative cells with pseudotypes could be blocked with anti-HTLV-I serum but failed to be significantly inhibited with anti-HIV serum or a V3-neutralizing anti-gp120 monoclonal antibody. This may represent a possibility...... by cell-free pseudotypes in CD4-negative cells. We suggest that although viral cofactors might expand the tropism of HIV in vivo, HIV and HTLV-I seem to induce common carbohydrate neutralization epitopes....
Casillo, Angela; Papa, Rosanna; Ricciardelli, Annarita; Sannino, Filomena; Ziaco, Marcello; Tilotta, Marco; Selan, Laura; Marino, Gennaro; Corsaro, Maria M; Tutino, Maria L; Artini, Marco; Parrilli, Ermenegilda
2017-01-01
Staphylococcus epidermidis is a harmless human skin colonizer responsible for ~20% of orthopedic device-related infections due to its capability to form biofilm. Nowadays there is an interest in the development of anti-biofilm molecules. Marine bacteria represent a still underexploited source of biodiversity able to synthesize a broad range of bioactive compounds, including anti-biofilm molecules. Previous results have demonstrated that the culture supernatant of Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125 impairs the formation of S. epidermidis biofilm. Further, evidence supports the hydrophobic nature of the active molecule, which has been suggested to act as a signal molecule. In this paper we describe an efficient activity-guided purification protocol which allowed us to purify this anti-biofilm molecule and structurally characterize it by NMR and mass spectrometry analyses. Our results demonstrate that the anti-biofilm molecule is pentadecanal, a long-chain fatty aldehyde, whose anti- S. epidermidis biofilm activity has been assessed using both static and dynamic biofilm assays. The specificity of its action on S. epidermidis biofilm has been demonstrated by testing chemical analogs of pentadecanal differing either in the length of the aliphatic chain or in their functional group properties. Further, indications of the mode of action of pentadecanal have been collected by studying the bioluminescence of a Vibrio harveyi reporter strain for the detection of autoinducer AI-2 like activities. The data collected suggest that pentadecanal acts as an AI-2 signal. Moreover, the aldehyde metabolic role and synthesis in the Antarctic source strain has been investigated. To the best of our knowledge, this is the first report on the identification of an anti-biofilm molecule form from cold-adapted bacteria and on the action of a long-chain fatty aldehyde acting as an anti-biofilm molecule against S. epidermidis .
Directory of Open Access Journals (Sweden)
Mohammad Asif
2010-01-01
Full Text Available There is increased focus on developed non-steroidal anti-inflammatory drugs (NSAIDs containing a pyridazine nucleus. The NSAIDs are one of the most commonly used medications worldwide to inhibit cyclooxygenase (COX-1 and COX-2 enzyme in varying extent by inhibiting prostaglandin (PGEs synthesis for the treatment of pain, inflammation, arthritis and edema. Their routine and long-term use causes gastrointestinal (GIT and renal toxicities. In order to minimize these side-effects, selective COX-2 inhibitors are prepared with an improved GIT and renal safety profile relative to other NSAIDs. The recent development toward the effective NSAIDs agents causes dual COX and lipooxygenase inhibitory effects because COX-2 inhibitors cause cardiovascular problems. The literature stimulated these above findings. Our attention has been focused on the series of pyridazine or other derivatives that were reported or will be reported in the future as anti-inflammatory, analgesic, anti-arthritic as well as anti-edemic agent.
Anti-HIV Effect of Liposomes Bearing CXCR4 Receptor Antagonist ...
African Journals Online (AJOL)
Keywords: Antagonist, CXCR4, Liposomes, Receptor, Inflammation, HIV. Tropical Journal of ... receptors and inhibits HIV-1 entry mediated through CCR3, CCR5, and ..... circulation, facilitating HIV-targeted drug delivery. By tissue distribution ...
Raja, K; Saravanakumar, A; Vijayakumar, R
2012-11-01
In this paper, aqueous extract of fresh leaves of Prosopis juliflora was used for the synthesis of silver (Ag) nanoparticles. UV-Vis spectroscopy studies were carried out to asses silver nanoparticles formation within 5 min, scanning electron microscopic was used to characterize shape of the Ag nanoparticles, X-ray diffraction analysis confirms the nanoparticles as crystalline silver and facecentered cubic type and Fourier transform infra-red assed that shows biomolecule compounds which are responsible for reduction and capping material of silver nanoparticles. The anti microbial activity of silver nanoparticle was performed using sewage. The approach of plant-mediated synthesis appears to be cost efficient, eco-friendly and easy methods. Copyright © 2012 Elsevier B.V. All rights reserved.
