Copy number variation of Fc gamma receptor genes in HIV-infected and HIV-tuberculosis co-infected individuals in sub-Saharan Africa.

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Lee R Machado

Full Text Available AIDS, caused by the retrovirus HIV, remains the largest cause of morbidity in sub-Saharan Africa yet almost all genetic studies have focused on cohorts from Western countries. HIV shows high co-morbidity with tuberculosis (TB, as HIV stimulates the reactivation of latent tuberculosis (TB. Recent clinical trials suggest that an effective anti-HIV response correlates with non-neutralising antibodies. Given that Fcγ receptors are critical in mediating the non-neutralising effects of antibodies, analysis of the extensive variation at Fcγ receptor genes is important. Single nucleotide variation and copy number variation (CNV of Fcγ receptor genes affects the expression profile, activatory/inhibitory balance, and IgG affinity of the Fcγ receptor repertoire of each individual. In this study we investigated whether CNV of FCGR2C, FCGR3A and FCGR3B as well as the HNA1 allotype of FCGR3B is associated with HIV load, response to highly-active antiretroviral therapy (HAART and co-infection with TB. We confirmed an effect of TB-co-infection status on HIV load and response to HAART, but no conclusive effect of the genetic variants we tested. We observed a small effect, in Ethiopians, of FCGR3B copy number, where deletion was more frequent in HIV-TB co-infected patients than those infected with HIV alone.

Development of an epitope-based HIV-1 vaccine strategy from HIV-1 lipopeptide to dendritic-based vaccines.

Science.gov (United States)

Surenaud, Mathieu; Lacabaratz, Christine; Zurawski, Gérard; Lévy, Yves; Lelièvre, Jean-Daniel

2017-10-01

Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche Nord&Sud Sida-HIV hépatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy.

Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children.

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Casartelli, Nicoletta; Di Matteo, Gigliola; Argentini, Claudio; Cancrini, Caterina; Bernardi, Stefania; Castelli, Guido; Scarlatti, Gabriella; Plebani, Anna; Rossi, Paolo; Doria, Margherita

2003-06-13

Evaluation of sequence evolution as well as structural defects and mutations of the human immunodeficiency virus-type 1 (HIV-1) nef gene in relation to disease progression in infected children. We examined a large number of nef alleles sequentially derived from perinatally HIV-1-infected children with different rates of disease progression: six non-progressors (NPs), four rapid progressors (RPs), and three slow progressors (SPs). Nef alleles (182 total) were isolated from patients' peripheral blood mononuclear cells (PBMCs), sequenced and analysed for their evolutionary pattern, frequency of mutations and occurrence of amino acid variations associated with different stages of disease. The evolution rate of the nef gene apparently correlated with CD4+ decline in all progression groups. Evidence for rapid viral turnover and positive selection for changes were found only in two SPs and two RPs respectively. In NPs, a higher proportion of disrupted sequences and mutations at various functional motifs were observed. Furthermore, NP-derived Nef proteins were often changed at residues localized in the folded core domain at cytotoxic T lymphocytes (CTL) epitopes (E(105), K(106), E(110), Y(132), K(164), and R(200)), while other residues outside the core domain are more often changed in RPs (A(43)) and SPs (N(173) and Y(214)). Our results suggest a link between nef gene functions and the progression rate in HIV-1-infected children. Moreover, non-progressor-associated variations in the core domain of Nef, together with the genetic analysis, suggest that nef gene evolution is shaped by an effective immune system in these patients.

HIV-1 infection during pregnancy and in children : significance of HIV-1 variability and the placental barrier

OpenAIRE

Casper, Charlotte

2001-01-01

With the global increase in human immunodeficiency virus 1 (HIV-1) infection in women of childbearing age, there has also been an alarming increase in the number of mother-to-child transmissions of HIV-1. Although antiretroviral therapy and Cesarian section have been demonstrated to significantly decrease the vertical transmission rate of , these interventions are not widely available in the developing world. Therefore, studies of the mechanisms of vertical transmission are ...

Introduction to global variational geometry

CERN Document Server

Krupka, Demeter

2015-01-01

The book is devoted to recent research in the global variational theory on smooth manifolds. Its main objective is an extension of the classical variational calculus on Euclidean spaces to (topologically nontrivial) finite-dimensional smooth manifolds; to this purpose the methods of global analysis of differential forms are used. Emphasis is placed on the foundations of the theory of variational functionals on fibered manifolds - relevant geometric structures for variational principles in geometry, physical field theory and higher-order fibered mechanics. The book chapters include: - foundations of jet bundles and analysis of differential forms and vector fields on jet bundles, - the theory of higher-order integral variational functionals for sections of a fibred space, the (global) first variational formula in infinitesimal and integral forms- extremal conditions and the discussion of Noether symmetries and generalizations,- the inverse problems of the calculus of variations of Helmholtz type- variational se...

HIV-1 subtype A gag variability and epitope evolution.

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Abidi, Syed Hani; Kalish, Marcia L; Abbas, Farhat; Rowland-Jones, Sarah; Ali, Syed

2014-01-01

The aim of this study was to examine the course of time-dependent evolution of HIV-1 subtype A on a global level, especially with respect to the dynamics of immunogenic HIV gag epitopes. We used a total of 1,893 HIV-1 subtype A gag sequences representing a timeline from 1985 through 2010, and 19 different countries in Africa, Europe and Asia. The phylogenetic relationship of subtype A gag and its epidemic dynamics was analysed through a Maximum Likelihood tree and Bayesian Skyline plot, genomic variability was measured in terms of G → A substitutions and Shannon entropy, and the time-dependent evolution of HIV subtype A gag epitopes was examined. Finally, to confirm observations on globally reported HIV subtype A sequences, we analysed the gag epitope data from our Kenyan, Pakistani, and Afghan cohorts, where both cohort-specific gene epitope variability and HLA restriction profiles of gag epitopes were examined. The most recent common ancestor of the HIV subtype A epidemic was estimated to be 1956 ± 1. A period of exponential growth began about 1980 and lasted for approximately 7 years, stabilized for 15 years, declined for 2-3 years, then stabilized again from about 2004. During the course of evolution, a gradual increase in genomic variability was observed that peaked in 2005-2010. We observed that the number of point mutations and novel epitopes in gag also peaked concurrently during 2005-2010. It appears that as the HIV subtype A epidemic spread globally, changing population immunogenetic pressures may have played a role in steering immune-evolution of this subtype in new directions. This trend is apparent in the genomic variability and epitope diversity of HIV-1 subtype A gag sequences.

HIV-1 subtype A gag variability and epitope evolution.

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Syed Hani Abidi

Full Text Available OBJECTIVE: The aim of this study was to examine the course of time-dependent evolution of HIV-1 subtype A on a global level, especially with respect to the dynamics of immunogenic HIV gag epitopes. METHODS: We used a total of 1,893 HIV-1 subtype A gag sequences representing a timeline from 1985 through 2010, and 19 different countries in Africa, Europe and Asia. The phylogenetic relationship of subtype A gag and its epidemic dynamics was analysed through a Maximum Likelihood tree and Bayesian Skyline plot, genomic variability was measured in terms of G → A substitutions and Shannon entropy, and the time-dependent evolution of HIV subtype A gag epitopes was examined. Finally, to confirm observations on globally reported HIV subtype A sequences, we analysed the gag epitope data from our Kenyan, Pakistani, and Afghan cohorts, where both cohort-specific gene epitope variability and HLA restriction profiles of gag epitopes were examined. RESULTS: The most recent common ancestor of the HIV subtype A epidemic was estimated to be 1956 ± 1. A period of exponential growth began about 1980 and lasted for approximately 7 years, stabilized for 15 years, declined for 2-3 years, then stabilized again from about 2004. During the course of evolution, a gradual increase in genomic variability was observed that peaked in 2005-2010. We observed that the number of point mutations and novel epitopes in gag also peaked concurrently during 2005-2010. CONCLUSION: It appears that as the HIV subtype A epidemic spread globally, changing population immunogenetic pressures may have played a role in steering immune-evolution of this subtype in new directions. This trend is apparent in the genomic variability and epitope diversity of HIV-1 subtype A gag sequences.

Further progress on defining highly conserved immunogenic epitopes for a global HIV vaccine

DEFF Research Database (Denmark)

De Groot, Anne S; Levitz, Lauren; Ardito, Matthew T

2012-01-01

Two major obstacles confronting HIV vaccine design have been the extensive viral diversity of HIV-1 globally and viral evolution driven by escape from CD8(+) cytotoxic T-cell lymphocyte (CTL)-mediated immune pressure. Regions of the viral genome that are not able to escape immune response...

Incursions from the epicentre: Southern theory, social science, and the global HIV research domain.

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Hodes, Rebecca; Morrell, Robert

2018-03-01

Research about HIV constitutes a global domain of academic knowledge. The patterns that structure this domain reflect inequalities in the production and dissemination of knowledge, as well as broader inequalities in geopolitics. Conventional metrics for assessing the value and impact of academic research reveal that "Northern" research remains dominant, while "Southern" research remains peripheral. Southern theory provides a framework for greater critical engagement with knowledge produced by researchers within the global South. With a focus on HIV social science, we show that investigators working in and from Africa have produced and disseminated knowledge fundamental to the global domain of HIV research, and argue that their epistemological contribution may be understood within the framework of Southern theory. Through repurposing a bibliometrical measure of citation count, we constitute a new archive of highly cited social science research. With a focus on South Africa, we situate this archive within changing historical contexts, connecting research findings to developments in medicine, health sciences and politics. We focus on two key themes in the evolution of HIV knowledge: (1) the significance of context and locality - the "setting" of HIV research; and (2) sex, race and risk - changing ideas about the social determinants of HIV transmission.

Glycosylation in HIV-1 envelope glycoprotein and its biological implications

KAUST Repository

Ho, Yung Shwen

2013-08-01

Glycosylation of HIV-1 envelope proteins (Env gp120/gp41) plays a vital role in viral evasion from the host immune response, which occurs through the masking of key neutralization epitopes and the presentation of the Env glycosylation as \\'self\\' to the host immune system. Env glycosylation is generally conserved, yet its continual evolution plays an important role in modulating viral infectivity and Env immunogenicity. Thus, it is believed that Env glycosylation, which is a vital part of the HIV-1 architecture, also controls intra- and inter-clade genetic variations. Discerning intra- and inter-clade glycosylation variations could therefore yield important information for understanding the molecular and biological differences between HIV clades and may assist in effectively designing Env-based immunogens and in clearly understanding HIV vaccines. This review provides an in-depth perspective of various aspects of Env glycosylation in the context of HIV-1 pathogenesis. © 2013 Future Medicine Ltd.

Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model.

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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.

HIV due to female sex work: regional and global estimates.

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Annette Prüss-Ustün

Full Text Available Female sex workers (FSWs are at high risk of HIV infection. Our objective was to determine the proportion of HIV prevalence in the general female adult population that is attributable to the occupational exposure of female sex work, due to unprotected sexual intercourse.Population attributable fractions of HIV prevalence due to female sex work were estimated for 2011. A systematic search was conducted to retrieve required input data from available sources. Data gaps of HIV prevalence in FSWs for 2011 were filled using multilevel modeling and multivariate linear regression. The fraction of HIV attributable to female sex work was estimated as the excess HIV burden in FSWs deducting the HIV burden in FSWs due to injecting drug use.An estimated fifteen percent of HIV in the general female adult population is attributable to (unsafe female sex work. The region with the highest attributable fraction is Sub Saharan Africa, but the burden is also substantial for the Caribbean, Latin America and South and Southeast Asia. We estimate 106,000 deaths from HIV are a result of female sex work globally, 98,000 of which occur in Sub-Saharan Africa. If HIV prevalence in other population groups originating from sexual contact with FSWs had been considered, the overall attributable burden would probably be much larger.Female sex work is an important contributor to HIV transmission and the global HIV burden. Effective HIV prevention measures exist and have been successfully targeted at key populations in many settings. These must be scaled up.FSWs suffer from high HIV burden and are a crucial core population for HIV transmission. Surveillance, prevention and treatment of HIV in FSWs should benefit both this often neglected vulnerable group and the general population.

HIV Due to Female Sex Work: Regional and Global Estimates

Science.gov (United States)

Prüss-Ustün, Annette; Wolf, Jennyfer; Driscoll, Tim; Degenhardt, Louisa; Neira, Maria; Calleja, Jesus Maria Garcia

2013-01-01

Introduction Female sex workers (FSWs) are at high risk of HIV infection. Our objective was to determine the proportion of HIV prevalence in the general female adult population that is attributable to the occupational exposure of female sex work, due to unprotected sexual intercourse. Methods Population attributable fractions of HIV prevalence due to female sex work were estimated for 2011. A systematic search was conducted to retrieve required input data from available sources. Data gaps of HIV prevalence in FSWs for 2011 were filled using multilevel modeling and multivariate linear regression. The fraction of HIV attributable to female sex work was estimated as the excess HIV burden in FSWs deducting the HIV burden in FSWs due to injecting drug use. Results An estimated fifteen percent of HIV in the general female adult population is attributable to (unsafe) female sex work. The region with the highest attributable fraction is Sub Saharan Africa, but the burden is also substantial for the Caribbean, Latin America and South and Southeast Asia. We estimate 106,000 deaths from HIV are a result of female sex work globally, 98,000 of which occur in Sub-Saharan Africa. If HIV prevalence in other population groups originating from sexual contact with FSWs had been considered, the overall attributable burden would probably be much larger. Discussion Female sex work is an important contributor to HIV transmission and the global HIV burden. Effective HIV prevention measures exist and have been successfully targeted at key populations in many settings. These must be scaled up. Conclusion FSWs suffer from high HIV burden and are a crucial core population for HIV transmission. Surveillance, prevention and treatment of HIV in FSWs should benefit both this often neglected vulnerable group and the general population. PMID:23717432

Geographic variation in sexual behavior can explain geospatial heterogeneity in the severity of the HIV epidemic in Malawi.

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Palk, Laurence; Blower, Sally

2018-02-09

In sub-Saharan Africa, where ~ 25 million individuals are infected with HIV and transmission is predominantly heterosexual, there is substantial geographic variation in the severity of epidemics. This variation has yet to be explained. Here, we propose that it is due to geographic variation in the size of the high-risk group (HRG): the group with a high number of sex partners. We test our hypothesis by conducting a geospatial analysis of data from Malawi, where ~ 13% of women and ~ 8% of men are infected with HIV. We used georeferenced HIV testing and behavioral data from ~ 14,000 participants of a nationally representative population-level survey: the 2010 Malawi Demographic and Health Survey (MDHS). We constructed gender-stratified epidemic surface prevalence (ESP) maps by spatially smoothing and interpolating the HIV testing data. We used the behavioral data to construct gender-stratified risk maps that reveal geographic variation in the size of the HRG. We tested our hypothesis by fitting gender-stratified spatial error regression (SER) models to the MDHS data. The ESP maps show considerable geographic variation in prevalence: 1-29% (women), 1-20% (men). Risk maps reveal substantial geographic variation in the size of the HRG: 0-40% (women), 16-58% (men). Prevalence and the size of the HRG are highest in urban centers. However, the majority of HIV-infected individuals (~75% of women, ~ 80% of men) live in rural areas, as does most of the HRG (~ 80% of women, ~ 85% of men). We identify a significant (P national average in districts where > 20% of women are in the HRG. Most importantly, the SER models show that geographic variation in the size of the HRG can explain a substantial proportion (73% for women, 67% for men) of the geographic variation in epidemic severity. Taken together, our results provide substantial support for our hypothesis. They provide a potential mechanistic explanation for the geographic variation in the severity

The global spread of HIV-1 subtype B epidemic

NARCIS (Netherlands)

G. Magiorkinis (Gkikas); K. Angelis (Konstantinos); I. Mamais (Ioannis); Katzourakis, A. (Aris); A. Hatzakis (Angelos); J. Albert (Jan); Lawyer, G. (Glenn); O. Hamouda (Osamah); D. Struck (Daniel); J. Vercauteren (Jurgen); A. Wensing (Amj); I. Alexiev (Ivailo); B. Åsjö (Birgitta); C. Balotta (Claudia); Gomes, P. (Perpétua); R.J. Camacho (Ricardo Jorge); S. Coughlan (Suzie); A. Griskevicius (Algirdas); Z. Grossman (Zehava); Horban, A. (Anders); L.G. Kostrikis (Leondios); Lepej, S.J. (Snjezana J.); K. Liitsola (Kirsi); M. Linka (Marek); C. Nielsen; D. Otelea (Dan); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Stöckl (Elisabeth); J.C. Schmit; A. Sonnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); Stylianou, D.C. (Dora C.); C.A.B. Boucher (Charles); Nikolopoulos, G. (Georgios); Vasylyeva, T. (Tetyana); Friedman, S.R. (Samuel R.); D.A.M.C. van de Vijver (David); G. Angarano (Guiseppe); M.L. Chaix (Marie Laure); A. de Luca (Andrea); K. Korn (Klaus); Loveday, C. (Clive); V. Soriano (Virtudes); S. Yerly (Sabine); M. Zazzi; A.M. Vandamme (Anne Mieke); D. Paraskevis (Dimitrios)

2016-01-01

textabstractHuman immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa

Factors Associated with Variations in Population HIV Prevalence across West Africa: Findings from an Ecological Analysis

Science.gov (United States)

Prudden, Holly J.; Beattie, Tara S.; Bobrova, Natalia; Panovska-Griffiths, Jasmina; Mukandavire, Zindoga; Gorgens, Marelize; Wilson, David; Watts, Charlotte H.

2015-01-01

Background Population HIV prevalence across West Africa varies substantially. We assess the national epidemiological and behavioural factors associated with this. Methods National, urban and rural data on HIV prevalence, the percentage of younger (15–24) and older (25–49) women and men reporting multiple (2+) partners in the past year, HIV prevalence among female sex workers (FSWs), men who have bought sex in the past year (clients), and ART coverage, were compiled for 13 countries. An Ecological analysis using linear regression assessed which factors are associated with national variations in population female and male HIV prevalence, and with each other. Findings National population HIV prevalence varies between 0 4–2 9% for men and 0 4–5.6% for women. ART coverage ranges from 6–23%. National variations in HIV prevalence are not shown to be associated with variations in HIV prevalence among FSWs or clients. Instead they are associated with variations in the percentage of younger and older males and females reporting multiple partners. HIV prevalence is weakly negatively associated with ART coverage, implying it is not increased survival that is the cause of variations in HIV prevalence. FSWs and younger female HIV prevalence are associated with client population sizes, especially older men. Younger female HIV prevalence is strongly associated with older male and female HIV prevalence. Interpretation In West Africa, population HIV prevalence is not significantly higher in countries with high FSW HIV prevalence. Our analysis suggests, higher prevalence occurs where more men buy sex, and where a higher percentage of younger women, and older men and women have multiple partnerships. If a sexual network between clients and young females exists, clients may potentially bridge infection to younger females. HIV prevention should focus both on commercial sex and transmission between clients and younger females with multiple partners. PMID:26698854

Factors Associated with Variations in Population HIV Prevalence across West Africa: Findings from an Ecological Analysis.

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Holly J Prudden

Full Text Available Population HIV prevalence across West Africa varies substantially. We assess the national epidemiological and behavioural factors associated with this.National, urban and rural data on HIV prevalence, the percentage of younger (15-24 and older (25-49 women and men reporting multiple (2+ partners in the past year, HIV prevalence among female sex workers (FSWs, men who have bought sex in the past year (clients, and ART coverage, were compiled for 13 countries. An Ecological analysis using linear regression assessed which factors are associated with national variations in population female and male HIV prevalence, and with each other.National population HIV prevalence varies between 0 4-2 9% for men and 0 4-5.6% for women. ART coverage ranges from 6-23%. National variations in HIV prevalence are not shown to be associated with variations in HIV prevalence among FSWs or clients. Instead they are associated with variations in the percentage of younger and older males and females reporting multiple partners. HIV prevalence is weakly negatively associated with ART coverage, implying it is not increased survival that is the cause of variations in HIV prevalence. FSWs and younger female HIV prevalence are associated with client population sizes, especially older men. Younger female HIV prevalence is strongly associated with older male and female HIV prevalence.In West Africa, population HIV prevalence is not significantly higher in countries with high FSW HIV prevalence. Our analysis suggests, higher prevalence occurs where more men buy sex, and where a higher percentage of younger women, and older men and women have multiple partnerships. If a sexual network between clients and young females exists, clients may potentially bridge infection to younger females. HIV prevention should focus both on commercial sex and transmission between clients and younger females with multiple partners.

The global spread of HIV-1 subtype B epidemic

NARCIS (Netherlands)

Magiorkinis, Gkikas; Angelis, Konstantinos; Mamais, Ioannis; Katzourakis, Aris; Hatzakis, Angelos; Albert, Jan; Lawyer, Glenn; Hamouda, Osamah; Struck, Daniel; Vercauteren, Jurgen; Wensing, Annemarie; Alexiev, Ivailo; Åsjö, Birgitta; Balotta, Claudia; Gomes, Perpétua; Camacho, Ricardo J.; Coughlan, Suzie; Griskevicius, Algirdas; Grossman, Zehava; Horban, Anders; Kostrikis, Leondios G.; Lepej, Snjezana J.; Liitsola, Kirsi; Linka, Marek; Nielsen, Claus; Otelea, Dan; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elizabeth; Schmit, Jean Claude; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Stylianou, Dora C.; Boucher, Charles A B; Nikolopoulos, Georgios; Vasylyeva, Tetyana; Friedman, Samuel R.; van de Vijver, David; Angarano, Gioacchino; Chaix, Marie Laure; de Luca, Andrea; Korn, Klaus; Loveday, Clive; Soriano, Vincent; Yerly, Sabine; Zazzi, Mauricio; Vandamme, Anne Mieke; Paraskevis, Dimitrios

2016-01-01

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti

The Effects of Time Lag and Cure Rate on the Global Dynamics of HIV-1 Model

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Nigar Ali

2017-01-01

Full Text Available In this research article, a new mathematical model of delayed differential equations is developed which discusses the interaction among CD4 T cells, human immunodeficiency virus (HIV, and recombinant virus with cure rate. The model has two distributed intracellular delays. These delays denote the time needed for the infection of a cell. The dynamics of the model are completely described by the basic reproduction numbers represented by R0, R1, and R2. It is shown that if R0<1, then the infection-free equilibrium is locally as well as globally stable. Similarly, it is proved that the recombinant absent equilibrium is locally as well as globally asymptotically stable if 11. Finally, numerical simulations are presented to illustrate our theoretical results. Our obtained results show that intracellular delay and cure rate have a positive role in the reduction of infected cells and the increasing of uninfected cells due to which the infection is reduced.