Sun, Xiao-Hong; Baltimore, David
1989-04-01
To study the effect of poliovirus protein 2A on cellular RNA translation, the tat control system of human immunodeficiency virus (HIV) was used. Protein 2A was expressed from a plasmid construct (pHIV/2A) incorporating the HIV long terminal repeat. Protein synthesis was measured by using chloramphenicol acetyltransferase as a reporter gene driven by the Rous sarcoma virus long terminal repeat. When HIV/2A was contransfected with the reporter, addition of a tat-producing plasmid caused at least a 50-fold drop in chloramphenicol acetyltransferase synthesis. A HeLa cell line carrying HIV/2A was established. In it, tat expression caused more than a 10-fold drop in chloramphenicol acetyltransferase synthesis from the reporter plasmid. Furthermore, 2A induction by tat caused cleavage of the cellular translation factor P220, a part of eukaryotic translation initiation factor 4F. Thus protein 2A can, by itself, carry out the inhibition of cellular protein synthesis characteristic of a poliovirus infection. Also, the HIV tat activation provides a very effective method to control gene expression in mammalian cells.
Directory of Open Access Journals (Sweden)
Patrícia de Lima Fonseca
Full Text Available Foram analisadas as práticas e os sentidos do aconselhamento para gestantes submetidas ao teste anti-HIV na admissão para o parto, e para profissionais de saúde que atuam na assistência à maternidade em Salvador, Brasil. Foi realizado um estudo qualitativo em uma maternidade, com observação participante e entrevistas semiestruturadas com 13 puérperas sem diagnóstico prévio para o HIV e sete profissionais de saúde. Observou-se que o exame anti-HIV é realizado de forma compulsória, sem considerar a autonomia da gestante, e que o aconselhamento se limita a informar o diagnóstico e dar orientações no pós-teste somente àquelas cujos resultados foram positivos. Os sentidos que permeiam o exame, assim como o entendimento da experiência e os significados construídos pelas puérperas, sobretudo quando se descobrem positivas para o HIV, não são abordados pelos profissionais, que não se sentem capacitados para acolherem a subjetividade das pacientes.
Directory of Open Access Journals (Sweden)
Patrícia de Lima Fonseca
2012-06-01
Full Text Available Foram analisadas as práticas e os sentidos do aconselhamento para gestantes submetidas ao teste anti-HIV na admissão para o parto, e para profissionais de saúde que atuam na assistência à maternidade em Salvador, Brasil. Foi realizado um estudo qualitativo em uma maternidade, com observação participante e entrevistas semiestruturadas com 13 puérperas sem diagnóstico prévio para o HIV e sete profissionais de saúde. Observou-se que o exame anti-HIV é realizado de forma compulsória, sem considerar a autonomia da gestante, e que o aconselhamento se limita a informar o diagnóstico e dar orientações no pós-teste somente àquelas cujos resultados foram positivos. Os sentidos que permeiam o exame, assim como o entendimento da experiência e os significados construídos pelas puérperas, sobretudo quando se descobrem positivas para o HIV, não são abordados pelos profissionais, que não se sentem capacitados para acolherem a subjetividade das pacientes.
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Appaji Mahesh Ashwini
2015-12-01
Full Text Available The aim of the present study was to investigate the GC-MS analysis, phytochemical screening, anti-oxidant, thrombolytic and anti-inflammatory activities of methanol extract of leaves of Exacum bicolor. FTIR analysis confirmed the presence of alcohol, phenols, alkanes, aromatic compounds, aldehyde and ethers. GC-MS analysis revealed the presence of eight phyto-constituents. The total phenol, flavonoid and alkaloid contents were 18.0 ± 0.2 mg/GAE/g, 13.1 ± 0.4 mg QE/g and 108.0 ± 1.2 mg AE/g respectively. The DPPH assay exhibited potent anti-oxidant abilities with IC50 8.8 µg/mL. Significant thrombolytic activity was demonstrated by clot lysis method (45.1 ± 0.8%. The methanol extract showed significant membrane stabilization on human red blood cell with IC50 value of 37.4 µg/mL. There was a significant correlation (R2>0.98 with total phenolic content versus anti-oxidant and anti-inflammatory activity. The above results confirmed that E. bicolor could be a promising anti-oxidant, thrombolytic and anti-inflammatory agent.