A European multicientre study on the comparison of HIV-1 viral loads between VERIS HIV-1 Assay and Roche COBAS® TAQMAN® HIV-1 test, Abbott RealTime HIV-1 Assay, and Siemens VERSANT HIV-1 Assay.

Science.gov (United States)

Braun, Patrick; Delgado, Rafael; Drago, Monica; Fanti, Diana; Fleury, Hervé; Hofmann, Jörg; Izopet, Jacques; Kühn, Sebastian; Lombardi, Alessandra; Mancon, Alessandro; Marcos, Mª Angeles; Mileto, Davide; Sauné, Karine; O'Shea, Siobhan; Pérez-Rivilla, Alfredo; Ramble, John; Trimoulet, Pascale; Vila, Jordi; Whittaker, Duncan; Artus, Alain; Rhodes, Daniel

2017-07-01

Viral load monitoring is essential for patients under treatment for HIV. Beckman Coulter has developed the VERIS HIV-1 Assay for use on the novel, automated DxN VERIS Molecular Diagnostics System. ¥ OBJECTIVES: Evaluation of the clinical performance of the new quantitative VERIS HIV-1 Assay at multiple EU laboratories. Method comparison with the VERIS HIV-1 Assay was performed with 415 specimens at 5 sites tested with COBAS ® AmpliPrep/COBAS ® TaqMan ® HIV-1 Test, v2.0, 169 specimens at 3 sites tested with RealTime HIV-1 Assay, and 202 specimens from 2 sites tested with VERSANT HIV-1 Assay. Patient monitoring sample results from 4 sites were also compared. Bland-Altman analysis showed the average bias between VERIS HIV-1 Assay and COBAS HIV-1 Test, RealTime HIV-1 Assay, and VERSANT HIV-1 Assay to be 0.28, 0.39, and 0.61 log 10 cp/mL, respectively. Bias at low end levels below 1000cp/mL showed predicted bias to be <0.3 log 10 cp/mL for VERIS HIV-1 Assay versus COBAS HIV-1 Test and RealTime HIV-1 Assay, and <0.5 log 10 cp/mL versus VERSANT HIV-1 Assay. Analysis on 174 specimens tested with the 0.175mL volume VERIS HIV-1 Assay and COBAS HIV-1 Test showed average bias of 0.39 log 10 cp/mL. Patient monitoring results using VERIS HIV-1 Assay demonstrated similar viral load trends over time to all comparators. The VERIS HIV-1 Assay for use on the DxN VERIS System demonstrated comparable clinical performance to COBAS ® HIV-1 Test, RealTime HIV-1 Assay, and VERSANT HIV-1 Assay. Copyright © 2017 Elsevier B.V. All rights reserved.

Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies

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Zhiqing Zhang

2016-11-01

Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection causes acquired immune deficiency syndrome (AIDS, a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

HIV-1 Nef in Macrophage-Mediated Disease Pathogenesis

Science.gov (United States)

Lamers, Susanna L.; Fogel, Gary B.; Singer, Elyse J.; Salemi, Marco; Nolan, David J.; Huysentruyt, Leanne C.; McGrath, Michael S.

2013-01-01

Combined anti-retroviral therapy (cART) has significantly reduced the number of AIDS-associated illnesses and changed the course of HIV-1 disease in developed countries. Despite the ability of cART to maintain high CD4+ T-cell counts, a number of macrophage-mediated diseases can still occur in HIV-infected subjects. These diseases include lymphoma, metabolic diseases, and HIV-associated neurological disorders. Within macrophages, the HIV-1 regulatory protein “Nef” can modulate surface receptors, interact with signaling pathways, and promote specific environments that contribute to each of these pathologies. Moreover, genetic variation in Nef may also guide the macrophage response. Herein, we review findings relating to the Nef–macrophage interaction and how this relationship contributes to disease pathogenesis. PMID:23215766

Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis

Science.gov (United States)

Rajasingham, Radha; Smith, Rachel M; Park, Benjamin J; Jarvis, Joseph N; Govender, Nelesh P; Chiller, Tom M; Denning, David W; Loyse, Angela; Boulware, David R

2018-01-01

Summary Background Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease. Methods We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per µL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/µL not on ART, and those with CD4 less than 100 cells per µL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis. Findings We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8–6·2) among people with a CD4 cell count of less than 100 cells per µL, with 278 000 (95% CI 195 500–340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600–282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600–193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400–234 300), with 135 900 (75%; [95% CI 93 900–163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10–19). Interpretation Our analysis highlights the substantial ongoing burden of HIV

The impact of the global economic crisis on HIV and AIDS ...

African Journals Online (AJOL)

This investigation sought to ascertain the extent to which the global economic crisis of 2008–2009 affected the delivery of HIV/AIDS-related services directed at pregnant and lactating mothers, children living with HIV and children orphaned through HIV in Zambia. Using a combined macroeconomic analysis and a multiple ...

Global dispersal pattern of HIV type 1 subtype CRF01-AE : A genetic trace of human mobility related to heterosexual sexual activities centralized in southeast Asia

NARCIS (Netherlands)

Angelis, Konstantinos; Albert, Jan; Mamais, Ioannis; Magiorkinis, Gkikas; Hatzakis, Angelos; Hamouda, Osamah; Struck, Daniel; Vercauteren, Jurgen; Wensing, Annemarie M J; Alexiev, Ivailo; Åsjö, Birgitta; Balotta, Claudia; Camacho, Ricardo J.; Coughlan, Suzie; Griskevicius, Algirdas; Grossman, Zehava; Horban, Andrzej; Kostrikis, Leondios G.; Lepej, Snjezana; Liitsola, Kirsi; Linka, Marek; Nielsen, Claus; Otelea, Dan; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Schmit, Jean Claude; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Boucher, Charles A B; Kaplan, Lauren; Vandamme, Anne Mieke; Paraskevis, Dimitrios

2015-01-01

Background. Human immunodeficiency virus type 1 (HIV-1) subtype CRF01-AE originated in Africa and then passed to Thailand, where it established a major epidemic. Despite the global presence of CRF01-AE, little is known about its subsequent dispersal pattern. Methods. We assembled a global data set

Recent progress in immune-based interventions to prevent HIV-1 transmission to children.

Science.gov (United States)

Voronin, Yegor; Jani, Ilesh; Graham, Barney S; Cunningham, Coleen K; Mofenson, Lynne M; Musoke, Philippa M; Permar, Sallie R; Scarlatti, Gabriella

2017-12-01

Globally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV-1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV-1 infection. Thus, for the global community to achieve elimination of new paediatric HIV-1 infections, innovative approaches need to be explored. Immune-based approaches to prevention of mother-to-child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS-free generation. Immune-based interventions to prevent MTCT of HIV-1 may include paediatric HIV vaccines and passive immunization approaches. Recent discoveries providing evidence of robust immune responses to HIV in infants open new and exciting prospects for paediatric HIV vaccines. Moreover, successful vaccination of infants has a different set of requirements than vaccination of adults and may be easier to achieve. Proof-of-concept has been established over the last two decades that passively administered HIV-1 Env-specific monoclonal antibody (mAbs) can prevent chimeric simian human immunodeficiency virus (SHIV) transmission to newborn nonhuman primates. There has been tremendous progress in isolating and characterizing broadly neutralizing antibodies to HIV, and clinical testing of these antibodies for treatment and prevention in both infants and adults is a major effort in the field. Immune-based interventions need to be actively explored as they can provide critically important tools to address persistent challenges in MTCT prevention. It is a pivotal time for the field with active discussions on the best strategy to further reduce HIV infection of infants and accomplish the World Health Organization Fast-Track 2030 goals to eliminate new paediatric HIV infections. © 2017 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.

Global Reduction in HIV-related Maternal Mortality: ART as a Key Strategy

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Hamisu M. Salihu, MD, PhD

2015-12-01

Full Text Available Dr. Holtz and colleagues present a synthesis of evidence from published studies over the previous decade on the collective impact of HIV-targeted interventions on maternal mortality. Amongst an assortment of interventions [that include antiretroviral therapy (ART, micronutrients (multivitamins, vitamin A and selenium, and antibiotics], only ART reduced maternal mortality among HIV-infected pregnant and post-partum mothers. These findings have fundamental and global strategic implications. They are also timely since they provide the evidence that ART reduces HIV-related maternal mortality, and by further enhancing access to ART in HIV-challenged and poor regions of the world, significant improvement in maternal morbidity and mortality indices could be attained. The paper bears good tidings and sound scientific proof that the financial investment made globally by government and non-governmental organizations and agencies to reduce the global burden of HIV/AIDS primarily by making ART more accessible to regions of the world most affected by the epidemic is beginning to show beneficial effects not only in terms of numerical reductions in the rates of new cases of HIV/AIDS among women, but also in maternal mortality levels.

Accounts from the field: a public relations perspective on global AIDS/HIV.

Science.gov (United States)

Bardhan, Nilanjana R

2002-01-01

This study is a theoretical as well as empirical exploration of the power and cultural differentials that mark and construct various intersecting discourses, specifically media discourse, on global AIDS/HIV. It applies the language and concepts of public relations to understand how the press coverage of the pandemic is associated with the variables that impact the newsmaking process as well as the public and policy implications of macro news frames generated over time. Theoretical work in the areas of agenda setting and news framing also instruct the conceptual framework of this analysis. Narrative analysis is used as a methodology to qualitatively analyze three pools of accounts-from people either living with AIDS/HIV, involved in AIDS/HIV work, or discursively engaged in the media construction of the pandemic; from transnational wire service journalists who cover the issue at global and regional levels; and policy shapers and communicators who are active at the global level. These three communities of respondents represent important stakeholders in the AIDS/HIV issue. The findings are analyzed from a public relations standpoint. Perhaps the most important finding of this study is that the public relations approaches used to address AIDS/HIV related issues need to be grounded in context-specific research and communicative practices that bring out the lived realities of AIDS/HIV at grassroots levels. The findings also posit that those situated at critical junctions between various stakeholders need to cultivate a finely balanced understanding of the etic and emic intersections and subjectivities of global/local AIDS/HIV.

Variations in the Biological Functions of HIV-1 Clade C Envelope in a SHIV-Infected Rhesus Macaque during Disease Progression.

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For Yue Tso

Full Text Available A better understanding of how the biological functions of the HIV-1 envelope (Env changes during disease progression may aid the design of an efficacious anti-HIV-1 vaccine. Although studies from patient had provided some insights on this issue, the differences in the study cohorts and methodology had make it difficult to reach a consensus of the variations in the HIV-1 Env functions during disease progression. To this end, an animal model that can be infected under controlled environment and reflect the disease course of HIV-1 infection in human will be beneficial. Such an animal model was previously demonstrated by the infection of macaque with SHIV, expressing HIV-1 clade C Env V1-V5 region. By using this model, we examined the changes in biological functions of Env in the infected animal over the entire disease course. Our data showed an increase in the neutralization resistance phenotype over time and coincided with the decrease in the net charges of the V1-V5 region. Infection of PBMC with provirus expressing various Env clones, isolated from the infected animal over time, showed a surprisingly better replicative fitness for viruses expressing the Env from early time point. Biotinylation and ELISA data also indicated a decrease of cell-surface-associated Env and virion-associated gp120 content with disease progression. This decrease did not affect the CD4-binding capability of Env, but were positively correlated with the decrease of Env fusion ability. Interestingly, some of these changes in biological functions reverted to the pre-AIDS level during advance AIDS. These data suggested a dynamic relationship between the Env V1-V5 region with the host immune pressure. The observed changes of biological functions in this setting might reflect and predict those occurring during natural disease progression in human.

nef gene sequence variation among HIV-1-infected African children

Czech Academy of Sciences Publication Activity Database

Chakraborty, R.; Reiniš, Milan; Rostron, T.; Philpott, S.; Dong, T.; D'Agostino, A.; Musoke, R.; de Silva, E.; Stumpf, M.; Weiser, B.; Burger, H.; Rowland-Jones, S.L.

2006-01-01

Roč. 7, č. 2 (2006), s. 75-84 ISSN 1464-2662 Grant - others:Fogarty International Center, NIH(US) 3D43TW00915; NIH(US) RO1 AI 42555 Institutional research plan: CEZ:AV0Z50520514 Keywords : HIV-1 nef gene * non-clade B * Kenya Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.674, year: 2006

Infarto cerebral em duas crianças infectadas pelo HIV-1 Ischaemic stroke in two children with HIV-1

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Cristiane Rocha

2003-12-01

Full Text Available Os quadros vasculares são incomuns não somente nos pacientes adultos (1% como também nas crianças. Nosso objetivo é alertar para a possibilidade da infecção pelo HIV-1 em crianças com manifestações cerebrovasculares. Das 204 crianças infectadas pelo HIV acompanhadas no Ambulatório de SIDA, descrevemos dois pacientes pré-escolares do gênero masculino, com quadro agudo febril, rebaixamento do nível de consciência, status epilepticus e hemiparesia como primeira manifestação de infecção pelo HIV-1. Nos dois casos evidenciou-se extensa isquemia em território da artéria cerebral média. Um dos pacientes evoluiu com tetraparesia espástica grave, sem contactuar com o meio, epilepsia parcial e óbito 4 anos após o diagnóstico, sem melhora do quadro neurológico. O outro paciente apresentou hemiparesia direita e afasia global, evoluindo com regressão completa do quadro neurológico. A infreqüência desses achados torna importante o seu relato, visando a inclusão da infecção pelo HIV-1 no diagnóstico diferencial das quadros cerebrovasculares na criança.Cerebral ischaemia caused by inflammatory vasculopathies has been described as a complication of human immunodeficiency virus (HIV infection. The goal of our study is to report two cases of pediatric human immunodeficiency virus infection and cerebrovascular manifestations. We describe two pre-school boys, from a group of 204 outpatients, who presented fever, seizures, hemiparesis and impairment of conscience level as a first symptom of HIV-1 infection. The serial imaging studies revealed infarction of middle cerebral artery in both cases. The first one child had a severe spastic tetraparesis and partial epilepsy and died four years later without any improvement despite of the antiretroviral therapy. The second patient had a right hemiparesis and global aphasia totally recovered two years later with antiretroviral and rehabilitation therapies. HIV infection should be included

A single gp120 residue can affect HIV-1 tropism in macaques.

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Gregory Q Del Prete

2017-09-01

Full Text Available Species-dependent variation in proteins that aid or limit virus replication determines the ability of lentiviruses to jump between host species. Identifying and overcoming these differences facilitates the development of animal models for HIV-1, including models based on chimeric SIVs that express HIV-1 envelope (Env glycoproteins, (SHIVs and simian-tropic HIV-1 (stHIV strains. Here, we demonstrate that the inherently poor ability of most HIV-1 Env proteins to use macaque CD4 as a receptor is improved during adaptation by virus passage in macaques. We identify a single amino acid, A281, in HIV-1 Env that consistently changes during adaptation in macaques and affects the ability of HIV-1 Env to use macaque CD4. Importantly, mutations at A281 do not markedly affect HIV-1 Env neutralization properties. Our findings should facilitate the design of HIV-1 Env proteins for use in non-human primate models and thus expedite the development of clinically relevant reagents for testing interventions against HIV-1.

Global Epidemiology of HIV Infection and Related Syndemics Affecting Transgender People

Science.gov (United States)

Scheim, Ayden; Xavier, Jessica; Reisner, Sari; Baral, Stefan

2016-01-01

Introduction: Transgender populations have been underrepresented in HIV epidemiologic studies and consequently in HIV prevention, care, and treatment programs. Since 2012, there has been a dramatic increase in research focused on transgender people. Studies highlight the burden of HIV and risk determinants, including intersecting stigmas, as drivers of syndemics among transgender populations. This review synthesizes the most recent global epidemiology of HIV infection and describes current gaps in research and interventions to inform prioritization of HIV research for transgender populations. Methods: A systematic review was conducted of the medical literature published between January 1, 2012 and November 30, 2015. The data focused on HIV prevalence, determinants of risk, and syndemics among transgender populations. Results: Estimates varied dramatically by location and subpopulation. Transfeminine individuals have some of the highest concentrated HIV epidemics in the world with laboratory-confirmed prevalence up to 40%. Data were sparse among trans masculine individuals; however, they suggest potential increased risk for trans masculine men who have sex with men (MSM). No prevalence data were available for transgender people across Sub-Saharan Africa or Eastern Europe/Central Asia. Emerging data consistently support the association of syndemic conditions with HIV risk in transgender populations. Discussion: Addressing syndemic conditions and gender-specific challenges is critical to ensure engagement and retention in HIV prevention by transgender populations. Future research should prioritize: filling knowledge gaps in HIV epidemiology; elucidating how stigma shapes syndemic factors to produce HIV and other deleterious effects on transgender health; and understanding how to effectively implement HIV interventions for transgender people. PMID:27429185

Canada's international response to HIV during times of global transition: a qualitative inquiry.

Science.gov (United States)

Nixon, Stephanie

2011-04-01

Canada's international response to HIV may be under threat given CIDA's new aid priorities that appear to exclude health. Drivers of this recent priority shift have been the influence of global aid trends among public sector donors and changes within the global HIV milieu itself. However, this is not the first time Canada has shifted in response to these two global trends. The era from 2000-2004 also witnessed dramatic changes in both the HIV field and in global thinking around international aid. As such, this article presents an evaluation of the Government of Canada's international response to HIV during the first era of transition (2000-2004) in order to derive lessons for decision-making around HIV in the current climate of change. In-depth, semi-structured interviews were conducted with 23 key informants with expertise regarding Canada's international response to HIV over time. Analysis involved multiple readings of transcripts to identify descriptive codes and establish intimacy with the data. Descriptive codes were then collapsed into thematic categories using a process of inductive reasoning. Canada's international response to HIV was perceived to be exemplary at times (e.g. seminal funding to WHO's "3-by-5" strategy), but also inconsistent (e.g., underutilized technical assistance capacity) and non-strategic (e.g., contradiction between investing in training health providers while poaching professionals to bolster Canada's workforce). Lessons from the 2000-2004 era of transition focus on strategic investments, the inextricable connection between HIV and development and strategy coherence. These results highlight that it is more constructive to ensure that Canadian development responses in all areas engage with both the upstream drivers of HIV as well as the impacts of the epidemic itself in order to achieve the greatest results from international investment and the most effective contributions to the lives of the people that these endeavours seek to

THE PREVALENCE OF HUMAN IMMUNODEFIENCY VIRUS-1 (HIV-1 SUBTYPES AND TRANSMISSION METHOD AMONG HIV/AIDS INFECTION PATIENT IN TULUNGAGUNG, EAST JAVA INDONESIA

Directory of Open Access Journals (Sweden)

Achmad Ardianto

2015-05-01

Full Text Available The rapid epidemic growth of HIV is continuing in Indonesia. There are some factors which have influenced the spreading of this epidemic in Indonesia, such as the poor awareness to avoid unsafe free sex attitude and the sharing of needles and syringes among intravenous drug users (IDUs. The sexual transmission of HIV has also apparently increased in Tulungagung. Commercial sex workers play a significant role in the spread of HIV in Tulungagung. People in Tulungagung have worked at other countries as Indonesian migrants. This condition can cause the increase number of HIV-1 case and the possibility of genetic variation (subtype HIV-1 in Tulungagung. This research is aimed to analyze the subtype and to determine estimation of transmission mode on infected patient of HIV-1 and AIDS who came to Seruni clinic Dr. Iskak hospital in Tulungagung. 40 HIV?AIDSpatients were interviewed to determine the subtype and the transmission mode. The results showed that 14 of 40 plasma samples (35% were successfully to amplified and sequenced. OverallCRF01-AE wereidentified as predominant subtype among HIV/AIDS patients in Tulungagung. Based on individual information, 31 of 40 subjects (77% were heterosexual transmission.

MAS NMR of HIV-1 protein assemblies

Science.gov (United States)

Suiter, Christopher L.; Quinn, Caitlin M.; Lu, Manman; Hou, Guangjin; Zhang, Huilan; Polenova, Tatyana

2015-04-01

The negative global impact of the AIDS pandemic is well known. In this perspective article, the utility of magic angle spinning (MAS) NMR spectroscopy to answer pressing questions related to the structure and dynamics of HIV-1 protein assemblies is examined. In recent years, MAS NMR has undergone major technological developments enabling studies of large viral assemblies. We discuss some of these evolving methods and technologies and provide a perspective on the current state of MAS NMR as applied to the investigations into structure and dynamics of HIV-1 assemblies of CA capsid protein and of Gag maturation intermediates.

Rational development of radiopharmaceuticals for HIV-1

International Nuclear Information System (INIS)

Lau, Chuen-Yen; Maldarelli, Frank; Eckelman, William C.; Neumann, Ronald D.

2014-01-01

The global battle against HIV-1 would benefit from a sensitive and specific radiopharmaceutical to localize HIV-infected cells. Ideally, this probe would be able to identify latently infected host cells containing replication competent HIV sequences. Clinical and research applications would include assessment of reservoirs, informing clinical management by facilitating assessment of burden of infection in different compartments, monitoring disease progression and monitoring response to therapy. A “rational” development approach could facilitate efficient identification of an appropriate targeted radiopharmaceutical. Rational development starts with understanding characteristics of the disease that can be effectively targeted and then engineering radiopharmaceuticals to hone in on an appropriate target, which in the case of HIV-1 (HIV) might be an HIV-specific product on or in the host cell, a differentially expressed gene product, an integrated DNA sequence specific enzymatic activity, part of the inflammatory response, or a combination of these. This is different from the current approach that starts with a radiopharmaceutical for a target associated with a disease, mostly from autopsy studies, without a strong rationale for the potential to impact patient care. At present, no targeted therapies are available for HIV latency, although a number of approaches are under study. Here we discuss requirements for a radiopharmaceutical useful in strategies targeting persistently infected cells. The radiopharmaceutical for HIV should be developed based on HIV biology, studied in an animal model and then in humans, and ultimately used in clinical and research settings

Gender inequality and HIV transmission: a global analysis.

Science.gov (United States)

Richardson, Eugene T; Collins, Sean E; Kung, Tiffany; Jones, James H; Hoan Tram, Khai; Boggiano, Victoria L; Bekker, Linda-Gail; Zolopa, Andrew R

2014-01-01

The HIV pandemic disproportionately impacts young women. Worldwide, young women aged 15-24 are infected with HIV at rates twice that of young men, and young women alone account for nearly a quarter of all new HIV infections. The incommensurate HIV incidence in young - often poor - women underscores how social and economic inequalities shape the HIV epidemic. Confluent social forces, including political and gender violence, poverty, racism, and sexism impede equal access to therapies and effective care, but most of all constrain the agency of women. HIV prevalence data was compiled from the 2010 UNAIDS Global Report. Gender inequality was assessed using the 2011 United Nations Human Development Report Gender Inequality Index (GII). Logistic regression models were created with predominant mode of transmission (heterosexual vs. MSM/IDU) as the dependent variable and GII, Muslim vs. non-Muslim, Democracy Index, male circumcision rate, log gross national income (GNI) per capita at purchasing power parity (PPP), and region as independent variables. There is a significant correlation between having a predominantly heterosexual epidemic and high gender inequality across all models. There is not a significant association between whether a country is predominantly Muslim, has a high/low GNI at PPP, has a high/low circumcision rate, and its primary mode of transmission. In addition, there are only three countries that have had a generalized epidemic in the past but no longer have one: Cambodia, Honduras, and Eritrea. GII data are available only for Cambodia and Honduras, and these countries showed a 37 and 34% improvement, respectively, in their Gender Inequality Indices between 1995 and 2011. During the same period, both countries reduced their HIV prevalence below the 1% threshold of a generalized epidemic. This represents limited but compelling evidence that improvements in gender inequality can lead to the abatement of generalized epidemics. Gender inequality is an

Copy number variation of KIR genes influences HIV-1 control

DEFF Research Database (Denmark)

Pelak, Kimberly; Need, Anna C; Fellay, Jacques

2011-01-01

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses t...

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Science.gov (United States)

Ortblad, Katrina F; Guinovart, Caterina; Lim, Stephen S; Wolock, Timothy M; Roberts, D Allen; Dansereau, Emily A; Graetz, Nicholas; Barber, Ryan M; Brown, Jonathan C; Wang, Haidong; Duber, Herbert C; Naghavi, Mohsen; Dicker, Daniel; Dandona, Lalit; Salomon, Joshua A; Heuton, Kyle R; Foreman, Kyle; Phillips, David E; Fleming, Thomas D; Flaxman, Abraham D; Phillips, Bryan K; Johnson, Elizabeth K; Coggeshall, Megan S; Abd-Allah, Foad; Ferede, Semaw; Abraham, Jerry P; Abubakar, Ibrahim; Abu-Raddad, Laith J; Abu-Rmeileh, Niveen Me; Achoki, Tom; Adeyemo, Austine Olufemi; Adou, Arsène Kouablan; Adsuar, José C; Agardh, Emilie Elisabet; Akena, Dickens; Al Kahbouri, Mazin J; Alasfoor, Deena; Albittar, Mohammed I; Alcalá-Cerra, Gabriel; Alegretti, Miguel Angel; Alemu, Zewdie Aderaw; Alfonso-Cristancho, Rafael; Alhabib, Samia; Ali, Raghib; Alla, Francois; Allen, Peter J; Alsharif, Ubai; Alvarez, Elena; Alvis-Guzman, Nelson; Amankwaa, Adansi A; Amare, Azmeraw T; Amini, Hassan; Ammar, Walid; Anderson, Benjamin O; Antonio, Carl Abelardo T; Anwari, Palwasha; Ärnlöv, Johan; Arsenijevic, Valentina S Arsic; Artaman, Ali; Asghar, Rana J; Assadi, Reza; Atkins, Lydia S; Badawi, Alaa; Balakrishnan, Kalpana; Banerjee, Amitava; Basu, Sanjay; Beardsley, Justin; Bekele, Tolesa; Bell, Michelle L; Bernabe, Eduardo; Beyene, Tariku Jibat; Bhala, Neeraj; Bhalla, Ashish; Bhutta, Zulfiqar A; Abdulhak, Aref Bin; Binagwaho, Agnes; Blore, Jed D; Basara, Berrak Bora; Bose, Dipan; Brainin, Michael; Breitborde, Nicholas; Castañeda-Orjuela, Carlos A; Catalá-López, Ferrán; Chadha, Vineet K; Chang, Jung-Chen; Chiang, Peggy Pei-Chia; Chuang, Ting-Wu; Colomar, Mercedes; Cooper, Leslie Trumbull; Cooper, Cyrus; Courville, Karen J; Cowie, Benjamin C; Criqui, Michael H; Dandona, Rakhi; Dayama, Anand; De Leo, Diego; Degenhardt, Louisa; Del Pozo-Cruz, Borja; Deribe, Kebede; Jarlais, Don C Des; Dessalegn, Muluken; Dharmaratne, Samath D; Dilmen, Uğur; Ding, Eric L; Driscoll, Tim R; Durrani, Adnan M; Ellenbogen, Richard G; Ermakov, Sergey Petrovich; Esteghamati, Alireza; Faraon, Emerito Jose A; Farzadfar, Farshad; Fereshtehnejad, Seyed-Mohammad; Fijabi, Daniel Obadare; Forouzanfar, Mohammad H; Paleo, Urbano Fra.; Gaffikin, Lynne; Gamkrelidze, Amiran; Gankpé, Fortuné Gbètoho; Geleijnse, Johanna M; Gessner, Bradford D; Gibney, Katherine B; Ginawi, Ibrahim Abdelmageem Mohamed; Glaser, Elizabeth L; Gona, Philimon; Goto, Atsushi; Gouda, Hebe N; Gugnani, Harish Chander; Gupta, Rajeev; Gupta, Rahul; Hafezi-Nejad, Nima; Hamadeh, Randah Ribhi; Hammami, Mouhanad; Hankey, Graeme J; Harb, Hilda L; Haro, Josep Maria; Havmoeller, Rasmus; Hay, Simon I; Hedayati, Mohammad T; Pi, Ileana B Heredia; Hoek, Hans W; Hornberger, John C; Hosgood, H Dean; Hotez, Peter J; Hoy, Damian G; Huang, John J; Iburg, Kim M; Idrisov, Bulat T; Innos, Kaire; Jacobsen, Kathryn H; Jeemon, Panniyammakal; Jensen, Paul N; Jha, Vivekanand; Jiang, Guohong; Jonas, Jost B; Juel, Knud; Kan, Haidong; Kankindi, Ida; Karam, Nadim E; Karch, André; Karema, Corine Kakizi; Kaul, Anil; Kawakami, Norito; Kazi, Dhruv S; Kemp, Andrew H; Kengne, Andre Pascal; Keren, Andre; Kereselidze, Maia; Khader, Yousef Saleh; Khalifa, Shams Eldin Ali Hassan; Khan, Ejaz Ahmed; Khang, Young-Ho; Khonelidze, Irma; Kinfu, Yohannes; Kinge, Jonas M; Knibbs, Luke; Kokubo, Yoshihiro; Kosen, S; Defo, Barthelemy Kuate; Kulkarni, Veena S; Kulkarni, Chanda; Kumar, Kaushalendra; Kumar, Ravi B; Kumar, G Anil; Kwan, Gene F; Lai, Taavi; Balaji, Arjun Lakshmana; Lam, Hilton; Lan, Qing; Lansingh, Van C; Larson, Heidi J; Larsson, Anders; Lee, Jong-Tae; Leigh, James; Leinsalu, Mall; Leung, Ricky; Li, Yichong; Li, Yongmei; De Lima, Graça Maria Ferreira; Lin, Hsien-Ho; Lipshultz, Steven E; Liu, Shiwei; Liu, Yang; Lloyd, Belinda K; Lotufo, Paulo A; Machado, Vasco Manuel Pedro; Maclachlan, Jennifer H; Magis-Rodriguez, Carlos; Majdan, Marek; Mapoma, Christopher Chabila; Marcenes, Wagner; Marzan, Melvin Barrientos; Masci, Joseph R; Mashal, Mohammad Taufiq; Mason-Jones, Amanda J; Mayosi, Bongani M; Mazorodze, Tasara T; Mckay, Abigail Cecilia; Meaney, Peter A; Mehndiratta, Man Mohan; Mejia-Rodriguez, Fabiola; Melaku, Yohannes Adama; Memish, Ziad A; Mendoza, Walter; Miller, Ted R; Mills, Edward J; Mohammad, Karzan Abdulmuhsin; Mokdad, Ali H; Mola, Glen Liddell; Monasta, Lorenzo; Montico, Marcella; Moore, Ami R; Mori, Rintaro; Moturi, Wilkister Nyaora; Mukaigawara, Mitsuru; Murthy, Kinnari S; Naheed, Aliya; Naidoo, Kovin S; Naldi, Luigi; Nangia, Vinay; Narayan, K M Venkat; Nash, Denis; Nejjari, Chakib; Nelson, Robert G; Neupane, Sudan Prasad; Newton, Charles R; Ng, Marie; Nisar, Muhammad Imran; Nolte, Sandra; Norheim, Ole F; Nowaseb, Vincent; Nyakarahuka, Luke; Oh, In-Hwan; Ohkubo, Takayoshi; Olusanya, Bolajoko O; Omer, Saad B; Opio, John Nelson; Orisakwe, Orish Ebere; Pandian, Jeyaraj D; Papachristou, Christina; Caicedo, Angel J Paternina; Patten, Scott B; Paul, Vinod K; Pavlin, Boris Igor; Pearce, Neil; Pereira, David M; Pervaiz, Aslam; Pesudovs, Konrad; Petzold, Max; Pourmalek, Farshad; Qato, Dima; Quezada, Amado D; Quistberg, D Alex; Rafay, Anwar; Rahimi, Kazem; Rahimi-Movaghar, Vafa; Rahman, Sajjad Ur; Raju, Murugesan; Rana, Saleem M; Razavi, Homie; Reilly, Robert Quentin; Remuzzi, Giuseppe; Richardus, Jan Hendrik; Ronfani, Luca; Roy, Nobhojit; Sabin, Nsanzimana; Saeedi, Mohammad Yahya; Sahraian, Mohammad Ali; Samonte, Genesis May J; Sawhney, Monika; Schneider, Ione J C; Schwebel, David C; Seedat, Soraya; Sepanlou, Sadaf G; Servan-Mori, Edson E; Sheikhbahaei, Sara; Shibuya, Kenji; Shin, Hwashin Hyun; Shiue, Ivy; Shivakoti, Rupak; Sigfusdottir, Inga Dora; Silberberg, Donald H; Silva, Andrea P; Simard, Edgar P; Singh, Jasvinder A; Skirbekk, Vegard; Sliwa, Karen; Soneji, Samir; Soshnikov, Sergey S; Sreeramareddy, Chandrashekhar T; Stathopoulou, Vasiliki Kalliopi; Stroumpoulis, Konstantinos; Swaminathan, Soumya; Sykes, Bryan L; Tabb, Karen M; Talongwa, Roberto Tchio; Tenkorang, Eric Yeboah; Terkawi, Abdullah Sulieman; Thomson, Alan J; Thorne-Lyman, Andrew L; Towbin, Jeffrey A; Traebert, Jefferson; Tran, Bach X; Dimbuene, Zacharie Tsala; Tsilimbaris, Miltiadis; Uchendu, Uche S; Ukwaja, Kingsley N; Uzun, Selen Begüm; Vallely, Andrew J; Vasankari, Tommi J; Venketasubramanian, N; Violante, Francesco S; Vlassov, Vasiliy Victorovich; Vollset, Stein Emil; Waller, Stephen; Wallin, Mitchell T; Wang, Linhong; Wang, XiaoRong; Wang, Yanping; Weichenthal, Scott; Weiderpass, Elisabete; Weintraub, Robert G; Westerman, Ronny; White, Richard A; Wilkinson, James D; Williams, Thomas Neil; Woldeyohannes, Solomon Meseret; Wong, John Q; Xu, Gelin; Yang, Yang C; Yano, Yuichiro; Yentur, Gokalp Kadri; Yip, Paul; Yonemoto, Naohiro; Yoon, Seok-Jun; Younis, Mustafa; Yu, Chuanhua; Jin, Kim Yun; El Sayed Zaki, Maysaa; Zhao, Yong; Zheng, Yingfeng; Zhou, Maigeng; Zhu, Jun; Zou, Xiao Nong; Lopez, Alan D; Vos, Theo

2014-01-01

Summary Background The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration. Methods To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets. Findings Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1�

HIV-1 transmission linkage in an HIV-1 prevention clinical trial

Energy Technology Data Exchange (ETDEWEB)

Leitner, Thomas [Los Alamos National Laboratory; Campbell, Mary S [UNIV OF WASHINGTON; Mullins, James I [UNIV OF WASHINGTON; Hughes, James P [UNIV OF WASHINGTON; Wong, Kim G [UNIV OF WASHINGTON; Raugi, Dana N [UNIV OF WASHINGTON; Scrensen, Stefanie [UNIV OF WASHINGTON

2009-01-01

HIV-1 sequencing has been used extensively in epidemiologic and forensic studies to investigate patterns of HIV-1 transmission. However, the criteria for establishing genetic linkage between HIV-1 strains in HIV-1 prevention trials have not been formalized. The Partners in Prevention HSV/HIV Transmission Study (ClinicaITrials.gov NCT00194519) enrolled 3408 HIV-1 serodiscordant heterosexual African couples to determine the efficacy of genital herpes suppression with acyclovir in reducing HIV-1 transmission. The trial analysis required laboratory confirmation of HIV-1 linkage between enrolled partners in couples in which seroconversion occurred. Here we describe the process and results from HIV-1 sequencing studies used to perform transmission linkage determination in this clinical trial. Consensus Sanger sequencing of env (C2-V3-C3) and gag (p17-p24) genes was performed on plasma HIV-1 RNA from both partners within 3 months of seroconversion; env single molecule or pyrosequencing was also performed in some cases. For linkage, we required monophyletic clustering between HIV-1 sequences in the transmitting and seroconverting partners, and developed a Bayesian algorithm using genetic distances to evaluate the posterior probability of linkage of participants sequences. Adjudicators classified transmissions as linked, unlinked, or indeterminate. Among 151 seroconversion events, we found 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) to have indeterminate transmissions. Nine (8.3%) were linked by consensus gag sequencing only and 8 (7.4%) required deep sequencing of env. In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage

Host-specific adaptation of HIV-1 subtype B in the Japanese population.

Science.gov (United States)

Chikata, Takayuki; Carlson, Jonathan M; Tamura, Yoshiko; Borghan, Mohamed Ali; Naruto, Takuya; Hashimoto, Masao; Murakoshi, Hayato; Le, Anh Q; Mallal, Simon; John, Mina; Gatanaga, Hiroyuki; Oka, Shinichi; Brumme, Zabrina L; Takiguchi, Masafumi

2014-05-01

The extent to which HIV-1 clade B strains exhibit population-specific adaptations to host HLA alleles remains incompletely known, in part due to incomplete characterization of HLA-associated HIV-1 polymorphisms (HLA-APs) in different global populations. Moreover, it remains unknown to what extent the same HLA alleles may drive significantly different escape pathways across populations. As the Japanese population exhibits distinctive HLA class I allele distributions, comparative analysis of HLA-APs between HIV-1 clade B-infected Japanese and non-Asian cohorts could shed light on these questions. However, HLA-APs remain incompletely mapped in Japan. In a cohort of 430 treatment-naive Japanese with chronic HIV-1 clade B infection, we identified 284 HLA-APs in Gag, Pol, and Nef using phylogenetically corrected methods. The number of HLA-associated substitutions in Pol, notably those restricted by HLA-B*52:01, was weakly inversely correlated with the plasma viral load (pVL), suggesting that the transmission and persistence of B*52:01-driven Pol mutations could modulate the pVL. Differential selection of HLA-APs between HLA subtype members, including those differing only with respect to substitutions outside the peptide-binding groove, was observed, meriting further investigation as to their mechanisms of selection. Notably, two-thirds of HLA-APs identified in Japan had not been reported in previous studies of predominantly Caucasian cohorts and were attributable to HLA alleles unique to, or enriched in, Japan. We also identified 71 cases where the same HLA allele drove significantly different escape pathways in Japan versus predominantly Caucasian cohorts. Our results underscore the distinct global evolution of HIV-1 clade B as a result of host population-specific cellular immune pressures. Cytotoxic T lymphocyte (CTL) escape mutations in HIV-1 are broadly predictable based on the HLA class I alleles expressed by the host. Because HLA allele distributions differ among

Decline in the prevalence HIV among pregnant women attending ...

African Journals Online (AJOL)

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The numbers of ANC sentinel sites and Regional coverage as well as ... revealed a decrease in the magnitude of HIV infection with variations by regions (THIS, 2005; ..... UNAIDS/WHO (1996) Working Group on Global HIV/AIDS and STI ...

Maximum weight of greenhouse effect to global temperature variation

International Nuclear Information System (INIS)

Sun, Xian; Jiang, Chuangye

2007-01-01

Full text: The global average temperature has risen by 0.74 0 C since the late 19th century. Many studies have concluded that the observed warming in the last 50 years may be attributed to increasing concentrations of anthropogenic greenhouse gases. But some scientists have a different point of view. Global climate change is affected not only by anthropogenic activities, but also constraints in climate system natural factors. How much is the influencing weight of C02's greenhouse effects to the global temperature variation? Does global climate continue warming or decreasing in the next 20 years? They are two hot spots in global climate change. The multi-timescales analysis method - Empirical mode decomposition (EMD) is used to diagnose global annual mean air temperature dataset for land surface provided by IPCC and atmospheric content of C02 provided by the Carbon Dioxide Information Analysis Center (CDIAC) during 1881-2002. The results show that: Global temperature variation contains quasi-periodic oscillations on four timescales (3 yr, 6 yr, 20 yr and 60 yr, respectively) and a century-scale warming trend. The variance contribution of IMF1-IMF4 and trend is 17.55%, 11.34%, 6.77%, 24.15% and 40.19%, respectively. The trend and quasi-60 yr oscillation of temperature variation are the most prominent; C02's greenhouse effect on global temperature variation is mainly century-scale trend. The contribution of C02 concentration to global temperature variability is not more than 40.19%, whereas 59.81% contribution to global temperature variation is non-greenhouse effect. Therefore, it is necessary to re-study the dominant factors that induce the global climate change; It has been noticed that on the periods of 20 yr and 60 yr oscillation, the global temperature is beginning to decreased in the next 20 years. If the present C02 concentration is maintained, the greenhouse effect will be too small to countercheck the natural variation in global climate cooling in the next 20

Production of HIV-1 vif mRNA Is Modulated by Natural Nucleotide Variations and SLSA1 RNA Structure in SA1D2prox Genomic Region

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Masako Nomaguchi

2017-12-01

Full Text Available Genomic RNA of HIV-1 contains localized structures critical for viral replication. Its structural analysis has demonstrated a stem-loop structure, SLSA1, in a nearby region of HIV-1 genomic splicing acceptor 1 (SA1. We have previously shown that the expression level of vif mRNA is considerably altered by some natural single-nucleotide variations (nSNVs clustering in SLSA1 structure. In this study, besides eleven nSNVs previously identified by us, we totally found nine new nSNVs in the SLSA1-containing sequence from SA1, splicing donor 2, and through to the start codon of Vif that significantly affect the vif mRNA level, and designated the sequence SA1D2prox (142 nucleotides for HIV-1 NL4-3. We then examined by extensive variant and mutagenesis analyses how SA1D2prox sequence and SLSA1 secondary structure are related to vif mRNA level. While the secondary structure and stability of SLSA1 was largely changed by nSNVs and artificial mutations introduced to restore the original NL4-3 form from altered ones by nSNVs, no clear association of the two SLSA1 properties with vif mRNA level was observed. In contrast, when naturally occurring SA1D2prox sequences that contain multiple nSNVs were examined, we attained significant inverse correlation between the vif level and SLSA1 stability. These results may suggest that SA1D2prox sequence adapts over time, and also that the altered SA1D2prox sequence, SLSA1 stability, and vif level are mutually related. In total, we show here that the entire SA1D2prox sequence and SLSA1 stability critically contribute to the modulation of vif mRNA level.

Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.

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Rami Kantor

2005-04-01

Full Text Available The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate.To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80% of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates.Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

Clinical presentation and opportunistic infections in HIV-1, HIV-2 and HIV-1/2 dual seropositive patients in Guinea-Bissau

DEFF Research Database (Denmark)

Sørensen, Allan; Jespersen, Sanne; Katzenstein, Terese L

2016-01-01

HIV-2 is prevalent. In this study, we aimed to characterize the clinical presentations among HIV-1, HIV-2 and HIV-1/2 dual seropositive patients. Methods: In a cross-sectional study, newly diagnosed HIV patients attending the HIV outpatient clinic at Hospital Nacional Sim~ao Mendes in Guinea......-Bissau were enrolled. Demographical and clinical data were collected and compared between HIV-1, HIV-2 and HIV-1/2 dual seropositive patients. Results: A total of 169 patients (76% HIV-1, 17% HIV-2 and 6% HIV 1/2) were included in the study between 21 March 2012 and 14 December 2012. HIV-1 seropositive...... antigen. Conclusion: HIV-1 and HIV-1/2 seropositive patients have lower CD4 cell counts than HIV-2 seropositive patients when diagnosed with HIV with only minor clinical and demographic differences among groups. Few patients were diagnosed with TB and cryptococcal disease was not found to be a major...

μ-opioid modulation of HIV-1 coreceptor expressionand HIV-1 replication

International Nuclear Information System (INIS)

Steele, Amber D.; Henderson, Earl E.; Rogers, Thomas J.

2003-01-01

A substantial proportion of HIV-1-infected individuals are intravenous drug users (IVDUs) who abuse opiates. Opioids induce a number of immunomodulatory effects that may directly influence HIV-1 disease progression. In the present report, we have investigated the effect of opioids on the expression of the major HIV-1 coreceptors CXCR4 and CCR5. For these studies we have focused on opiates which are ligands for the μ-opioid receptor. Our results show that DAMGO, a selective μ-opioid agonist, increases CXCR4 and CCR5 expression in both CD3 + lymphoblasts and CD14 + monocytes three- to fivefold. Furthermore, DAMGO-induced elevation of HIV-1 coreceptor expression translates into enhanced replication of both X4 and R5 viral strains of HIV-1. We have confirmed the role of the μ-opioid receptor based on the ability of a μ-opioid receptor-selective antagonist to block the effects of DAMGO. We have also found that morphine enhances CXCR4 and CCR5 expression and subsequently increases both X4 and R5 HIV-1 infection. We suggest that the capacity of μ-opioids to increase HIV-1 coreceptor expression and replication may promote viral binding, trafficking of HIV-1-infected cells, and enhanced disease progression

Use of four next-generation sequencing platforms to determine HIV-1 coreceptor tropism.