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Sophia Pathai
Full Text Available HIV infection is associated with an increased risk of age-related morbidity mediated by immune dysfunction, atherosclerosis and inflammation. Changes in retinal vessel calibre may reflect cumulative structural damage arising from these mechanisms. The relationship of retinal vessel calibre with clinical and demographic characteristics was investigated in a population of HIV-infected individuals in South Africa.Case-control study of 491 adults ≥30 years, composed of 242 HIV-infected adults and 249 age- and gender-matched HIV-negative controls. Retinal vessel calibre was measured using computer-assisted techniques to determine mean arteriolar and venular diameters of each eye.The median age was 40 years (IQR: 35-48 years. Among HIV-infected adults, 87.1% were receiving highly active antiretroviral therapy (HAART (median duration, 58 months, their median CD4 count was 468 cells/µL, and 84.3% had undetectable plasma viral load. Unadjusted mean retinal arteriolar diameters were 163.67±17.69 µm in cases and 161.34±17.38 µm in controls (p = 0.15. Unadjusted mean venular diameters were 267.77±18.21 µm in cases and 270.81±18.98 µm in controls (p = 0.07. Age modified the effect of retinal arteriolar and venular diameters in relation to HIV status, with a tendency towards narrower retinal diameters in HIV cases but not in controls. Among cases, retinal arteriolar diameters narrowed with increasing duration of HAART, independently of age (167.83 µm 6 years, p-trend = 0.02, and with a HIV viral load >10,000 copies/mL while on HAART (p = 0.05. HIV-related venular changes were not detected.Narrowing of retinal arteriolar diameters is associated with HAART duration and viral load, and may reflect heightened inflammatory and pro-atherogenic states of the systemic vasculature. Measurement of retinal vascular calibre could be an innovative non-invasive method of estimating vascular risk in HIV-infected individuals.
Directory of Open Access Journals (Sweden)
Branka Zorc
2012-01-01
Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.
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Maria Tereza S. Barbosa
2003-04-01
Full Text Available Neste trabalho, utilizaram-se os algoritmos EM e EMS aplicados ao método do Cálculo Retroativo para estimar a magnitude da epidemia do HIV no Brasil. Fazendo-se suposições a respeito do comportamento dos infectados, em relação à utilização da terapia combinada das drogas anti-retrovirais, construíram-se cinco cenários para a epidemia brasileira. O objetivo foi o de ilustrar os impactos que a utilização da terapia combinada das drogas anti-retrovirais possam estar tendo ou possam vir a ter na incubação do vírus e, por conseguinte, nas avaliações da epidemia realizadas a partir dos casos de Aids notificados.We applied the back-calculation method to estimate the magnitude of the HIV epidemic in Brazil, using the EM and EMS algorithms. Under certain assumptions regarding the behavior of infected patients towards combined antiretroviral therapy, we discuss five different scenarios applied to the Brazilian epidemic. Our objective was to illustrate the impact of combined antiretroviral treatment on the incubation period and thus on estimates of the size of the HIV-infected population, based on reported AIDS cases.
Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance
Energy Technology Data Exchange (ETDEWEB)
Ghosh,A.; Sridhar, P.; Leshchenko, S.; Hussain, A.; Li, J.; Kovalevsky, A.; Walters, D.; Wedelind, J.; Grum-Tokars, V.; et al.
2006-01-01
Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Angstroms resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
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Ahmad Mohammadi-Farani
2017-01-01
Full Text Available Objective(s: Alzheimer’s disease (AD as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs. Materials and Methods: A new series of phthalimide derivatives (compounds 4a-4j were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions. Results: According to the obtained results, electron withdrawing groups (Cl, F at position 3 and an electron donating group (methoxy at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM and 4i (p-Methoxy, IC50 = 20.3 nM were the most active compounds in this series and exerted superior potency than donepezil (410 nM. Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase. Conclusion: Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.
Reactivation of latent HIV-1 by new semi-synthetic ingenol esters
Energy Technology Data Exchange (ETDEWEB)
Pandeló José, Diego [Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 (Brazil); Bartholomeeusen, Koen [Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703 (United States); Delveccio da Cunha, Rodrigo; Abreu, Celina Monteiro [Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 (Brazil); Glinski, Jan [PlantaAnalytica LLC, Danbury, CT 06810 (United States); Barbizan Ferreira da Costa, Thais; Bacchi Rabay, Ana Flávia Mello; Pianowski Filho, Luiz Francisco [Kyolab Laboratories, Valinhos, São Paulo 13273-105 (Brazil); Dudycz, Lech W. [Lex Company Research Laboratories, Shirley 01464, MA (United States); Ranga, Udaykumar [Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064 (India); Peterlin, Boris Matija [Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703 (United States); Pianowski, Luiz Francisco [Kyolab Laboratories, Valinhos, São Paulo 13273-105 (Brazil); Tanuri, Amilcar [Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 (Brazil); Aguiar, Renato Santana, E-mail: santana@biologia.ufrj.br [Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 (Brazil)
2014-08-15
The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. ING B activated PKC isoforms followed by NF-κB nuclear translocation. As virus reactivation is dependent on intact NF-κB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART. - Highlights: • 3-caproyl-ingenol (ING B) reactivates latent HIV better than SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. • ING B promotes PKC activation and NF-kB translocation to the nucleus. • ING B activates virus transcription of B and non-B subtypes of HIV-1. • ING B activates HIV transcription in infected primary resting CD4+ T cells. • ING B induces higher levels of P-TEFb components in human primary cells.