Science.gov (United States)

Archer, John; Weber, Jan; Henry, Kenneth; Winner, Dane; Gibson, Richard; Lee, Lawrence; Paxinos, Ellen; Arts, Eric J; Robertson, David L; Mimms, Larry; Quiñones-Mateu, Miguel E

2012-01-01

HIV-1 coreceptor tropism assays are required to rule out the presence of CXCR4-tropic (non-R5) viruses prior treatment with CCR5 antagonists. Phenotypic (e.g., Trofile™, Monogram Biosciences) and genotypic (e.g., population sequencing linked to bioinformatic algorithms) assays are the most widely used. Although several next-generation sequencing (NGS) platforms are available, to date all published deep sequencing HIV-1 tropism studies have used the 454™ Life Sciences/Roche platform. In this study, HIV-1 co-receptor usage was predicted for twelve patients scheduled to start a maraviroc-based antiretroviral regimen. The V3 region of the HIV-1 env gene was sequenced using four NGS platforms: 454™, PacBio® RS (Pacific Biosciences), Illumina®, and Ion Torrent™ (Life Technologies). Cross-platform variation was evaluated, including number of reads, read length and error rates. HIV-1 tropism was inferred using Geno2Pheno, Web PSSM, and the 11/24/25 rule and compared with Trofile™ and virologic response to antiretroviral therapy. Error rates related to insertions/deletions (indels) and nucleotide substitutions introduced by the four NGS platforms were low compared to the actual HIV-1 sequence variation. Each platform detected all major virus variants within the HIV-1 population with similar frequencies. Identification of non-R5 viruses was comparable among the four platforms, with minor differences attributable to the algorithms used to infer HIV-1 tropism. All NGS platforms showed similar concordance with virologic response to the maraviroc-based regimen (75% to 80% range depending on the algorithm used), compared to Trofile (80%) and population sequencing (70%). In conclusion, all four NGS platforms were able to detect minority non-R5 variants at comparable levels suggesting that any NGS-based method can be used to predict HIV-1 coreceptor usage.

Use of four next-generation sequencing platforms to determine HIV-1 coreceptor tropism.

Directory of Open Access Journals (Sweden)

John Archer

Full Text Available HIV-1 coreceptor tropism assays are required to rule out the presence of CXCR4-tropic (non-R5 viruses prior treatment with CCR5 antagonists. Phenotypic (e.g., Trofile™, Monogram Biosciences and genotypic (e.g., population sequencing linked to bioinformatic algorithms assays are the most widely used. Although several next-generation sequencing (NGS platforms are available, to date all published deep sequencing HIV-1 tropism studies have used the 454™ Life Sciences/Roche platform. In this study, HIV-1 co-receptor usage was predicted for twelve patients scheduled to start a maraviroc-based antiretroviral regimen. The V3 region of the HIV-1 env gene was sequenced using four NGS platforms: 454™, PacBio® RS (Pacific Biosciences, Illumina®, and Ion Torrent™ (Life Technologies. Cross-platform variation was evaluated, including number of reads, read length and error rates. HIV-1 tropism was inferred using Geno2Pheno, Web PSSM, and the 11/24/25 rule and compared with Trofile™ and virologic response to antiretroviral therapy. Error rates related to insertions/deletions (indels and nucleotide substitutions introduced by the four NGS platforms were low compared to the actual HIV-1 sequence variation. Each platform detected all major virus variants within the HIV-1 population with similar frequencies. Identification of non-R5 viruses was comparable among the four platforms, with minor differences attributable to the algorithms used to infer HIV-1 tropism. All NGS platforms showed similar concordance with virologic response to the maraviroc-based regimen (75% to 80% range depending on the algorithm used, compared to Trofile (80% and population sequencing (70%. In conclusion, all four NGS platforms were able to detect minority non-R5 variants at comparable levels suggesting that any NGS-based method can be used to predict HIV-1 coreceptor usage.

Immune defence against HIV-1 infection in HIV-1-exposed seronegative persons.

Science.gov (United States)

Schmechel, S C; Russell, N; Hladik, F; Lang, J; Wilson, A; Ha, R; Desbien, A; McElrath, M J

2001-11-01

Rare individuals who are repeatedly exposed to HIV-1 through unprotected sexual contact fail to acquire HIV-1 infection. These persons represent a unique study population to evaluate mechanisms by which HIV-1 replication is either prevented or controlled. We followed longitudinally a group of healthy HIV-1 seronegative persons each reporting repeated high-risk sexual activities with their HIV-1-infected partner at enrollment. The volunteers were primarily (90%) male homosexuals, maintaining high risk activities with their known infected partner (45%) or multiple other partners (61%). We evaluated the quantity and specificity of HIV-1-specific T cells in 31 exposed seronegatives (ES) using a IFN-gamma ELISPOT assay to enumerate T cells recognizing epitopes within HIV-1 Env, Gag, Pol and Nef. PBMC from only three of the 31 volunteers demonstrated ex vivo HIV-1-specific IFN-gamma secretion, in contrast to nearly 30% exhibiting cytolytic responses in previous studies. These findings suggest that if T cell responses in ES are induced by HIV-1 exposure, the frequency is at low levels in most of them, and below the level of detection using the ELISPOT assay. Alternative approaches to improve the sensitivity of detection may include use of dendritic cells as antigen-presenting cells in the ex vivo assay and more careful definition of the risk behavior and extent of HIV-1 exposure in conjunction with the evaluation of T cell responses.

Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

Science.gov (United States)

Sarafianos, Stefan G; Das, Kalyan; Hughes, Stephen H; Arnold, Eddy

2004-12-01

HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

The next 5 years of global HIV/AIDS policy: critical gaps and strategies for effective responses.

Science.gov (United States)

Szekeres, Greg

2008-08-01

The University of California, Los Angeles Program in Global Health performed a landscape analysis based on interviews conducted between November 2006 and February 2007 with 35 key informants from major international organizations conducting HIV/AIDS work. Institutions represented included multilateral organizations, foundations, and governmental and non-governmental organizations. The purpose of this analysis is to assist major foundations and other institutions to understand better the international HIV/AIDS policy landscape and to formulate research and development programmes that can make a significant contribution to moving important issues forward in the HIV/AIDS policy arena. Topics identified during the interviews were organized around the four major themes of the Ford Foundation's Global HIV/AIDS Initiative: leadership and leadership development; equity; accountability; and global partnerships. Key informants focused on the need for a visionary response to the HIV pandemic, the need to maintain momentum, ways to improve the scope of leadership development programmes, ideas for improving gender equity and addressing regional disparities and the needs of vulnerable populations, recommendations for strengthening accountability mechanisms among governments, foundations, and civil society and on calling for increased collaboration and partnership among key players in the global HIV/AIDS response.

The Case for Adolescent HIV Vaccination in South Africa

OpenAIRE

Moodley, Nishila; Gray, Glenda; Bertram, Melanie

2016-01-01

Abstract Despite comprising 0.7% of the world population, South Africa is home to 18% of the global human immunodeficiency virus (HIV) prevalence. Unyielding HIV subepidemics among adolescents threaten national attempts to curtail the disease burden. Should an HIV vaccine become available, establishing its point of entry into the health system becomes a priority. This study assesses the impact of school-based HIV vaccination and explores how variations in vaccine characteristics affect cost-e...

How does mother-to-child transmission of HIV differ among African populations? Lessons from MBL2 genetic variation in Zimbabweans.

Science.gov (United States)

Mhandire, Kudakwashe; Pharo, Gavin; Kandawasvika, Gwendolene Q; Duri, Kerina; Swart, Marelize; Stray-Pedersen, Babill; Dandara, Collet

2014-07-01

Mannose binding lectin (MBL) is a pathogen pattern recognition protein involved in antimicrobial activities. Variation in MBL2 gene has been extensively implicated in differential outcomes of infectious diseases in studies conducted outside Africa, but virtually very little is known on the role of this candidate gene in the African continent. We investigated human genetic variations in MBL2 in a Zimbabwean pediatric population and their putative associations with HIV infection in perinatally exposed children. One hundred and four children aged 7 to 9 years comprising 68 perinatally exposed to HIV (32 who were born infected and 36 who were uninfected) and 36 unexposed controls were recruited. DNA samples were genotyped for MBL2 polymorphisms using PCR-RFLP and sequencing. HIV infected children had markedly variable and significantly lower mean height (p=0.03) and weight (p=0.005) when compared to the uninfected children. Using all samples, frequencies for MBL2 genetic variants for the Zimbabwean population were calculated. Twelve single nucleotide polymorphisms were observed and minor alleles occurred with the following frequencies: -550C>G (G: 0.02), -435G>A (A: 0.08), -428A>C (C: 0.39), -394A>G (A: 0.39), -328AGAGAA ins/del (AGAGAA ins: 0.44), -245G>A (A: 0.05), -221C>G (C: 0.12), -111A>T (T: 0.10), -70C>T (C: 0.46), +4C>T (C: 0.45), novel -595G>A (A: 0.02), and 170G>A (0.24). We found that the MBL2 +4T variant displayed a trend for association with reduced risk of HIV transmission from mother-to-child but the remaining vast majority of the genetic markers did not show a significant association. We conclude (1) the MBL2 gene is highly polymorphic in the Zimbabwean population, and (2) MBL2 genetic variation does not appear to play a major role in influencing the risk of mother-to-child HIV transmission in our study sample. These observations contest the hitherto significant role of this candidate gene for HIV transmission from mother-to-child in non

Neuropsychological performance in patients with asymptomatic HIV-1 infection.

Science.gov (United States)

Martínez-Banfi, Martha; Vélez, Jorge I; Perea, M Victoria; García, Ricardo; Puentes-Rozo, Pedro J; Mebarak Chams, Moises; Ladera, Valentina

2018-05-01

Human immunodeficiency virus (HIV-1) infection and acquired immunodeficiency syndrome (AIDS) lead to neurocognitive disorders; however, there is still much knowledge to be gained regarding HIV-associated neurocognitive disorders. The purpose of this study was to assess the cognitive performance, instrumental activities of daily living, depression, and anxiety in patients with asymptomatic HIV-1 infections compared with seronegative participants without neurocognitive impairment. We studied a sample consisted of 60 patients with asymptomatic HIV-1 infections and 60 seronegative participants without neurocognitive impairment from the city of Barranquilla, Colombia, with a mean age of 36.07 years. A protocol of neuropsychological and psychopathological tests was applied to the participants. The group of patients with asymptomatic HIV infections significantly underperformed on tasks that assessed global cognitive screening, attention span, learning, phonemic verbal fluency, auditory-verbal comprehension, information processing speed, cognitive flexibility, and motor skills compared to the group of seronegative participants. No significant differences were found in memory, visual confrontation naming, vocabulary, inhibition, and instrumental activities of daily living. Additionally, the patients with asymptomatic HIV-1 infection had a higher anxiety index than the seronegative participants, but no significant difference was found in depression. A correlation was found between depression and anxiety. In conclusion, the patients with asymptomatic HIV-1 infection had lower cognitive performances than the seronegative participants in the cognitive functions mentioned above and more anxiety but still performed the instrumental activities of daily living.

Dynamic Variation in Sexual Contact Rates in a Cohort of HIV-Negative Gay Men.

Science.gov (United States)

Romero-Severson, E O; Volz, E; Koopman, J S; Leitner, T; Ionides, E L

2015-08-01

Human immunodeficiency virus (HIV) transmission models that include variability in sexual behavior over time have shown increased incidence, prevalence, and acute-state transmission rates for a given population risk profile. This raises the question of whether dynamic variation in individual sexual behavior is a real phenomenon that can be observed and measured. To study this dynamic variation, we developed a model incorporating heterogeneity in both between-person and within-person sexual contact patterns. Using novel methodology that we call iterated filtering for longitudinal data, we fitted this model by maximum likelihood to longitudinal survey data from the Centers for Disease Control and Prevention's Collaborative HIV Seroincidence Study (1992-1995). We found evidence for individual heterogeneity in sexual behavior over time. We simulated an epidemic process and found that inclusion of empirically measured levels of dynamic variation in individual-level sexual behavior brought the theoretical predictions of HIV incidence into closer alignment with reality given the measured per-act probabilities of transmission. The methods developed here provide a framework for quantifying variation in sexual behaviors that helps in understanding the HIV epidemic among gay men. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Bayesian spatial semi-parametric modeling of HIV variation in Kenya.

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Oscar Ngesa

Full Text Available Spatial statistics has seen rapid application in many fields, especially epidemiology and public health. Many studies, nonetheless, make limited use of the geographical location information and also usually assume that the covariates, which are related to the response variable, have linear effects. We develop a Bayesian semi-parametric regression model for HIV prevalence data. Model estimation and inference is based on fully Bayesian approach via Markov Chain Monte Carlo (McMC. The model is applied to HIV prevalence data among men in Kenya, derived from the Kenya AIDS indicator survey, with n = 3,662. Past studies have concluded that HIV infection has a nonlinear association with age. In this study a smooth function based on penalized regression splines is used to estimate this nonlinear effect. Other covariates were assumed to have a linear effect. Spatial references to the counties were modeled as both structured and unstructured spatial effects. We observe that circumcision reduces the risk of HIV infection. The results also indicate that men in the urban areas were more likely to be infected by HIV as compared to their rural counterpart. Men with higher education had the lowest risk of HIV infection. A nonlinear relationship between HIV infection and age was established. Risk of HIV infection increases with age up to the age of 40 then declines with increase in age. Men who had STI in the last 12 months were more likely to be infected with HIV. Also men who had ever used a condom were found to have higher likelihood to be infected by HIV. A significant spatial variation of HIV infection in Kenya was also established. The study shows the practicality and flexibility of Bayesian semi-parametric regression model in analyzing epidemiological data.

Globalization and its methodological discontents: Contextualizing globalization through the study of HIV/AIDS

Science.gov (United States)

2011-01-01

There remains considerable discontent between globalization scholars about how to conceptualize its meaning and in regards to epistemological and methodological questions concerning how we can come to understand how these processes ultimately operate, intersect and transform our lives. This article argues that to better understand what globalization is and how it affects issues such as global health, we must take a differentiating approach, which focuses on how the multiple processes of globalization are encountered and informed by different social groups and with how these encounters are experienced within particular contexts. The article examines the heuristic properties of qualitative field research as a means to help better understand how the intersections of globalization are manifested within particular locations. To do so, the article focuses on three recent case studies conducted on globalization and HIV/AIDS and explores how these cases can help us to understand the contextual permutations involved within the processes of globalization. PMID:21861895

Globalization and its methodological discontents: Contextualizing globalization through the study of HIV/AIDS

Directory of Open Access Journals (Sweden)

Labonté Ronald

2011-08-01

Full Text Available Abstract There remains considerable discontent between globalization scholars about how to conceptualize its meaning and in regards to epistemological and methodological questions concerning how we can come to understand how these processes ultimately operate, intersect and transform our lives. This article argues that to better understand what globalization is and how it affects issues such as global health, we must take a differentiating approach, which focuses on how the multiple processes of globalization are encountered and informed by different social groups and with how these encounters are experienced within particular contexts. The article examines the heuristic properties of qualitative field research as a means to help better understand how the intersections of globalization are manifested within particular locations. To do so, the article focuses on three recent case studies conducted on globalization and HIV/AIDS and explores how these cases can help us to understand the contextual permutations involved within the processes of globalization.

Estimates of global HIV/AIDS mortality, prevalence and incidence rates, and their association with the Human Development Index

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Kamyar Mansori; Erfan Ayubi; Fatemeh Khosravi Shadmani; Shiva Mansouri Hanis; Somayeh Khazaei; Mohadeseh Sani; Yousef Moradi; Salman Khazaei; Abolfazl Mohammadbeigi

2017-01-01

Background: HIV/AIDS is one of greatest global public health concerns today due to the high incidence, prevalence and mortality rates. The aim of this research was investigate and estimate the global HIV/AIDS mortality, prevalence and incidence rates, and explore their associations with the Human Development Index. Methods: The global age-standardized rates of mortality, prevalence and incidence of HIV/AIDS were obtained from the UNAIDS for different countries in 2015. The human developm...

Rare HIV-1 Subtype J Genomes and a New H/U/CRF02_AG Recombinant Genome Suggests an Ancient Origin of HIV-1 in Angola.

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Bártolo, Inês; Calado, Rita; Borrego, Pedro; Leitner, Thomas; Taveira, Nuno

2016-08-01

Angola has an extremely diverse HIV-1 epidemic fueled in part by the frequent interchange of people with the Democratic Republic of Congo (DRC) and Republic of Congo (RC). Characterization of HIV-1 strains circulating in Angola should help to better understand the origin of HIV-1 subtypes and recombinant forms and their transmission dynamics. In this study we characterize the first near full-length HIV-1 genomic sequences from HIV-1 infected individuals from Angola. Samples were obtained in 1993 from three HIV-1 infected patients living in Cabinda, Angola. Near full-length genomic sequences were obtained from virus isolates. Maximum likelihood phylogenetic tree inference and analyses of potential recombination patterns were performed to evaluate the sequence classifications and origins. Phylogenetic and recombination analyses revealed that one virus was a pure subtype J, another mostly subtype J with a small uncertain region, and the final virus was classified as a H/U/CRF02_AG recombinant. Consistent with their epidemiological data, the subtype J sequences were more closely related to each other than to other J sequences previously published. Based on the env gene, taxa from Angola occur throughout the global subtype J phylogeny. HIV-1 subtypes J and H are present in Angola at low levels since at least 1993. Low transmission efficiency and/or high recombination potential may explain their limited epidemic success in Angola and worldwide. The high diversity of rare subtypes in Angola suggests that Angola was part of the early establishment of the HIV-1 pandemic.

The spread and effect of HIV-1 infection in sub-Saharan Africa.

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Buvé, Anne; Bishikwabo-Nsarhaza, Kizito; Mutangadura, Gladys

2002-06-08

Africa is the continent most severely affected by the global HIV-1 epidemic, with east and southern Africa in general more severely affected than west and central Africa. Differences in the spread of the epidemic can be accounted for by a complex interplay of sexual behaviour and biological factors that affect the probability of HIV-1 transmission per sex act. Sexual behaviour patterns are determined by cultural and socioeconomic contexts. In sub-Saharan Africa, some traditions and socioeconomic developments have contributed to the extensive spread of HIV-1 infection, including the subordinate position of women, impoverishment and decline of social services, rapid urbanisation and modernisation, and wars and conflicts. Populations in many parts of Africa are becoming trapped in a vicious circle as the HIV-1 epidemic leads to high mortality rates in young and economically productive age groups, and thus leads to further impoverishment. Interventions to control HIV-1 should not only target individuals, but also aim to change those aspects of cultural and socioeconomic context that increase the vulnerability to HIV-1 of people and communities.

Controlling the HIV/AIDS epidemic: current status and global challenges

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Thorsten eDemberg

2012-08-01

Full Text Available This review provides an overview of the current status of the global HIV pandemic and strategies to bring it under control. It updates numerous preventive approaches including behavioral interventions, male circumcision, pre- and post-exposure prophylaxis, vaccines, and microbicides. The manuscript summarizes current anti-retroviral treatment options, their impact in the western world, and difficulties faced by emerging and resource-limited nations in providing and maintaining appropriate treatment regimens. Current clinical and pre-clinical approaches towards a cure for HIV are described, including new drug compounds that target viral reservoirs and gene therapy approaches aimed at altering susceptibility to HIV infection. Recent progress in vaccine development is summarized, including novel approaches and new discoveries.

Influenza vaccination of HIV-1-positive and HIV-1-negative former intravenous drug users.

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Amendola, A; Boschini, A; Colzani, D; Anselmi, G; Oltolina, A; Zucconi, R; Begnini, M; Besana, S; Tanzi, E; Zanetti, A R

2001-12-01

The immunogenicity of an anti-influenza vaccine was assessed in 409 former intravenous drug user volunteers and its effect on the levels of HIV-1 RNA, proviral DNA and on CD4+ lymphocyte counts in a subset HIV-1-positive subjects was measured. HIV-1-positive individuals (n = 72) were divided into three groups on the basis of their CD4+ lymphocyte counts, while the 337 HIV-1-negative participants were allocated into group four. Haemagglutination inhibiting (HI) responses varied from 45.8 to 70% in the HIV-1-positive subjects and were significantly higher in group four (80.7% responses to the H1N1 strain, 81.6% to the H3N2 strain, and 83% to the B strain). The percentage of subjects with HI protective antibody titres (> or = 1:40) increased significantly after vaccination, especially in HIV-1 uninfected subjects. Immunization caused no significant changes in CD4+ counts and in neither plasma HIV-1 RNA nor proviral DNA levels. Therefore, vaccination against influenza may benefit persons infected by HIV-1. Copyright 2001 Wiley-Liss, Inc.

Effect of menstrual cycle on HIV-1 levels in the peripheral blood and genital tract. WHS 001 Study Team.

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Reichelderfer, P S; Coombs, R W; Wright, D J; Cohn, J; Burns, D N; Cu-Uvin, S; Baron, P A; Coheng, M H; Landay, A L; Beckner, S K; Lewis, S R; Kovacs, A A

2000-09-29

To assess the variation in HIV-1 over the menstrual cycle, including RNA levels in the female genital tract, plasma HIV-1-RNA levels, CD4 cell counts, and culturable virus. A prospective analysis of 55 HIV-1-infected women. Blood and genital tract specimens were collected weekly over 8 weeks, spanning two complete menstrual cycles. Applying repeated-measures models that used menses as the reference level, the variation in viral RNA levels was compared in endocervical canal fluid and cells (collected by Sno-strips and cytobrush, respectively) and ectocervicovaginal lavage (CVL) fluid. Repeated-measures models were also used to assess the variation in plasma CD4 cell counts and viral load. Shedding patterns differed among the three sampling methods, independent of genital tract co-infections. Genital tract HIV-1-RNA levels from CVL fluid and endocervical canal cytobrush specimens were highest during menses and lowest immediately thereafter (P = 0.001 and P = 0.04). The HIV-1-RNA level in endocervical canal fluid was highest in the week preceding menses (P = 0.003). The menstrual cycle had no effect on blood levels of RNA (P = 0.62), culturable virus (P = 0.34), or CD4 cell counts (P = 0.55). HIV-1-RNA levels were higher in endocervical canal fluid than in peripheral blood plasma during the late luteal phase (P = 0.03). HIV-1-RNA levels vary with the menstrual cycle in the female genital tract but not the blood compartment. HIV-1-RNA levels are higher in endocervical canal fluid than in blood plasma. These findings may have important implications for sex-specific pathogenesis, heterosexual transmission, and contraceptive hormone interventions in HIV-1-infected women.

Semen Bacterial Concentrations and HIV-1 RNA Shedding Among HIV-1-Seropositive Kenyan Men.

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Korhonen, Christine J; Srinivasan, Sujatha; Huang, Dandi; Ko, Daisy L; Sanders, Eduard J; Peshu, Norbert M; Krieger, John N; Muller, Charles H; Coombs, Robert W; Fredricks, David N; Graham, Susan M

2017-03-01

HIV-1 is transmitted through semen from men to their sexual partners. Genital infections can increase HIV-1 RNA shedding in semen, but shedding also occurs in the absence of typical pathogens. We hypothesized that higher bacterial concentrations in semen would be associated with higher HIV-1 RNA levels. We analyzed semen samples from 42 HIV-1-seropositive Kenyan men using quantitative polymerase chain reaction (PCR) to assess bacterial concentrations and real-time PCR to measure HIV-1 RNA levels. Generalized estimation equations were used to evaluate associations between these 2 measures. Broad-range 16S rRNA gene PCR with pyrosequencing was performed on a subset of 13 samples to assess bacterial community composition. Bacteria were detected in 96.6% of 88 samples by quantitative PCR. Semen bacterial concentration and HIV-1 RNA levels were correlated 0.30 (P = 0.01). The association between bacterial concentration and HIV-1 RNA detection was not significant after adjustment for antiretroviral therapy (ART) (adjusted odds ratio: 1.27, 95% CI: 0.84 to 1.91). Factors associated with semen bacterial concentration included insertive anal sex (adjusted beta 0.92, 95% CI: 0.12 to 1.73) and ART use (adjusted beta: -0.77, 95% CI: -1.50 to 0.04). Among 13 samples with pyrosequencing data, Corynebacterium spp., Staphylococcus spp., and Streptococcus spp. were most frequently detected. Most of these HIV-1-infected men had bacteria in their semen. ART use was associated with undetectable semen HIV-1 RNA and lower semen bacterial concentrations, whereas insertive anal sex was associated with higher bacterial concentrations. Additional studies evaluating the relationship between semen bacteria, inflammation, mucosal immunity, and HIV-1 shedding are needed to understand implications for HIV-1 transmission.

HIV-1 molecular epidemiology among newly diagnosed HIV-1 individuals in Hebei, a low HIV prevalence province in China.

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Lu, Xinli; Kang, Xianjiang; Liu, Yongjian; Cui, Ze; Guo, Wei; Zhao, Cuiying; Li, Yan; Chen, Suliang; Li, Jingyun; Zhang, Yuqi; Zhao, Hongru

2017-01-01

New human immunodeficiency virus type 1 (HIV-1) diagnoses are increasing rapidly in Hebei. The aim of this study presents the most extensive HIV-1 molecular epidemiology investigation in Hebei province in China thus far. We have carried out the most extensive systematic cross-sectional study based on newly diagnosed HIV-1 positive individuals in 2013, and characterized the molecular epidemiology of HIV-1 based on full length gag-partial pol gene sequences in the whole of Hebei. Nine HIV-1 genotypes based on full length gag-partial pol gene sequence were identified among 610 newly diagnosed naïve individuals. The four main genotypes were circulating recombinant form (CRF)01_AE (53.4%), CRF07_BC (23.4%), subtype B (15.9%), and unique recombinant forms URFs (4.9%). Within 1 year, three new genotypes (subtype A1, CRF55_01B, CRF65_cpx), unknown before in Hebei, were first found among men who have sex with men (MSM). All nine genotypes were identified in the sexually contracted HIV-1 population. Among 30 URFs, six recombinant patterns were revealed, including CRF01_AE/BC (40.0%), CRF01_AE/B (23.3%), B/C (16.7%), CRF01_AE/C (13.3%), CRF01_AE/B/A2 (3.3%) and CRF01_AE/BC/A2 (3.3%), plus two potential CRFs. This study elucidated the complicated characteristics of HIV-1 molecular epidemiology in a low HIV-1 prevalence northern province of China and revealed the high level of HIV-1 genetic diversity. All nine HIV-1 genotypes circulating in Hebei have spread out of their initial risk groups into the general population through sexual contact, especially through MSM. This highlights the urgency of HIV prevention and control in China.

HIV-1 molecular epidemiology among newly diagnosed HIV-1 individuals in Hebei, a low HIV prevalence province in China.

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Xinli Lu

Full Text Available New human immunodeficiency virus type 1 (HIV-1 diagnoses are increasing rapidly in Hebei. The aim of this study presents the most extensive HIV-1 molecular epidemiology investigation in Hebei province in China thus far. We have carried out the most extensive systematic cross-sectional study based on newly diagnosed HIV-1 positive individuals in 2013, and characterized the molecular epidemiology of HIV-1 based on full length gag-partial pol gene sequences in the whole of Hebei. Nine HIV-1 genotypes based on full length gag-partial pol gene sequence were identified among 610 newly diagnosed naïve individuals. The four main genotypes were circulating recombinant form (CRF01_AE (53.4%, CRF07_BC (23.4%, subtype B (15.9%, and unique recombinant forms URFs (4.9%. Within 1 year, three new genotypes (subtype A1, CRF55_01B, CRF65_cpx, unknown before in Hebei, were first found among men who have sex with men (MSM. All nine genotypes were identified in the sexually contracted HIV-1 population. Among 30 URFs, six recombinant patterns were revealed, including CRF01_AE/BC (40.0%, CRF01_AE/B (23.3%, B/C (16.7%, CRF01_AE/C (13.3%, CRF01_AE/B/A2 (3.3% and CRF01_AE/BC/A2 (3.3%, plus two potential CRFs. This study elucidated the complicated characteristics of HIV-1 molecular epidemiology in a low HIV-1 prevalence northern province of China and revealed the high level of HIV-1 genetic diversity. All nine HIV-1 genotypes circulating in Hebei have spread out of their initial risk groups into the general population through sexual contact, especially through MSM. This highlights the urgency of HIV prevention and control in China.

Multiply to conquer: Copy number variations at Ppd-B1 and Vrn-A1 facilitate global adaptation in wheat.

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Würschum, Tobias; Boeven, Philipp H G; Langer, Simon M; Longin, C Friedrich H; Leiser, Willmar L

2015-07-29

Copy number variation was found to be a frequent type of DNA polymorphism in the human genome often associated with diseases but its importance in crops and the effects on agronomic traits are still largely unknown. Here, we employed a large worldwide panel of 1110 winter wheat varieties to assess the frequency and the geographic distribution of copy number variants at the Photoperiod-B1 (Ppd-B1) and the Vernalization-A1 (Vrn-A1) loci as well as their effects on flowering time under field conditions. We identified a novel four copy variant of Vrn-A1 and based on the phylogenetic relationships among the lines show that the higher copy variants at both loci are likely to have arisen independently multiple times. In addition, we found that the frequency of the different copy number variants at both loci reflects the environmental conditions in the varieties' region of origin and based on multi-location field trials show that Ppd-B1 copy number has a substantial effect on the fine-tuning of flowering time. In conclusion, our results show the importance of copy number variation at Ppd-B1 and Vrn-A1 for the global adaptation of wheat making it a key factor for wheat success in a broad range of environments and in a wider context substantiate the significant role of copy number variation in crops.

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

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Atluri VSR

2016-08-01

Full Text Available Venkata Subba Rao Atluri* Rahul Dev Jayant* Sudheesh Pilakka-Kanthikeel, Gabriella Garcia, Thangavel Samikkannu, Adriana Yndart, Ajeet Kaushik, Madhavan Nair Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA *These authors contributed equally to this work Abstract: Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP-bound tissue inhibitor of metalloproteinase-1 (TIMP1 protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the

HIV/STI interventions targeting women who experience forced sex: A systematic review of global literature.

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Deming, Michelle E; Bhochhibhoya, Amir; Ingram, LaDrea; Stafford, Crystal; Li, Xiaoming

2018-04-12

Women are disproportionately affected by HIV in many regions of the world and they represent the fastest growing demographic in the HIV epidemic. In addition, sexual violence against women is a global public health issue which increases women's vulnerability of HIV/STI acquisition. However, the relationship between sexual violence and HIV/STI risk are complex and contribute to the growing epidemic of women infected with HIV/STIs. Our purpose for this review is to examine existing HIV/STI interventions that target women who experience forced sex. Interventions designed to address women's unique needs in HIV/STI prevention are critical in reducing women's vulnerability to HIV/STIs.

HIV-1 vaccines

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Excler, Jean-Louis; Robb, Merlin L; Kim, Jerome H

2014-01-01

The development of a safe and effective preventive HIV-1 vaccine remains a public health priority. Despite scientific difficulties and disappointing results, HIV-1 vaccine clinical development has, for the first time, established proof-of-concept efficacy against HIV-1 acquisition and identified vaccine-associated immune correlates of risk. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop correlated with decreased risk of HIV infection, while Env-specific IgA directly correlated with increased risk. The development of vaccine strategies such as improved envelope proteins formulated with potent adjuvants and DNA and vectors expressing mosaics, or conserved sequences, capable of eliciting greater breadth and depth of potentially relevant immune responses including neutralizing and non-neutralizing antibodies, CD4+ and CD8+ cell-mediated immune responses, mucosal immune responses, and immunological memory, is now proceeding quickly. Additional human efficacy trials combined with other prevention modalities along with sustained funding and international collaboration remain key to bring an HIV-1 vaccine to licensure. PMID:24637946

The future of HIV vaccine research and the role of the Global HIV Vaccine Enterprise.

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Voronin, Yegor; Manrique, Amapola; Bernstein, Alan

2010-09-01

This review covers the role of the Global HIV Vaccine Enterprise (the Enterprise), an alliance of independent organizations committed to development of a safe and effective HIV vaccine. It discusses the history, impact on the field, and future directions and initiatives of the alliance in the context of recent progress in HIV vaccine research and development. Significant progress has been made in the field since the release of the 2005 Scientific Strategic Plan (the Plan) of the Enterprise. Over the last year, the Enterprise embarked on an impact assessment of the 2005 Plan and the development of the 2010 Plan. Enterprise Working Groups identified key priorities in the field, several of which are discussed in this review, including changing the nature, purpose and process of clinical trials, increasing and facilitating data sharing, and optimizing existing and mobilizing new resources. This time is an important moment in HIV vaccine research. New clinical trial and laboratory results have created new opportunities to advance the search for an HIV vaccine and reinvigorated the field. The Enterprise will publish its 2010 Plan this year, providing a framework for setting new priorities and directions and encouraging new and existing partners to embark on a shared scientific agenda.

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015

NARCIS (Netherlands)

Wang, Haidong; Wolock, Tim M.; Carter, Austin; Nguyen, Grant; Kyu, Hmwe Hmwe; Gakidou, Emmanuela; Hay, Simon I.; Mills, Edward J.; Trickey, Adam; Msemburi, William; Coates, Matthew M.; Mooney, Meghan D.; Fraser, Maya S.; Sligar, Amber; Salomon, Joshua; Larson, Heidi J.; Friedman, Joseph; Abajobir, Amanuel Alemu; Abate, Kalkidan Hassen; Abbas, Kaja M.; Abd El Razek, Mohamed Magdy; Abd-Allah, Foad; Abdulle, Abdishakur M.; Abera, Semaw Ferede; Abubakar, Ibrahim; Abu-Raddad, Laith J.; Abu-Rmeileh, Niveen M. E.; Abyu, Gebre Yitayih; Adebiyi, Akindele Olupelumi; Adedeji, Isaac Akinkunmi; Adelekan, Ademola Lukman; Adofo, Koranteng; Adou, Arsene Kouablan; Ajala, Oluremi N.; Akinyemiju, Tomi F.; Akseer, Nadia; Al Lami, Faris Hasan; Al-Aly, Ziyad; Alam, Khurshid; Alam, Noore K. M.; Alasfoor, Deena; Aldhahri, Saleh Fahed S.; Aldridge, Robert William; Alegretti, Miguel Angel; Aleman, Alicia V.; Alemu, Zewdie Aderaw; Alfonso-Cristancho, Rafael; Ali, Raghib; Amare, Azmeraw T.; Hoek, Hans W.

Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral

Trans-dissemination of exosomes from HIV-1-infected cells fosters both HIV-1 trans-infection in resting CD4+ T lymphocytes and reactivation of the HIV-1 reservoir.

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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.

Temporal Variation and Association of Aflatoxin B1 Albumin-Adduct Levels with Socio-Economic and Food Consumption Factors in HIV Positive Adults

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Pauline E. Jolly

2015-11-01

Full Text Available The association between aflatoxin exposure and alteration in immune responses observed in humans suggest that aflatoxin could suppress the immune system and work synergistically with HIV to increase disease severity and progression to AIDS. No longitudinal study has been conducted to assess exposure to aflatoxin (AF among HIV positive individuals. We examined temporal variation in AFB1 albumin adducts (AF-ALB in HIV positive Ghanaians, and assessed the association with socioeconomic and food consumption factors. We collected socioeconomic and food consumption data for 307 HIV positive antiretroviral naive adults and examined AF-ALB levels at recruitment (baseline and at six (follow-up 1 and 12 (follow-up 2 months post-recruitment, by age, gender, socioeconomic status (SES and food consumption patterns. Generalized linear models were used to examine the influence of socioeconomic and food consumption factors on changes in AF-ALB levels over the study period, adjusting for other covariates. AF-ALB levels (pg/mg albumin were lower at baseline (mean AF-ALB: 14.9, SD: 15.9, higher at six months (mean AF-ALB: 23.3, SD: 26.6, and lower at 12 months (mean AF-ALB: 15.3, SD: 15.4. Participants with the lowest SES had the highest AF-ALB levels at baseline and follow up-2 compared with those with higher SES. Participants who bought less than 20% of their food and who stored maize for less than two months had lower AF-ALB levels. In the adjusted models, there was a statistically significant association between follow up time and season (dry or rainy season on AF-ALB levels over time (p = 0.04. Asymptomatic HIV-positive Ghanaians had high plasma AF-ALB levels that varied according to season, socioeconomic status, and food consumption patterns. Steps need to be taken to ensure the safety and security of the food supply for the population, but in particular for the most vulnerable groups such as HIV positive people.

A comparison of parallel pyrosequencing and sanger clone-based sequencing and its impact on the characterization of the genetic diversity of HIV-1.

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Binhua Liang

Full Text Available BACKGROUND: Pyrosequencing technology has the potential to rapidly sequence HIV-1 viral quasispecies without requiring the traditional approach of cloning. In this study, we investigated the utility of ultra-deep pyrosequencing to characterize genetic diversity of the HIV-1 gag quasispecies and assessed the possible contribution of pyrosequencing technology in studying HIV-1 biology and evolution. METHODOLOGY/PRINCIPAL FINDINGS: HIV-1 gag gene was amplified from 96 patients using nested PCR. The PCR products were cloned and sequenced using capillary based Sanger fluorescent dideoxy termination sequencing. The same PCR products were also directly sequenced using the 454 pyrosequencing technology. The two sequencing methods were evaluated for their ability to characterize quasispecies variation, and to reveal sites under host immune pressure for their putative functional significance. A total of 14,034 variations were identified by 454 pyrosequencing versus 3,632 variations by Sanger clone-based (SCB sequencing. 11,050 of these variations were detected only by pyrosequencing. These undetected variations were located in the HIV-1 Gag region which is known to contain putative cytotoxic T lymphocyte (CTL and neutralizing antibody epitopes, and sites related to virus assembly and packaging. Analysis of the positively selected sites derived by the two sequencing methods identified several differences. All of them were located within the CTL epitope regions. CONCLUSIONS/SIGNIFICANCE: Ultra-deep pyrosequencing has proven to be a powerful tool for characterization of HIV-1 genetic diversity with enhanced sensitivity, efficiency, and accuracy. It also improved reliability of downstream evolutionary and functional analysis of HIV-1 quasispecies.

Biologic interactions between HSV-2 and HIV-1 and possible implications for HSV vaccine development.

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Schiffer, Joshua T; Gottlieb, Sami L

2017-09-25

Development of a safe and effective vaccine against herpes simplex virus type 2 (HSV-2) has the potential to limit the global burden of HSV-2 infection and disease, including genital ulcer disease and neonatal herpes, and is a global sexual and reproductive health priority. Another important potential benefit of an HSV-2 vaccine would be to decrease HIV infections, as HSV-2 increases the risk of HIV-1 acquisition several-fold. Acute and chronic HSV-2 infection creates ulcerations and draws dendritic cells and activated CD4+ T cells into genital mucosa. These cells are targets for HIV entry and replication. Prophylactic HSV-2 vaccines (to prevent infection) and therapeutic vaccines (to modify or treat existing infections) are currently under development. By preventing or modifying infection, an effective HSV-2 vaccine could limit HSV-associated genital mucosal inflammation and thus HIV risk. However, a vaccine might have competing effects on HIV risk depending on its mechanism of action and cell populations generated in the genital mucosa. In this article, we review biologic interactions between HSV-2 and HIV-1, consider HSV-2 vaccine development in the context of HIV risk, and discuss implications and research needs for future HSV vaccine development. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Impact of Global Institutions on National Health HIV/AIDS Policy Making in Developing Countries

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Zhanat Mokushev

2013-09-01

Full Text Available This article explores the relationship of global institutions such as the International Monetary Fund, World Trade Organization, World Bank, and individual developing countries in social health policy making in terms of HIV and AIDS. We examine the role of IGOs and NGOs in regarding to HIV/AIDS issues then analyse the TRIPs agreement as a tool for developing countries to negotiate with International organisations in global health policy decisions.

Developing strategies for HIV-1 eradication

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Durand, Christine M.; Blankson, Joel N.; Siliciano, Robert F.

2014-01-01

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication, transforming the outlook for infected patients. However, reservoirs of replication-competent forms of the virus persist during HAART, and when treatment is stopped, high rates of HIV-1 replication return. Recent insights into HIV-1 latency, as well as a report that HIV-1 infection was eradicated in one individual, have renewed interest in finding a cure for HIV-1 infection. Strategies for HIV-1 eradication include gene therapy and hematopoietic stem cell transplantation, stimulating host immunity to control HIV-1 replication, and targeting latent HIV-1 in resting memory CD4+ T cells. Future efforts should aim to provide better understanding of how to reconstitute the CD4+ T cell compartment with genetically engineered cells, exert immune control over HIV-1 replication, and identify and eliminate all viral reservoirs. PMID:22867874

Semen Bacterial Concentrations and HIV-1 RNA Shedding Among HIV-1–Seropositive Kenyan Men

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Srinivasan, Sujatha; Huang, Dandi; Ko, Daisy L.; Sanders, Eduard J.; Peshu, Norbert M.; Krieger, John N.; Muller, Charles H.; Coombs, Robert W.; Fredricks, David N.; Graham, Susan M.

2017-01-01

Introduction: HIV-1 is transmitted through semen from men to their sexual partners. Genital infections can increase HIV-1 RNA shedding in semen, but shedding also occurs in the absence of typical pathogens. We hypothesized that higher bacterial concentrations in semen would be associated with higher HIV-1 RNA levels. Methods: We analyzed semen samples from 42 HIV-1–seropositive Kenyan men using quantitative polymerase chain reaction (PCR) to assess bacterial concentrations and real-time PCR to measure HIV-1 RNA levels. Generalized estimation equations were used to evaluate associations between these 2 measures. Broad-range 16S rRNA gene PCR with pyrosequencing was performed on a subset of 13 samples to assess bacterial community composition. Results: Bacteria were detected in 96.6% of 88 samples by quantitative PCR. Semen bacterial concentration and HIV-1 RNA levels were correlated 0.30 (P = 0.01). The association between bacterial concentration and HIV-1 RNA detection was not significant after adjustment for antiretroviral therapy (ART) (adjusted odds ratio: 1.27, 95% CI: 0.84 to 1.91). Factors associated with semen bacterial concentration included insertive anal sex (adjusted beta 0.92, 95% CI: 0.12 to 1.73) and ART use (adjusted beta: −0.77, 95% CI: −1.50 to 0.04). Among 13 samples with pyrosequencing data, Corynebacterium spp., Staphylococcus spp., and Streptococcus spp. were most frequently detected. Conclusion: Most of these HIV-1–infected men had bacteria in their semen. ART use was associated with undetectable semen HIV-1 RNA and lower semen bacterial concentrations, whereas insertive anal sex was associated with higher bacterial concentrations. Additional studies evaluating the relationship between semen bacteria, inflammation, mucosal immunity, and HIV-1 shedding are needed to understand implications for HIV-1 transmission. PMID:27861240

Resveratrol Reactivates Latent HIV through Increasing Histone Acetylation and Activating Heat Shock Factor 1.

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Zeng, Xiaoyun; Pan, Xiaoyan; Xu, Xinfeng; Lin, Jian; Que, Fuchang; Tian, Yuanxin; Li, Lin; Liu, Shuwen

2017-06-07

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.

Conflict-affected displaced persons need to benefit more from HIV and malaria national strategic plans and Global Fund grants

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Paik Eugene

2010-01-01

Full Text Available Abstract Background Access to HIV and malaria control programmes for refugees and internally displaced persons (IDPs is not only a human rights issue but a public health priority for affected populations and host populations. The primary source of funding for malaria and HIV programmes for many countries is the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund. This article analyses the current HIV and malaria National Strategic Plans (NSPs and Global Fund approved proposals from rounds 1-8 for countries in Africa hosting populations with refugees and/or IDPs to document their inclusion. Methods The review was limited to countries in Africa as they constitute the highest caseload of refugees and IDPs affected by HIV and malaria. Only countries with a refugee and/or IDP population of ≥ 10,000 persons were included. NSPs were retrieved from primary and secondary sources while approved Global Fund proposals were obtained from the organisation's website. Refugee figures were obtained from the United Nations High Commissioner for Refugees' database and IDP figures from the Internal Displacement Monitoring Centre. The inclusion of refugees and IDPs was classified into three categories: 1 no reference; 2 referenced; and 3 referenced with specific activities. Findings A majority of countries did not mention IDPs (57% compared with 48% for refugees in their HIV NSPs. For malaria, refugees were not included in 47% of NSPs compared with 44% for IDPs. A minority (21-29% of HIV and malaria NSPs referenced and included activities for refugees and IDPs. There were more approved Global Fund proposals for HIV than malaria for countries with both refugees and IDPs, respectively. The majority of countries with ≥10,000 refugees and IDPs did not include these groups in their approved proposals (61%-83% with malaria having a higher rate of exclusion than HIV. Interpretation Countries that have signed the 1951 refugee convention have an obligation

Increased Risk of HIV-1 Transmission in Pregnancy: A Prospective Study among African HIV-1 Serodiscordant Couples

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MUGO, Nelly R.; HEFFRON, Renee; DONNELL, Deborah; WALD, Anna; WERE, Edwin O.; REES, Helen; CELUM, Connie; KIARIE, James N.; COHEN, Craig R.; KAYINTEKORE, Kayitesi; BAETEN, Jared M.