Virucidal activity of the dendrimer microbicide SPL7013 against HIV-1.
Telwatte, Sushama; Moore, Katie; Johnson, Adam; Tyssen, David; Sterjovski, Jasminka; Aldunate, Muriel; Gorry, Paul R; Ramsland, Paul A; Lewis, Gareth R; Paull, Jeremy R A; Sonza, Secondo; Tachedjian, Gilda
2011-06-01
Topical microbicides for use by women to prevent the transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. SPL7013 is a dendrimer with broad-spectrum activity against HIV type I (HIV-1) and -2 (HIV-2), herpes simplex viruses type-1 (HSV-1) and -2 (HSV-2) and human papillomavirus. SPL7013 [3% (w/w)] has been formulated in a mucoadhesive carbopol gel (VivaGel®) for use as a topical microbicide. Previous studies showed that SPL7013 has similar potency against CXCR4-(X4) and CCR5-using (R5) strains of HIV-1 and that it blocks viral entry. However, the ability of SPL7013 to directly inactivate HIV-1 is unknown. We examined whether SPL7013 demonstrates virucidal activity against X4 (NL4.3, MBC200, CMU02 clade EA and 92UG046 clade D), R5 (Ba-L, NB25 and 92RW016 clade A) and dual-tropic (R5X4; MACS1-spln) HIV-1 using a modified HLA-DR viral capture method and by polyethylene glycol precipitation. Evaluation of virion integrity was determined by ultracentrifugation through a sucrose cushion and detection of viral proteins by Western blot analysis. SPL7013 demonstrated potent virucidal activity against X4 and R5X4 strains, although virucidal activity was less potent for the 92UG046 X4 clade D isolate. Where potent virucidal activity was observed, the 50% virucidal concentrations were similar to the 50% effective concentrations previously reported in drug susceptibility assays, indicating that the main mode of action of SPL7013 is by direct viral inactivation for these strains. In contrast, SPL7013 lacked potent virucidal activity against R5 HIV-1 strains. Evaluation of the virucidal mechanism showed that SPL7013-treated NL4.3, 92UG046 and MACS1-spln virions were intact with no significant decrease in gp120 surface protein with respect to p24 capsid content compared to the corresponding untreated virus. These studies demonstrate that SPL
Energy Technology Data Exchange (ETDEWEB)
Rafati, Amir Abbas, E-mail: aa_rafati@basu.ac.ir; Afraz, Ahmadreza
2014-06-01
The zidovudine (ZDV) is the first drug approved for the treatment of HIV virus infection. The detection and determination of this drug are very importance in human serum because of its undesirable effects. A new ZDV sensor was fabricated on the basis of nanocomposite of silver nanofilm (Ag-NF) and multiwalled carbon nanotubes (MWCNTs) immobilized on glassy carbon electrode (GCE). The modified electrodes were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), cyclic voltammetry (CV), and linear sweep voltammetry (LSV) techniques. Results showed that the electrodeposited silver has a nanofilm structure and further electrochemical studies showed that the prepared nanocomposite has high electrocatalytic activity and is appropriate for using in sensors. The amperometric technique under optimal conditions is used for the determination of ZDV ranging from 0.1 to 400 ppm (0.37 μM–1.5 mM) with a low detection limit of 0.04 ppm (0.15 μM) (S/N = 3) and good sensitivity. The prepared sensor possessed accurate and rapid response to ZDV and shows an average recovery of 98.6% in real samples. - Highlights: • New anti-HIV drug sensor was fabricated on the basis of nanomaterials composite. • The GCE modified by prepared hydrophilic MWCNT silver nanoparticles. • Silver nanofilm electrodeposited on MWCNT/GCE and characterized by SEM, EDX, CV and LSV • Response of electrode to ZDV was thoroughly investigated by electrochemical techniques.