2011-01-01

Background Physiologic and behavioral changes during pregnancy may alter HIV-1 susceptibility and infectiousness. Prospective studies exploring pregnancy and HIV-1 acquisition risk in women have found inconsistent results. No study has explored the effect of pregnancy on HIV-1 transmission risk from HIV-1 infected women to male partners. Methods In a prospective study of African HIV-1 serodiscordant couples, we evaluated the relationship between pregnancy and the risk of 1) HIV-1 acquisition among women and 2) HIV-1 transmission from women to men. Results 3321 HIV-1 serodiscordant couples were enrolled, 1085 (32.7%) with HIV-1 susceptible female partners and 2236 (67.3%) with susceptible male partners. HIV-1 incidence in women was 7.35 versus 3.01 per 100 person-years during pregnant and non-pregnant periods (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.33–4.09). This effect was attenuated and not statistically significant after adjusting for sexual behavior and other confounding factors (adjusted HR 1.71, 95% CI 0.93–3.12). HIV-1 incidence in male partners of infected women was 3.46 versus 1.58 per 100 person-years when their partners were pregnant versus not pregnant (HR 2.31, 95% CI 1.22–4.39). This effect was not attenuated in adjusted analysis (adjusted HR 2.47, 95% CI 1.26–4.85). Conclusions HIV-1 risk increased two-fold during pregnancy. Elevated risk of HIV-1 acquisition in pregnant women appeared in part to be explained by behavioral and other factors. This is the first study to show pregnancy increased the risk of female-to-male HIV-1 transmission, which may reflect biological changes of pregnancy that could increase HIV-1 infectiousness. PMID:21785321

Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

DEFF Research Database (Denmark)

Baxter, J D; Dunn, D; White, E

2015-01-01

OBJECTIVES: HIV-1 transmitted drug resistance (TDR) in treatment-naïve individuals is a well-described phenomenon. Baseline genotypic resistance testing is considered standard of care in most developed areas of the world. The aim of this analysis was to characterize HIV-1 TDR and the use of resis......OBJECTIVES: HIV-1 transmitted drug resistance (TDR) in treatment-naïve individuals is a well-described phenomenon. Baseline genotypic resistance testing is considered standard of care in most developed areas of the world. The aim of this analysis was to characterize HIV-1 TDR and the use...... on a modified 2009 World Health Organization definition to reflect newer resistance mutations. RESULTS: Baseline resistance testing was available in 1946 study participants. Higher rates of testing occurred in Europe (86.7%), the USA (81.3%) and Australia (89.9%) as compared with Asia (22.2%), South America (1...

Inequities in access to HIV prevention services for transgender men: results of a global survey of men who have sex with men.

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Scheim, Ayden I; Santos, Glenn-Milo; Arreola, Sonya; Makofane, Keletso; Do, Tri D; Hebert, Patrick; Thomann, Matthew; Ayala, George

2016-01-01

Free or low-cost HIV testing, condoms, and lubricants are foundational HIV prevention strategies, yet are often inaccessible for men who have sex with men (MSM). In the global context of stigma and poor healthcare access, transgender (trans) MSM may face additional barriers to HIV prevention services. Drawing on data from a global survey of MSM, we aimed to describe perceived access to prevention services among trans MSM, examine associations between stigma and access, and compare access between trans MSM and cisgender (non-transgender) MSM. The 2014 Global Men's Health and Rights online survey was open to MSM (inclusive of trans MSM) from any country and available in seven languages. Baseline data (n=3857) were collected from July to October 2014. Among trans MSM, correlations were calculated between perceived service accessibility and anti-transgender violence, healthcare provider stigma, and discrimination. Using a nested matched-pair study design, trans MSM were matched 4:1 to cisgender MSM on age group, region, and HIV status, and conditional logistic regression models compared perceived access to prevention services by transgender status. About 3.4% of respondents were trans men, of whom 69 were included in the present analysis. The average trans MSM participant was 26 to 35 years old (56.5%); lived in western Europe, North America, or Oceania (75.4%); and reported being HIV-negative (98.6%). HIV testing, condoms, and lubricants were accessible for 43.5, 53.6, and 26.1% of trans MSM, respectively. Ever having been arrested or convicted due to being trans and higher exposure to healthcare provider stigma in the past six months were associated with less access to some prevention services. Compared to matched cisgender controls, trans MSM reported significantly lower odds of perceived access to HIV testing (OR=0.57, 95% CI=0.33, 0.98) and condom-compatible lubricants (OR=0.54, 95% CI=0.30, 0.98). This first look at access to HIV prevention services for trans MSM

Prevention of HIV-1 Infection with Early Antiretroviral Therapy: Treatment as -

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Gilada, Ishwar; Gilada, T.

2014-07-01

There are 34.2 million living with HIV/AIDS globally according to the UNAIDS. The incidence is 2.5 million new infections every year. Out of the 24.8 million patients eligible for antiretroviral treatment, only 8 million are actually receiving it. Nearly 1.7 million people (4658 per day) die of the disease every year i.e., 4658/day, making HIV/AIDS a planetary emergency. The most disturbing fact is that more than 50% of the infected people do not reveal their HIV status to their sexual partners. The UN Sec-Gen Ban Ki-moon suggested "3 Zeros"--Zero Infection, Zero Stigma, Zero AIDS-deaths in 2008...

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8(+ T cell responses in HIV-1-infected individuals.

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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.

The US Food and Drug Administration's tentative approval process and the global fight against HIV.

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Chahal, Harinder Singh; Murray, Jeffrey S; Shimer, Martin; Capella, Peter; Presto, Ryan; Valdez, Mary Lou; Lurie, Peter G

2017-12-01

In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. In this paper, we describe the

Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition

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Limou, Sophie; Delaneau, Olivier; van Manen, Daniëlle; An, Ping; Sezgin, Efe; Le Clerc, Sigrid; Coulonges, Cédric; Troyer, Jennifer L.; Veldink, Jan H.; van den Berg, Leonard H.; Spadoni, Jean-Louis; Taing, Lieng; Labib, Taoufik; Montes, Matthieu; Delfraissy, Jean-François; Schachter, François; O’Brien, Stephen J.; Buchbinder, Susan; van Natta, Mark L.; Jabs, Douglas A.; Froguel, Philippe; Schuitemaker, Hanneke; Winkler, Cheryl A.

2012-01-01

Background. To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10−5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10−8. Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation. PMID:22362864

The global response to HIV in men who have sex with men.

Science.gov (United States)

Beyrer, Chris; Baral, Stefan D; Collins, Chris; Richardson, Eugene T; Sullivan, Patrick S; Sanchez, Jorge; Trapence, Gift; Katabira, Elly; Kazatchkine, Michel; Ryan, Owen; Wirtz, Andrea L; Mayer, Kenneth H

2016-07-09

Gay, bisexual, and other men who have sex with men (MSM) continue to have disproportionately high burdens of HIV infection in countries of low, middle, and high income in 2016. 4 years after publication of a Lancet Series on MSM and HIV, progress on reducing HIV incidence, expanding sustained access to treatment, and realising human rights gains for MSM remains markedly uneven and fraught with challenges. Incidence densities in MSM are unacceptably high in countries as diverse as China, Kenya, Thailand, the UK, and the USA, with substantial disparities observed in specific communities of MSM including young and minority populations. Although some settings have achieved sufficient coverage of treatment, pre-exposure prophylaxis (PrEP), and human rights protections for sexual and gender minorities to change the trajectory of the HIV epidemic in MSM, these are exceptions. The roll-out of PrEP has been notably slow and coverage nowhere near what will be required for full use of this new preventive approach. Despite progress on issues such as marriage equality and decriminalisation of same-sex behaviour in some countries, there has been a marked increase in anti-gay legislation in many countries, including Nigeria, Russia, and The Gambia. The global epidemic of HIV in MSM is ongoing, and global efforts to address it remain insufficient. This must change if we are ever to truly achieve an AIDS-free generation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of host cell variation on the neutralization of HIV-1 in vitro

NARCIS (Netherlands)

Polonis, Victoria R.; Schuitemaker, Hanneke; Bunnik, Evelien M.; Brown, Bruce K.; Scarlatti, Gabriella

2009-01-01

PURPOSE OF REVIEW: In this review we present current advances in our understanding of HIV-1 neutralization assays that employ primary cell types, as compared with those that utilize cell lines and the newer, more standardized pseudovirus assays. A commentary on the challenges of standardizing

Hyperthermia stimulates HIV-1 replication.

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Ferdinand Roesch

Full Text Available HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C and Heat Shock Proteins (HSPs modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.

A Meta-Analysis of the Metabolic Syndrome Prevalence in the Global HIV-Infected Population.

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Kim A Nguyen

Full Text Available Cardio-metabolic risk factors are of increasing concern in HIV-infected individuals, particularly with the advent of antiretroviral therapy (ART and the subsequent rise in longevity. However, the prevalence of cardio-metabolic abnormalities in this population and the differential contribution, if any, of HIV specific factors to their distribution, are poorly understood. Therefore, we conducted a systematic review and meta-analysis to estimate the global prevalence of metabolic syndrome (MS in HIV-infected populations, its variation by the different diagnostic criteria, severity of HIV infection, ART used and other major predictive characteristics.We performed a comprehensive search on major databases for original research articles published between 1998 and 2015. The pooled overall prevalence as well as by specific groups and subgroups were computed using random effects models.A total of 65 studies across five continents comprising 55094 HIV-infected participants aged 17-73 years (median age 41 years were included in the final meta-analysis. The overall prevalence of MS according to the following criteria were: ATPIII-2001:16.7% (95%CI: 14.6-18.8, IDF-2005: 18% (95%CI: 14.0-22.4, ATPIII-2004-2005: 24.6% (95%CI: 20.6-28.8, Modified ATPIII-2005: 27.9% (95%CI: 6.7-56.5, JIS-2009: 29.6% (95%CI: 22.9-36.8, and EGIR: 31.3% (95%CI: 26.8-36.0. By some MS criteria, the prevalence was significantly higher in women than in men (IDF-2005: 23.2% vs. 13.4, p = 0.030, in ART compared to non-ART users (ATPIII-2001: 18.4% vs. 11.8%, p = 0.001, and varied significantly by participant age, duration of HIV diagnosis, severity of infection, non-nucleoside reverse transcriptase inhibitors (NNRTIs use and date of study publication. Across criteria, there were significant differences in MS prevalence by sub-groups such as in men, the Americas, older publications, regional studies, younger adults, smokers, ART-naïve participants, NNRTIs users, participants with shorter

Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2

Science.gov (United States)

Celum, Connie; Wald, Anna; Lingappa, Jairam R.; Magaret, Amalia S.; Wang, Richard S.; Mugo, Nelly; Mujugira, Andrew; Baeten, Jared M.; Mullins, James I.; Hughes, James P.; Bukusi, Elizabeth A.; Cohen, Craig R.; Katabira, Elly; Ronald, Allan; Kiarie, James; Farquhar, Carey; Stewart, Grace John; Makhema, Joseph; Essex, Myron; Were, Edwin; Fife, Kenneth H.; de Bruyn, Guy; Gray, Glenda E.; McIntyre, James A.; Manongi, Rachel; Kapiga, Saidi; Coetzee, David; Allen, Susan; Inambao, Mubiana; Kayitenkore, Kayitesi; Karita, Etienne; Kanweka, William; Delany, Sinead; Rees, Helen; Vwalika, Bellington; Stevens, Wendy; Campbell, Mary S.; Thomas, Katherine K.; Coombs, Robert W.; Morrow, Rhoda; Whittington, William L.H.; McElrath, M. Juliana; Barnes, Linda; Ridzon, Renee; Corey, Lawrence

2010-01-01

BACKGROUND Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, ≥250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P = 0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log10 copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir

Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.

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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.

Global Dynamics of HIV Infection of CD4+ T Cells and Macrophages

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A. M. Elaiw

2013-01-01

Full Text Available We study the global dynamics of an HIV infection model describing the interaction of the HIV with CD4+ T cells and macrophages. The incidence rate of virus infection and the growth rate of the uninfected CD4+ T cells and macrophages are given by general functions. We have incorporated two types of distributed delays into the model to account for the time delay between the time the uninfected cells are contacted by the virus particle and the time for the emission of infectious (matures virus particles. We have established a set of conditions which are sufficient for the global stability of the steady states of the model. Using Lyapunov functionals and LaSalle's invariant principle, we have proven that if the basic reproduction number R0 is less than or equal to unity, then the uninfected steady state is globally asymptotically stable (GAS, and if the infected steady state exists, then it is GAS.

HIV-1 genetic diversity and its distribution characteristics among newly diagnosed HIV-1 individuals in Hebei province, China.

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Lu, Xinli; Zhao, Cuiying; Wang, Wei; Nie, Chenxi; Zhang, Yuqi; Zhao, Hongru; Chen, Suliang; Cui, Ze

2016-01-01

Since the first HIV-1 case in 1989, Hebei province has presented a clearly rising trend of HIV-1 prevalence, and HIV-1 genetic diversity has become the vital barrier to HIV prevention and control in this area. To obtain detailed information of HIV-1 spread in different populations and in different areas of Hebei, a cross-sectional HIV-1 molecular epidemiological investigation was performed across the province. Blood samples of 154 newly diagnosed HIV-1 individuals were collected from ten prefectures in Hebei using stratified sampling. Partial gag and env genes were amplified and sequenced. HIV-1 genotypes were identified by phylogenetic tree analyses. Among the 139 subjects genotyped, six HIV-1 subtypes were identified successfully, including subtype B (41.0 %), CRF01_AE (40.3 %), CRF07_BC (11.5 %), CRF08_BC (4.3 %), unique recombinant forms (URFs) (1.4 %) and subtype C (1.4 %). Subtype B was identified as the most frequent subtype. Two URF recombination patterns were the same as CRF01_AE/B. HIV-1 genotype distribution showed a significant statistical difference in different demographic characteristics, such as source (P  0.05). The differences in HIV-1 genotype distribution were closely associated with transmission routes. Particularly, all six subtype strains were found in heterosexuals, showing that HIV-1 has spread from the high-risk populations to the general populations in Hebei, China. In addition, CRF01_AE instead of subtype B has become the major strain of HIV-1 infection among homosexuals. Our study revealed HIV-1 evolution and genotype distribution by investigating newly diagnosed HIV-1 individuals in Hebei, China. This study provides important information to enhance the strategic plan for HIV prevention and control in China.

Lack of integrase inhibitors associated resistance mutations among HIV-1C isolates.

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Mulu, Andargachew; Maier, Melanie; Liebert, Uwe Gerd

2015-12-01

Although biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. Thus, the aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or resistance mutations in HIV-1C Ethiopian clinical isolates prior to the introduction of INIs. Plasma samples from chronically infected drug naïve patients (N = 45), of whom the PR and RT sequence was determined previously, were used to generate population based sequences of HIV-1 integrase. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. Resistance mutations were interpreted according to the Stanford HIV drug resistance database ( http://hivdb.stanford.edu ) and the updated International Antiviral Society (IAS)-USA mutation lists. Moreover, rates of polymorphisms in the current isolates were compared with South African and global HIV-1C isolates. All subjects were infected with HIV-1C concordant to the protease (PR) and reverse transcriptase (RT) regions. Neither major resistance-associated IN mutations (T66I/A/K, E92Q/G, T97A, Y143HCR, S147G, Q148H/R/K, and N155H) nor silent mutations known to change the genetic barrier were observed. Moreover, the DDE-catalytic motif (D64G/D116G/E152 K) and signature HHCC zinc-binding motifs at codon 12, 16, 40 and 43 were found to be highly conserved. However, compared to other South African subtype C isolates, the rate of polymorphism was variable at various positions. Although the sample size is small, the findings suggest that this drug class could be effective in Ethiopia and other southern African countries where HIV-1C is predominantly circulating. The data will contribute to define the importance of integrase polymorphism and to improve resistance interpretation algorithms in HIV-1C isolates.

Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles

International Nuclear Information System (INIS)

Peretti, Silvia; Schiavoni, Ilaria; Pugliese, Katherina; Federico, Maurizio

2006-01-01

We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies

HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis

Science.gov (United States)

2018-01-01

ABSTRACT Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions. To identify the antiviral functions of HIV-1-specific IgA elicited by vaccination, we cloned HIV-1 envelope-specific IgA monoclonal antibodies (MAbs) by memory B cell cultures from peripheral blood mononuclear cells from an RV144 vaccinee and produced two IgA clonal cell lines (HG129 and HG130) producing native, nonrecombinant IgA MAbs. The HG129 and HG130 MAbs mediated phagocytosis by monocytes, and HG129 blocked HIV-1 Env glycoprotein binding to galactosylceramide, an alternative HIV-1 receptor. These findings elucidate potential antiviral functions of vaccine-elicited HIV-1 envelope-specific IgA that may act to block HIV-1 acquisition at the portal of entry by preventing HIV-1 binding to galactosylceramide and mediating antibody Fc receptor-mediated virion phagocytosis. Furthermore, these findings highlight the complex and diverse interactions of vaccine-elicited IgA with pathogens that depend on IgA fine specificity and form (e.g., multimeric or monomeric) in the systemic circulation and mucosal compartments. IMPORTANCE Host-pathogen interactions in vivo involve numerous immune mechanisms that can lead to pathogen clearance. Understanding the nature of antiviral immune mechanisms can inform the design of efficacious HIV-1 vaccine strategies. Evidence suggests that both neutralizing and nonneutralizing antibodies can mediate some protection against HIV in animal models. Although numerous studies have characterized the

Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.

Science.gov (United States)

Hake, Anna; Pfeifer, Nico

2017-10-01

Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient's viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.

Identifying HIV-1 dual infections

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Cornelissen Marion

2007-09-01

Full Text Available Abstract Transmission of human immunodeficiency virus (HIV is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus and superinfections (second infection after a specific immune response to the first infecting strain has developed can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA, counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the

Glycosylation in HIV-1 envelope glycoprotein and its biological implications

KAUST Repository

Ho, Yung Shwen; Saksena, Nitin K.

2013-01-01

architecture, also controls intra- and inter-clade genetic variations. Discerning intra- and inter-clade glycosylation variations could therefore yield important information for understanding the molecular and biological differences between HIV clades and may

Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice.

Science.gov (United States)

Wu, Xilin; Guo, Jia; Niu, Mengyue; An, Minghui; Liu, Li; Wang, Hui; Jin, Xia; Zhang, Qi; Lam, Ka Shing; Wu, Tongjin; Wang, Hua; Wang, Qian; Du, Yanhua; Li, Jingjing; Cheng, Lin; Tang, Hang Ying; Shang, Hong; Zhang, Linqi; Zhou, Paul; Chen, Zhiwei

2018-04-23

The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene-encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 μg/ml (range HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus-transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for the prevention and treatment of HIV-1 infection.

HIV-1 Latency in Monocytes/Macrophages

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Amit Kumar

2014-04-01

Full Text Available Human immunodeficiency virus type 1 (HIV-1 targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host.

Molecular epidemiology of HIV-1 infection in Europe: An overview.

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Beloukas, Apostolos; Psarris, Alexandros; Giannelou, Polina; Kostaki, Evangelia; Hatzakis, Angelos; Paraskevis, Dimitrios

2016-12-01

Human Immunodeficiency Virus type 1 (HIV-1) is characterised by vast genetic diversity. Globally circulating HIV-1 viruses are classified into distinct phylogenetic strains (subtypes, sub-subtypes) and several recombinant forms. Here we describe the characteristics and evolution of European HIV-1 epidemic over time through a review of published literature and updated queries of existing HIV-1 sequence databases. HIV-1 in Western and Central Europe was introduced in the early-1980s in the form of subtype B, which is still the predominant clade. However, in Eastern Europe (Former Soviet Union (FSU) countries and Russia) the predominant strain, introduced into Ukraine in the mid-1990s, is subtype A (A FSU ) with transmission mostly occurring in People Who Inject Drugs (PWID). In recent years, the epidemic is evolving towards a complex tapestry with an increase in the prevalence of non-B subtypes and recombinants in Western and Central Europe. Non-B epidemics are mainly associated with immigrants, heterosexuals and females but more recently, non-B clades have also spread amongst groups where non-B strains were previously absent - non-immigrant European populations and amongst men having sex with men (MSM). In some countries, non-B clades have spread amongst the native population, for example subtype G in Portugal and subtype A in Greece, Albania and Cyprus. Romania provides a unique case where sub-subtype F1 has predominated throughout the epidemic. In contrast, HIV-1 epidemic in FSU countries remains more homogeneous with A FSU clade predominating in all countries. The differences between the evolution of the Western epidemic and the Eastern epidemic may be attributable to differences in transmission risk behaviours, lifestyle and the patterns of human mobility. The study of HIV-1 epidemic diversity provides a useful tool by which we can understand the history of the pandemic in addition to allowing us to monitor the spread and growth of the epidemic over time

Analysis of dinucleotide signatures in HIV-1 subtype B genomes

Indian Academy of Sciences (India)

It was also shown that the profile generated by taking all dinucleotides together ... Keywords. genome signature; DRAP; HIV-1; chaos game representation. Journal of .... be used to quantify low levels of variation as are observed within species ..... Dayton A.I., Sodroski J.G., Rosen C.A., Goh W.C. and Haseltine. W.A. 1986 ...

HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues.

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Lamers, Susanna L; Gray, Rebecca R; Salemi, Marco; Huysentruyt, Leanne C; McGrath, Michael S

2011-01-01

Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations. Some intermixing between the HIV-1 subpopulations was evident, especially in patients that died from pathologies other than HIV-associated dementia. Interestingly, the major tissue harboring virus from both the brain and peripheral tissues was the meninges. These results show that (1) HIV-1 is clearly capable of migrating out of the brain, (2) the meninges are the most likely primary transport tissues, and (3) infected brain macrophages comprise an important HIV reservoir during highly active antiretroviral therapy. Copyright © 2010 Elsevier B.V. All rights reserved.

Towards 'reflexive epidemiology': Conflation of cisgender male and transgender women sex workers and implications for global understandings of HIV prevalence.

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Perez-Brumer, Amaya G; Oldenburg, Catherine E; Reisner, Sari L; Clark, Jesse L; Parker, Richard G

2016-01-01

The HIV epidemic has had a widespread impact on global scientific and cultural discourses related to gender, sexuality, and identity. 'Male sex workers' have been identified as a 'key population' in the global HIV epidemic; however, there are methodological and conceptual challenges for defining inclusion and exclusion of transgender women within this group. To assess these potential implications, this study employs self-critique and reflection to grapple with the empiric and conceptual implications of shifting understandings of sexuality and gender within the externally re-created etic category of 'MSM' and 'transgender women' in epidemiologic HIV research. We conducted a sensitivity analysis of our previously published meta-analysis which aimed to identify the scope of peer-reviewed articles assessing HIV prevalence among male sex workers globally between 2004 and 2013. The inclusion of four studies previously excluded due to non-differentiation of cisgender male from transgender women participants (studies from Spain, Thailand, India, and Brazil: 421 total participants) increased the overall estimate of global HIV prevalence among 'men' who engage in sex work from 10.5% (95% CI 9.4-11.5%) to 10.8% (95% CI 9.8-11.8%). The combination of social science critique with empiric epidemiologic analysis represents a first step in defining and operationalising 'reflexive epidemiology'. Grounded in the context of sex work and HIV prevention, this paper highlights the multiplicity of genders and sexualities across a range of social and cultural settings, limitations of existing categories (i.e. 'MSM', 'transgender'), and their global implications for epidemiologic estimates of HIV prevalence.

Global response to HIV: treatment as prevention, or treatment for treatment?

NARCIS (Netherlands)

Sigaloff, Kim C. E.; Lange, Joep M. A.; Montaner, Julio

2014-01-01

The concept of "treatment as prevention" has emerged as a means to curb the global HIV epidemic. There is, however, still ongoing debate about the evidence on when to start antiretroviral therapy in resource-poor settings. Critics have brought forward multiple arguments against a "test and treat"

Global evidence directing regional preventive strategies in Southeast Asia for fighting TB/HIV.

Science.gov (United States)

Aung, Myo Nyein; Moolphate, Saiyud; Paudel, Damodar; Jayathunge Ph, Mangalasiri; Duangrithi, Duangjai; Wangdi, Kinley; Aung, Thin Nyein Nyein; Lorga, Thaworn; Higuchi, Kazue

2013-03-14

Tuberculosis (TB) and human immunodeficiency virus (HIV) co-epidemics form a huge burden of disease in the Southeast Asia region. Five out of eleven nations in this region are high TB/HIV burden countries: Myanmar, Thailand, India, Indonesia and Nepal. The trends of TB incidence in these countries have been rising in recent years, in contrast to a falling global trend. Experts in the field of TB control and health service providers have been perplexed by the association of TB and HIV infections which causes a mosaic clinical presentation, a unique course with poor treatment outcomes including death. We conducted a review of contemporary evidence relating to TB/HIV control with the aims of assisting integrated health system responses in Southeast Asia and demystifying current evidence to facilitate translating it into practice.

[Study on the molecular-epidemiological characteristics of HIV-1 in Shenzhen, 1992-2008].

Science.gov (United States)

Zhao, Guang-lu; Yu, Wei; Zhang, Juan-juan; Chen, Lin; Feng, Tie-jian; Wang, Feng; Hong, Fu-chang; Wang, Xiao-hui; Li, Qing

2012-01-01

To investigate the epidemiological characteristics of HIV-1 subtype in Shenzhen from 1992 to 2008. 489 HIV-1 positive plasma samples were collected from 1992 to 2008 in Shenzhen. HIV-1 env genes were amplified by nested-PCR from RNA. Phylogenetic analysis was performed on data regarding the nucleotide sequence. A total of 464 sequences were amplified and genotyped. Data from this study revealed that CRF01_AE was a predominant HIV-1 subtype in Shenzhen (64.4%, 299/464), followed by subtypes CRF_BC (17.5%, 81/464), B' (14.7%, 68/464) and B (2.4%, 11/464). Subtype C (0.4%, 2/464), A1 (0.2%, 1/464), CRF02_AG (0.2%, 1/464) and CRF06_cpx (0.2%, 1/464) were also prevalent in Shenzhen. CRF01_AE and CRF_BC were predominant among heterosexuals, homosexuals and injection drug users, while B' was predominant among blood donors. Results from phylogenetic tree analysis showed that some of the HIV-1 clusters had been defined in CRF01_AE strains at different time or groups with different transmission routes. Cross-infections were also seen. CRF01_AE was the predominant HIV-1 subtype in Shenzhen while CRF_BC, B, B', C, A1, CRF02_AG and a small amount of CRF06_cpx or recombinant subtypes were prevalent in this city. Different subtypes showed great variation in the process of epidemics.

The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria.

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Alyson C Yoder

2017-02-01

Full Text Available Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 primarily targets mucosal compartments during acute infection in vivo. Moreover, early HIV-1 infection causes extensive depletion of CD4+ T cells in the gastrointestinal tract that herald persistent inflammation due to the translocation of enteric microbes to the systemic circulation. Here, we profiled the transcriptome of primary intestinal CD4+ T cells infected ex vivo with transmitted/founder (TF HIV-1. Infections were performed in the presence or absence of Prevotella stercorea, a gut microbe enriched in the mucosa of HIV-1-infected individuals that enhanced both TF HIV-1 replication and CD4+ T cell death ex vivo. In the absence of bacteria, HIV-1 triggered a cellular shutdown response involving the downregulation of HIV-1 reactome genes, while perturbing genes linked to OX40, PPAR and FOXO3 signaling. However, in the presence of bacteria, HIV-1 did not perturb these gene sets or pathways. Instead, HIV-1 enhanced granzyme expression and Th17 cell function, inhibited G1/S cell cycle checkpoint genes and triggered downstream cell death pathways in microbe-exposed gut CD4+ T cells. To gain insights on these differential effects, we profiled the gene expression landscape of HIV-1-uninfected gut CD4+ T cells exposed to bacteria. Microbial exposure upregulated genes involved in cellular proliferation, MAPK activation, Th17 cell differentiation and type I interferon signaling. Our findings reveal that microbial exposure influenced how HIV-1 altered the gut CD4+ T cell transcriptome, with potential consequences for HIV-1 susceptibility, cell survival and inflammation. The HIV-1- and microbe-altered pathways unraveled here may serve as a

Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

Energy Technology Data Exchange (ETDEWEB)

Di Nunzio, Francesca, E-mail: francesca.di-nunzio@pasteur.fr [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Fricke, Thomas [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States); Miccio, Annarita [University of Modena e Reggio Emilia, Centro di Medicina Rigenerativa, Modena (Italy); Valle-Casuso, Jose Carlos; Perez, Patricio [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States); Souque, Philippe [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Rizzi, Ermanno; Severgnini, Marco [Institute of Biomedical Technologies, CNR, Milano (Italy); Mavilio, Fulvio [University of Modena e Reggio Emilia, Centro di Medicina Rigenerativa, Modena (Italy); Genethon, Evry (France); Charneau, Pierre [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Diaz-Griffero, Felipe, E-mail: felipe.diaz-griffero@einstein.yu.edu [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States)

2013-05-25

The early steps of HIV-1 replication involve the entry of HIV-1 into the nucleus, which is characterized by viral interactions with nuclear pore components. HIV-1 developed an evolutionary strategy to usurp the nuclear pore machinery and chromatin in order to integrate and efficiently express viral genes. In the current work, we studied the role of nucleoporins 153 and 98 (Nup153 and Nup98) in infection of human Jurkat lymphocytes by HIV-1. We showed that Nup153-depleted cells exhibited a defect in nuclear import, while depletion of Nup 98 caused a slight defect in HIV integration. To explore the biochemical viral determinants for the requirement of Nup153 and Nup98 during HIV-1 infection, we tested the ability of these nucleoporins to interact with HIV-1 cores. Our findings showed that both nucleoporins bind HIV-1 cores suggesting that this interaction is important for HIV-1 nuclear import and/or integration. Distribution analysis of integration sites in Nup153-depleted cells revealed a reduced tendency of HIV-1 to integrate in intragenic sites, which in part could account for the large infectivity defect observed in Nup153-depleted cells. Our work strongly supports a role for Nup153 in HIV-1 nuclear import and integration. - Highlights: ► We studied the role of Nup98 and Nup153 in HIV-1 infection. ► Nup98 binds the HIV-1 core and is involved in HIV-1 integration. ► Nup153 binds the HIV-1 core and is involved in HIV-1 nuclear import. ► Depletion of Nup153 decreased the integration of HIV-1 in transcriptionally active sites.

Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

International Nuclear Information System (INIS)

Di Nunzio, Francesca; Fricke, Thomas; Miccio, Annarita; Valle-Casuso, Jose Carlos; Perez, Patricio; Souque, Philippe; Rizzi, Ermanno; Severgnini, Marco; Mavilio, Fulvio; Charneau, Pierre; Diaz-Griffero, Felipe

2013-01-01

The early steps of HIV-1 replication involve the entry of HIV-1 into the nucleus, which is characterized by viral interactions with nuclear pore components. HIV-1 developed an evolutionary strategy to usurp the nuclear pore machinery and chromatin in order to integrate and efficiently express viral genes. In the current work, we studied the role of nucleoporins 153 and 98 (Nup153 and Nup98) in infection of human Jurkat lymphocytes by HIV-1. We showed that Nup153-depleted cells exhibited a defect in nuclear import, while depletion of Nup 98 caused a slight defect in HIV integration. To explore the biochemical viral determinants for the requirement of Nup153 and Nup98 during HIV-1 infection, we tested the ability of these nucleoporins to interact with HIV-1 cores. Our findings showed that both nucleoporins bind HIV-1 cores suggesting that this interaction is important for HIV-1 nuclear import and/or integration. Distribution analysis of integration sites in Nup153-depleted cells revealed a reduced tendency of HIV-1 to integrate in intragenic sites, which in part could account for the large infectivity defect observed in Nup153-depleted cells. Our work strongly supports a role for Nup153 in HIV-1 nuclear import and integration. - Highlights: ► We studied the role of Nup98 and Nup153 in HIV-1 infection. ► Nup98 binds the HIV-1 core and is involved in HIV-1 integration. ► Nup153 binds the HIV-1 core and is involved in HIV-1 nuclear import. ► Depletion of Nup153 decreased the integration of HIV-1 in transcriptionally active sites

Cytoplasmic Dynein Promotes HIV-1 Uncoating

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Paulina Pawlica

2014-11-01

Full Text Available Retroviral capsid (CA cores undergo uncoating during their retrograde transport (toward the nucleus, and/or after reaching the nuclear membrane. However, whether HIV-1 CA core uncoating is dependent upon its transport is not understood. There is some evidence that HIV-1 cores retrograde transport involves cytoplasmic dynein complexes translocating on microtubules. Here we investigate the role of dynein-dependent transport in HIV-1 uncoating. To interfere with dynein function, we depleted dynein heavy chain (DHC using RNA interference, and we over-expressed p50/dynamitin. In immunofluorescence microscopy experiments, DHC depletion caused an accumulation of CA foci in HIV-1 infected cells. Using a biochemical assay to monitor HIV-1 CA core disassembly in infected cells, we observed an increase in amounts of intact (pelletable CA cores upon DHC depletion or p50 over-expression. Results from these two complementary assays suggest that inhibiting dynein-mediated transport interferes with HIV-1 uncoating in infected cells, indicating the existence of a functional link between HIV-1 transport and uncoating.

Global epidemiological trends and variations in the burden of gallbladder cancer.

Science.gov (United States)

Are, Chandrakanth; Ahmad, Humera; Ravipati, Advaitaa; Croo, Darren; Clarey, Dillon; Smith, Lynette; Price, Ray R; Butte, Jean M; Gupta, Sameer; Chaturvedi, Arun; Chowdhury, Sanjib

2017-04-01

The aim of this study is to describe the trends and variations in the global burden of gallbladder cancer (GBC) with an emphasis on geographic variations and female gender. Data (2012-2030) relating to GBC was extracted from GLOBOCAN 2012 database and analyzed. The results of our study document a rising global burden of GBC with geographic and gender variations. The highest burden was noted in the WPRO region (based on WHO regions), Asia (based on continents) and India, Chile, and China (based on countries). The less developed regions of the world account for the majority of the global burden of GBC. The geographic variations are also present within individual countries such as in India and Chile. Females are afflicted at a much higher rate with GBC and this predilection is exaggerated in countries with higher incidence such as India and Chile. In females, people of certain ethnic groups and lower socio-economic standing are at a higher risk. Our study demonstrates a rising global burden of GBC with some specific data on geographic and gender-based variations which can be used to develop strategies at the global as well as the high-risk individual country level. © 2017 Wiley Periodicals, Inc.

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013

DEFF Research Database (Denmark)

Murray, Christopher J L; Ortblad, Katrina F; Guinovart, Caterina

2014-01-01

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for betw...

Recognition of HIV-1 peptides by host CTL is related to HIV-1 similarity to human proteins.

Directory of Open Access Journals (Sweden)

Morgane Rolland

Full Text Available BACKGROUND: While human immunodeficiency virus type 1 (HIV-1-specific cytotoxic T lymphocytes preferentially target specific regions of the viral proteome, HIV-1 features that contribute to immune recognition are not well understood. One hypothesis is that similarities between HIV and human proteins influence the host immune response, i.e., resemblance between viral and host peptides could preclude reactivity against certain HIV epitopes. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the extent of similarity between HIV-1 and the human proteome. Proteins from the HIV-1 B consensus sequence from 2001 were dissected into overlapping k-mers, which were then probed against a non-redundant database of the human proteome in order to identify segments of high similarity. We tested the relationship between HIV-1 similarity to host encoded peptides and immune recognition in HIV-infected individuals, and found that HIV immunogenicity could be partially modulated by the sequence similarity to the host proteome. ELISpot responses to peptides spanning the entire viral proteome evaluated in 314 individuals showed a trend indicating an inverse relationship between the similarity to the host proteome and the frequency of recognition. In addition, analysis of responses by a group of 30 HIV-infected individuals against 944 overlapping peptides representing a broad range of individual HIV-1B Nef variants, affirmed that the degree of similarity to the host was significantly lower for peptides with reactive epitopes than for those that were not recognized. CONCLUSIONS/SIGNIFICANCE: Our results suggest that antigenic motifs that are scarcely represented in human proteins might represent more immunogenic CTL targets not selected against in the host. This observation could provide guidance in the design of more effective HIV immunogens, as sequences devoid of host-like features might afford superior immune reactivity.

No evidence of association between HIV-1 and malaria in populations with low HIV-1 prevalence.

Directory of Open Access Journals (Sweden)

Diego F Cuadros

Full Text Available The geographic overlap between HIV-1 and malaria has generated much interest in their potential interactions. A variety of studies have evidenced a complex HIV-malaria interaction within individuals and populations that may have dramatic effects, but the causes and implications of this co-infection at the population level are still unclear. In a previous publication, we showed that the prevalence of malaria caused by the parasite Plasmodium falciparum is associated with HIV infection in eastern sub-Saharan Africa. To complement our knowledge of the HIV-malaria co-infection, the objective of this work was to assess the relationship between malaria and HIV prevalence in the western region of sub-Saharan Africa.Population-based cross-sectional data were obtained from the HIV/AIDS Demographic and Health Surveys conducted in Burkina Faso, Ghana, Guinea, Mali, Liberia and Cameroon, and the malaria atlas project. Using generalized linear mixed models, we assessed the relationship between HIV-1 and Plasmodium falciparum parasite rate (PfPR adjusting for important socio-economic and biological cofactors. We found no evidence that individuals living in areas with stable malaria transmission (PfPR>0.46 have higher odds of being HIV-positive than individuals who live in areas with PfPR≤0.46 in western sub-Saharan Africa (estimated odds ratio 1.14, 95% confidence interval 0.86-1.50. In contrast, the results suggested that PfPR was associated with being infected with HIV in Cameroon (estimated odds ratio 1.56, 95% confidence interval 1.23-2.00.Contrary to our previous research on eastern sub-Saharan Africa, this study did not identify an association between PfPR and infection with HIV in western sub-Saharan Africa, which suggests that malaria might not play an important role in the spread of HIV in populations where the HIV prevalence is low. Our work highlights the importance of understanding the epidemiologic effect of co-infection and the relevant

Re-thinking global health sector efforts for HIV and tuberculosis epidemic control: promoting integration of programme activities within a strengthened health system.

Science.gov (United States)

Maher, Dermot

2010-07-05

The global financial crisis threatens global health, particularly exacerbating diseases of inequality, e.g. HIV/AIDS, and diseases of poverty, e.g. tuberculosis. The aim of this paper is to reconsider established practices and policies for HIV and tuberculosis epidemic control, aiming at delivering better results and value for money. This may be achieved by promoting greater integration of HIV and tuberculosis control programme activities within a strengthened health system. HIV and tuberculosis share many similarities in terms of their disease burden and the recommended stratagems for their control. HIV and tuberculosis programmes implement similar sorts of control activities, e.g. case finding and treatment, which depend for success on generic health system issues, including vital registration, drug procurement and supply, laboratory network, human resources, and financing. However, the current health system approach to HIV and tuberculosis control often involves separate specialised services. Despite some recent progress, collaboration between the programmes remains inadequate, progress in obtaining synergies has been slow, and results remain far below those needed to achieve universal access to key interventions. A fundamental re-think of the current strategic approach involves promoting integrated delivery of HIV and tuberculosis programme activities as part of strengthened general health services: epidemiological surveillance, programme monitoring and evaluation, community awareness of health-seeking behavior, risk behaviour modification, infection control, treatment scale-up (first-line treatment regimens), drug-resistance surveillance, containing and countering drug-resistance (second-line treatment regimens), research and development, global advocacy and global partnership. Health agencies should review policies and progress in HIV and tuberculosis epidemic control, learn mutual lessons for policy development and scaling up interventions, and identify ways

Re-thinking global health sector efforts for HIV and tuberculosis epidemic control: promoting integration of programme activities within a strengthened health system

Directory of Open Access Journals (Sweden)

Maher Dermot

2010-07-01

Full Text Available Abstract Background The global financial crisis threatens global health, particularly exacerbating diseases of inequality, e.g. HIV/AIDS, and diseases of poverty, e.g. tuberculosis. The aim of this paper is to reconsider established practices and policies for HIV and tuberculosis epidemic control, aiming at delivering better results and value for money. This may be achieved by promoting greater integration of HIV and tuberculosis control programme activities within a strengthened health system. Discussion HIV and tuberculosis share many similarities in terms of their disease burden and the recommended stratagems for their control. HIV and tuberculosis programmes implement similar sorts of control activities, e.g. case finding and treatment, which depend for success on generic health system issues, including vital registration, drug procurement and supply, laboratory network, human resources, and financing. However, the current health system approach to HIV and tuberculosis control often involves separate specialised services. Despite some recent progress, collaboration between the programmes remains inadequate, progress in obtaining synergies has been slow, and results remain far below those needed to achieve universal access to key interventions. A fundamental re-think of the current strategic approach involves promoting integrated delivery of HIV and tuberculosis programme activities as part of strengthened general health services: epidemiological surveillance, programme monitoring and evaluation, community awareness of health-seeking behavior, risk behaviour modification, infection control, treatment scale-up (first-line treatment regimens, drug-resistance surveillance, containing and countering drug-resistance (second-line treatment regimens, research and development, global advocacy and global partnership. Health agencies should review policies and progress in HIV and tuberculosis epidemic control, learn mutual lessons for policy

Global Electric Circuit Diurnal Variation Derived from Storm Overflight and Satellite Optical Lightning Datasets

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Mach, Douglas M.; Blakeslee, R. J.; Bateman, M. J.; Bailey, J. C.

2011-01-01

We have combined analyses of over 1000 high altitude aircraft observations of electrified clouds with diurnal lightning statistics from the Lightning Imaging Sensor (LIS) and Optical Transient Detector (OTD) to produce an estimate of the diurnal variation in the global electric circuit. Using basic assumptions about the mean storm currents as a function of flash rate and location, and the global electric circuit, our estimate of the current in the global electric circuit matches the Carnegie curve diurnal variation to within 4% for all but two short periods of time. The agreement with the Carnegie curve was obtained without any tuning or adjustment of the satellite or aircraft data. Mean contributions to the global electric circuit from land and ocean thunderstorms are 1.1 kA (land) and 0.7 kA (ocean). Contributions to the global electric circuit from ESCs are 0.22 kA for ocean storms and 0.04 kA for land storms. Using our analysis, the mean total conduction current for the global electric circuit is 2.0 kA.

Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention.

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Andrew Mujugira

Full Text Available Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort.HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24-36 months.From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758 of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28-40 and (26-39 respectively]. Most couples (98% were married, with a median duration of partnership of 7.0 years (IQR 3.0-14.0 and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1-2.0]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2-8; 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log(10 copies/mL (IQR 3.31-4.53 and median CD4 count was 496 cells/µL (IQR 375-662; the majority (64% had WHO stage 1 HIV-1 disease.Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov NCT00557245.

Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia

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Hammond Robert R

2004-05-01

Full Text Available Abstract HIV-1-associated dementia remains a common subacute to chronic central nervous system degeneration in adult and pediatric HIV-1 infected populations. A number of viral and host factors have been implicated including the HIV-1 120 kDa envelope glycoprotein (gp120. In human post-mortem studies using confocal scanning laser microscopy for microtubule-associated protein 2 and synaptophysin, neuronal dendritic pathology correlated with dementia. In the present study, primary human CNS cultures exposed to HIV-1 gp120 at 4 weeks in vitro suffered gliosis and dendritic damage analogous to that described in association with HIV-1-associated dementia.

Human endogenous retrovirus K Gag coassembles with HIV-1 Gag and reduces the release efficiency and infectivity of HIV-1.

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Monde, Kazuaki; Contreras-Galindo, Rafael; Kaplan, Mark H; Markovitz, David M; Ono, Akira

2012-10-01

Human endogenous retroviruses (HERVs), which are remnants of ancestral retroviruses integrated into the human genome, are defective in viral replication. Because activation of HERV-K and coexpression of this virus with HIV-1 have been observed during HIV-1 infection, it is conceivable that HERV-K could affect HIV-1 replication, either by competition or by cooperation, in cells expressing both viruses. In this study, we found that the release efficiency of HIV-1 Gag was 3-fold reduced upon overexpression of HERV-K(CON) Gag. In addition, we observed that in cells expressing Gag proteins of both viruses, HERV-K(CON) Gag colocalized with HIV-1 Gag at the plasma membrane. Furthermore, HERV-K(CON) Gag was found to coassemble with HIV-1 Gag, as demonstrated by (i) processing of HERV-K(CON) Gag by HIV-1 protease in virions, (ii) coimmunoprecipitation of virion-associated HERV-K(CON) Gag with HIV-1 Gag, and (iii) rescue of a late-domain-defective HERV-K(CON) Gag by wild-type (WT) HIV-1 Gag. Myristylation-deficient HERV-K(CON) Gag localized to nuclei, suggesting cryptic nuclear trafficking of HERV-K Gag. Notably, unlike WT HERV-K(CON) Gag, HIV-1 Gag failed to rescue myristylation-deficient HERV-K(CON) Gag to the plasma membrane. Efficient colocalization and coassembly of HIV-1 Gag and HERV-K Gag also required nucleocapsid (NC). These results provide evidence that HIV-1 Gag heteromultimerizes with HERV-K Gag at the plasma membrane, presumably through NC-RNA interaction. Intriguingly, HERV-K Gag overexpression reduced not only HIV-1 release efficiency but also HIV-1 infectivity in a myristylation- and NC-dependent manner. Altogether, these results indicate that Gag proteins of endogenous retroviruses can coassemble with HIV-1 Gag and modulate the late phase of HIV-1 replication.

Critical interactions between the Global Fund-supported HIV programs and the health system in Ghana.

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Atun, Rifat; Pothapregada, Sai Kumar; Kwansah, Janet; Degbotse, D; Lazarus, Jeffrey V

2011-08-01

The support of global health initiatives in recipient countries has been vigorously debated. Critics are concerned that disease-specific programs may be creating vertical and parallel service delivery structures that to some extent undermine health systems. This case study of Ghana aimed to explore how the Global Fund-supported HIV program interacts with the health system there and to map the extent and nature of integration of the national disease program across 6 key health systems functions. Qualitative interviews of national stakeholders were conducted to understand the perceptions of the strengths and weaknesses of the relationship between Global Fund-supported activities and the health system and to identify positive synergies and unintended consequences of integration. Ghana has a well-functioning sector-wide approach to financing its health system, with a strong emphasis on integrated care delivery. Ghana has benefited from US $175 million of approved Global Fund support to address the HIV epidemic, accounting for almost 85% of the National AIDS Control Program budget. Investments in infrastructure, human resources, and commodities have enabled HIV interventions to increase exponentially. Global Fund-supported activities have been well integrated into key health system functions to strengthen them, especially financing, planning, service delivery, and demand generation. Yet, with governance and monitoring and evaluation functions, parallel structures to national systems have emerged, leading to inefficiencies. This case study demonstrates that interactions and integration are highly varied across different health system functions, and strong government leadership has facilitated the integration of Global Fund-supported activities within national programs.

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

The Oncolytic Virus MG1 Targets and Eliminates Cells Latently Infected With HIV-1: Implications for an HIV Cure.

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Ranganath, Nischal; Sandstrom, Teslin S; Burke Schinkel, Stephanie C; Côté, Sandra C; Angel, Jonathan B

2018-02-14

Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1-infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial.

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Mary S Campbell

2011-03-01

Full Text Available Characterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519 was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners.We obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥ 50%. Adjudicators classified each seroconversion, finding 108 (71.5% linked, 40 (26.5% unlinked, and 3 (2.0% indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%. Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters.In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner

Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

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Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

2016-01-01

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

Global Considerations in Human Immunodeficiency Virus-Associated Respiratory Disease.

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Rylance, Jamie; Meghji, Jamilah; Miller, Robert F; Ferrand, Rashida A

2016-04-01

Respiratory tract infection, particularly tuberculosis, is a major cause of mortality among human immunodeficiency virus (HIV)-infected individuals. Antiretroviral therapy (ART) has resulted in a dramatic increase in survival, although coverage of HIV treatment remains low in many parts of the world. There is a concurrent growing burden of chronic noninfectious respiratory disease as a result of increased survival. Many risk factors associated with the development of respiratory disease, such as cigarette smoking and intravenous drug use, are overrepresented among people living with HIV. In addition, there is emerging evidence that HIV infection may directly cause or accelerate the course of chronic lung disease. This review summarizes the clinical spectrum and epidemiology of respiratory tract infections and noninfectious pulmonary pathologies, and factors that explain the global variation in HIV-associated respiratory disease. The potential for enhancing diagnoses of noninfective chronic conditions through the use of clinical algorithms is discussed. We also consider issues in assessment and management of HIV-related respiratory disease in view of the increasing global scale up of ART. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Will the global HIV response fail gay and bisexual men and other men who have sex with men?

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Ayala, George; Santos, Glenn-Milo

2016-01-01

Gay and bisexual men and other men who have sex with men are among the small number of groups for whom HIV remains uncontrolled worldwide. Although there have been recent and notable decreases in HIV incidence across several countries, prevalence and incidence is consistently higher or rising among men who have sex with men when compared with other groups. In 2014, MSMGF (the Global Forum on MSM & HIV) conducted its third biennial Global Men's Health and Rights Study, an international, multilingual, web-based cross-sectional survey of men who have sex with men recruited through online convenience sampling. We tested hypothesized correlates (selected a priori ) of successfully achieving each step along the HIV prevention and treatment continuum by fitting separate generalized estimating equation models adjusted for clustering by country in multivariate analyses. All models controlled for ability to meet basic financial needs, age, healthcare coverage, having a regular provider, region and country-level income. Higher provider discrimination and sexual stigma were associated with lower odds of perceived access to services, service utilization and virologic suppression. Conversely, accessing services from community-based organizations focused on lesbian, gay, bisexual and transgender people; greater engagement in gay community; and comfort with healthcare providers were associated with higher odds of achieving steps along the prevention and treatment continuum. To meet accelerated global HIV targets, global leaders must adopt a differentiated and bolder response, in keeping with current epidemiologic trends and community-based research. The HIV-related needs of gay and bisexual men and other men who have sex with men must be addressed openly, quickly and with sufficient resources to support evidence-based, community-led and human rights-affirming interventions at scale.

HIV scale-up in Mozambique: Exceptionalism, normalisation and global health

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Høg, Erling

2014-01-01

The large-scale introduction of HIV and AIDS services in Mozambique from 2000 onwards occurred in the context of deep political commitment to sovereign nation-building and an important transition in the nation's health system. Simultaneously, the international community encountered a willing state partner that recognised the need to take action against the HIV epidemic. This article examines two critical policy shifts: sustained international funding and public health system integration (the move from parallel to integrated HIV services). The Mozambican government struggles to support its national health system against privatisation, NGO competition and internal brain drain. This is a sovereignty issue. However, the dominant discourse on self-determination shows a contradictory twist: it is part of the political rhetoric to keep the sovereignty discourse alive, while the real challenge is coordination, not partnerships. Nevertheless, we need more anthropological studies to understand the political implications of global health funding and governance. Other studies need to examine the consequences of public health system integration for the quality of access to health care. PMID:24499102

Conservation of HIV-1 T cell epitopes across time and clades

DEFF Research Database (Denmark)

Levitz, Lauren; Koita, Ousmane A; Sangare, Kotou

2012-01-01

HIV genomic sequence variability has complicated efforts to generate an effective globally relevant vaccine. Regions of the viral genome conserved in sequence and across time may represent the "Achilles' heel" of HIV. In this study, highly conserved T-cell epitopes were selected using immunoinfor...

European Multicenter Study on Analytical Performance of Veris HIV-1 Assay.

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Braun, Patrick; Delgado, Rafael; Drago, Monica; Fanti, Diana; Fleury, Hervé; Hofmann, Jörg; Izopet, Jacques; Kalus, Ulrich; Lombardi, Alessandra; Marcos, Maria Angeles; Mileto, Davide; Sauné, Karine; O'Shea, Siobhan; Pérez-Rivilla, Alfredo; Ramble, John; Trimoulet, Pascale; Vila, Jordi; Whittaker, Duncan; Artus, Alain; Rhodes, Daniel W

2017-07-01

The analytical performance of the Veris HIV-1 assay for use on the new, fully automated Beckman Coulter DxN Veris molecular diagnostics system was evaluated at 10 European virology laboratories. The precision, analytical sensitivity, performance with negative samples, linearity, and performance with HIV-1 groups/subtypes were evaluated. The precision for the 1-ml assay showed a standard deviation (SD) of 0.14 log 10 copies/ml or less and a coefficient of variation (CV) of ≤6.1% for each level tested. The 0.175-ml assay showed an SD of 0.17 log 10 copies/ml or less and a CV of ≤5.2% for each level tested. The analytical sensitivities determined by probit analysis were 19.3 copies/ml for the 1-ml assay and 126 copies/ml for the 0.175-ml assay. The performance with 1,357 negative samples demonstrated 99.2% with not detected results. Linearity using patient samples was shown from 1.54 to 6.93 log 10 copies/ml. The assay performed well, detecting and showing linearity with all HIV-1 genotypes tested. The Veris HIV-1 assay demonstrated analytical performance comparable to that of currently marketed HIV-1 assays. (DxN Veris products are Conformité Européenne [CE]-marked in vitro diagnostic products. The DxN Veris product line has not been submitted to the U.S. FDA and is not available in the U.S. market. The DxN Veris molecular diagnostics system is also known as the Veris MDx molecular diagnostics system and the Veris MDx system.). Copyright © 2017 American Society for Microbiology.

Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients.

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Gringeri, A; Santagostino, E; Muça-Perja, M; Mannucci, P M; Zagury, J F; Bizzini, B; Lachgar, A; Carcagno, M; Rappaport, J; Criscuolo, M; Blattner, W; Burny, A; Gallo, R C; Zagury, D

1998-01-01

To antagonize the deleterious effects of the HIV-1 toxin extracellular Tat on uninfected immune cells, we developed a new strategy of anti-HIV-1 vaccine using an inactivated but immunogenic Tat (Tat toxoid). Tat toxoid has been assayed for safety and immunogenicity in seropositive patients. The phase I vaccine clinical trial testing Tat toxoid preparation in Seppic Isa 51 oil adjuvant was performed on 14 HIV-1-infected asymptomatic although biologically immunocompromised individuals (500-200 CD4+ cells/mm3). Following as many as 8 injections, no clinical defects were observed. All patients exhibited an antibody (Ab) response to Tat, and some had cell-mediated immunity (CMI) as evaluated by skin test in vivo and T-cell proliferation in vitro. These results provide initial evidence of safety and potency of Tat toxoid vaccination in HIV-1-infected individuals.

Climatic driving forces in inter-annual variation of global FPAR

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Peng, Dailiang; Liu, Liangyun; Yang, Xiaohua; Zhou, Bin

2012-09-01

Fraction of Absorbed Photosynthetically Active Radiation (FPAR) characterizes vegetation canopy functioning and its energy absorption capacity. In this paper, we focus on climatic driving forces in inter-annual variation of global FPAR from 1982 to 2006 by Global Historical Climatology Network (GHCN-Monthly) data. Using FPAR-Simple Ratio Vegetation Index (SR) relationship, Advanced Very High Resolution Radiometer (AVHRR) Global Inventory Modeling and Mapping Studies (GIMMS) Normalized Difference Vegetation Index (NDVI) was used to estimate FPAR at the global scale. The correlation between inter-annual variation of FPAR and temperature, precipitation derived from GHCN-Monthly was examined, during the periods of March-May (MAM), June-August (JJA), September-November (SON), and December-February (DJF) over from 1982 to 2006. The analysis of climatic influence on global FPAR revealed the significant correlation with temperature and precipitation in some meteorological stations area, and a more significant correlation with precipitation was found than which with temperature. Some stations in the regions between 30° N and 60° N and around 30° S in South America, where the annual FPAR variation showed a significant positive correlation with temperature (P forest of Africa and Amazon during the dry season of JJA and SON.

Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr-Importin α interactions as a novel HIV-1 therapy

International Nuclear Information System (INIS)

Suzuki, Tatsunori; Yamamoto, Norio; Nonaka, Mizuho; Hashimoto, Yoshie; Matsuda, Go; Takeshima, Shin-nosuke; Matsuyama, Megumi; Igarashi, Tatsuhiko; Miura, Tomoyuki; Tanaka, Rie; Kato, Shingo; Aida, Yoko

2009-01-01

The development of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus (HIV) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. One such target is the interaction between Vpr, one of the accessory gene products of HIV-1 and Importin α, which is crucial, not only for the nuclear import of Vpr, but also for HIV-1 replication in macrophages. We have identified a potential parent compound, hematoxylin, which suppresses Vpr-Importin α interaction, thereby inhibiting HIV-1 replication in a Vpr-dependent manner. Analysis by real-time PCR demonstrated that hematoxylin specifically inhibited nuclear import step of pre-integration complex. Thus, hematoxylin is a new anti-HIV-1 inhibitor that targets the nuclear import of HIV-1 via the Vpr-Importin α interaction, suggesting that a specific inhibitor of the interaction between viral protein and the cellular factor may provide a new strategy for HIV-1 therapy.

Artificial 64-Residue HIV-1 Enhancer-Binding Peptide Is a Potent Inhibitor of Viral Replication in HIV-1-Infected Cells.

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Oufir, Mouhssin; Bisset, Leslie R; Hoffmann, Stefan R K; Xue, Gongda; Klauser, Stephan; Bergamaschi, Bianca; Gervaix, Alain; Böni, Jürg; Schüpbach, Jörg; Gutte, Bernd

2011-01-01

An artificial HIV-1 enhancer-binding peptide was extended by nine consecutive arginine residues at the C-terminus and by the nuclear localization signal of SV40 large T antigen at the N-terminus. The resulting synthetic 64-residue peptide was found to bind to the two enhancers of the HIV-1 long terminal repeat, cross the plasma membrane and the nuclear envelope of human cells, and suppress the HIV-1 enhancer-controlled expression of a green fluorescent protein reporter gene. Moreover, HIV-1 replication is inhibited by this peptide in HIV-1-infected CEM-GFP cells as revealed by HIV-1 p24 ELISA and real-time RT-PCR of HIV-1 RNA. Rapid uptake of this intracellular stable and inhibitory peptide into the cells implies that this peptide may have the potential to attenuate HIV-1 replication in vivo.

Dynamics of Preferential Substrate Recognition in HIV-1 Protease: Redefining the Substrate Envelope

Science.gov (United States)

Özen, Ayşegül; Haliloğlu, Türkan; Schiffer, Celia A.

2011-01-01

HIV-1 protease (PR) permits viral maturation by processing the Gag and Gag-Pro-Pol polyproteins. Though HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy, the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates the consideration of drug resistance in novel drug-design strategies. Drug-resistant HIV-1 PR variants, while no longer efficiently inhibited, continue to efficiently hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we defined as the “substrate envelope”. We previously showed that resistance mutations arise where PIs protrude beyond the substrate envelope, as these regions are crucial for drug binding but not for substrate recognition. Here, we extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. Seven molecular dynamics simulations of PR-substrate complexes were performed to estimate the conformational flexibility of substrates in their complexes. Interdependency of the substrate-protease interactions may compensate for the variations in cleavage-site sequences, and explain how a diverse set of sequences can be recognized as substrates by the same enzyme. This diversity may be essential for regulating sequential processing of substrates. We also define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance. PMID:21762811

The (Mis)appropriation of HIV/AIDS advocacy strategies in Global Mental Health: towards a more nuanced approach.

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Howell, Alison; Mills, China; Rushton, Simon

2017-07-01

Mental health is increasingly finding a place on global health and international development agendas. Advocates for Global Mental Health (GMH), and international organizations such as the World Health Organization (WHO) and the World Bank, argue that treatments available in high-income countries should also be made available in low- and middle-income countries. Such arguments are often made by comparing mental health to infectious diseases, including the relative disease and economic burdens they impose, and pointing to the applicability of the right to access treatment for mental health, not only infectious diseases. HIV/AIDS advocacy in particular has been held up by GMH advocates as offering an appropriate strategy for generating global commitment. There is a need to assess how health issues are framed not only in relation to social goods outside of health (such as human rights, security or development), but also in relation to other health or disease models, and how health policy and practice is shaped as a result. The article debates the merits and consequences of likening mental health to HIV/AIDS, and identifies four major problems with the model for GMH advocacy being developed through these analogies: 1. An inappropriately universalizing global approach to context-specific problems; 2. A conception of human rights that focuses on the right to access treatment at the expense of the right to refuse it; 3. A tendency to treat poverty as a psychiatric issue, rather than recognizing that mental distress can be the result of poverty and other forms of inequality; 4. The prioritization of destigmatization of disease over social justice models. There are significant problems with the wholesale adoption of an (often simplified) version of HIV/AIDS advocacy as a model for GMH. Yet critical engagement with the important and nuanced differences between HIV/AIDS and mental health may nevertheless point to some possibilities for productive engagement and cross

HIV-1 subtype A infection in a community of intravenous drug users in Pakistan

Directory of Open Access Journals (Sweden)

Khan Muhammad N

2006-11-01

Full Text Available Abstract Background Data on the subtypes of HIV in a population help in predicting the potential foci of epidemic, tracking the routes of infection and following the patterns of the virus' genetic divergence. Globally, the most prevalent HIV infection is the HIV-1 subtype C. In Asia, predominant subtypes of HIV-1 are B, C, and CRF-01AE. During the last few years, HIV prevalence in Pakistan has taken the form of a concentrated epidemic in at least two high risk groups, namely, Intravenous Drug Users (IDUs and Male Sex Workers (MSWs. Factors that have facilitated the proliferation of HIV infection include transmission through a large number of repatriates and needle-sharing intravenous drug users, unscreened blood transfusions, and sexual illiteracy. The HIV subtypes infecting Pakistani populations have not been explored to date. In this study, we analyzed HIV-1 subtypes from in a high-risk community of IDUs in Karachi, the largest city of Pakistan. Methods Samples were collected from 34 IDUs after their informed consent. In addition, the study subjects were administered a questionnaire regarding their sexual behavior and travel history. For HIV analysis, DNA was extracted from the samples and analyzed for HIV types and subtypes using subtype-specific primers in a nested polymerase chain reaction (PCR. The results from this PCR were further confirmed using the Heteroduplex Mobility Assay (HMA. Results We found HIV-1 subtype A in all the 34 samples analyzed. A few of the study subjects were found to have a history of travel and stay in the United Arab Emirates. The same subjects also admitted to having contact with commercial sex workers during their stay abroad. Conclusion Our study therefore shows clade A HIV-1 to be prevalent among the IDUs in Karachi. As the prevalence of HIV in Pakistan continues to rise, more work needs to be done to track the infection, and to analyze the strains of HIV spreading through the country.

Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons.

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Maria Florencia Quiroga

Full Text Available Tuberculosis (TB remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA, its circulating form DHEA-suphate (DHEA-s and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS, a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD, HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB, whereas dehydroepiandrosterone sulfate (DHEA-s levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

Picomolar dichotomous activity of gnidimacrin against HIV-1.

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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.

Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics

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Lythgoe, Katrina A.; Blanquart, François

2016-01-01

The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body’s viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation. PMID:27706164

HIV-1 envelope glycoprotein

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Caulfield, Michael; Cupo, Albert; Dean, Hansi; Hoffenberg, Simon; King, C. Richter; Klasse, P. J.; Marozsan, Andre; Moore, John P.; Sanders, Rogier W.; Ward, Andrew; Wilson, Ian; Julien, Jean-Philippe

2017-08-22

The present application relates to novel HIV-1 envelope glycoproteins, which may be utilized as HIV-1 vaccine immunogens, and antigens for crystallization, electron microscopy and other biophysical, biochemical and immunological studies for the identification of broad neutralizing antibodies. The present invention encompasses the preparation and purification of immunogenic compositions, which are formulated into the vaccines of the present invention.

Artificial 64-Residue HIV-1 Enhancer-Binding Peptide Is a Potent Inhibitor of Viral Replication in HIV-1-Infected Cells

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Mouhssin Oufir

2011-01-01

Full Text Available An artificial HIV-1 enhancer-binding peptide was extended by nine consecutive arginine residues at the C-terminus and by the nuclear localization signal of SV40 large T antigen at the N-terminus. The resulting synthetic 64-residue peptide was found to bind to the two enhancers of the HIV-1 long terminal repeat, cross the plasma membrane and the nuclear envelope of human cells, and suppress the HIV-1 enhancer-controlled expression of a green fluorescent protein reporter gene. Moreover, HIV-1 replication is inhibited by this peptide in HIV-1-infected CEM-GFP cells as revealed by HIV-1 p24 ELISA and real-time RT-PCR of HIV-1 RNA. Rapid uptake of this intracellular stable and inhibitory peptide into the cells implies that this peptide may have the potential to attenuate HIV-1 replication in vivo.

Global sea level variations from altimetry, GRACE and Argo data over 2005–2014

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Wei Feng

2015-07-01

Full Text Available Total sea level variations (SLVs are caused by two major components: steric variations due to thermal expansion of seawater, and mass-induced variations due to mass exchange between ocean and land. In this study, the global SLV and its steric and mass components were estimated by satellite altimetry, Argo float data and the Gravity Recovery and Climate Experiment (GRACE data over 2005–2014. Space gravimetry observations from GRACE suggested that two-thirds of the global mean sea level rise rate observed by altimetry (i.e., 3.1 ± 0.3 mm/a from 2005 to 2014 could be explained by an increase in ocean mass. Furthermore, the global mean sea level was observed to drop significantly during the 2010/2011 La Niña event, which may be attributed to the decline of ocean mass and steric SLV. Since early 2011, the global mean sea level began to rise rapidly, which was attributed to an increase in ocean mass. The findings in this study suggested that the global mean sea-level budget was closed from 2005 to 2014 based on altimetry, GRACE, and Argo data.

Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

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Yu-Ping Chiang

2014-12-01

Full Text Available Individual differences in susceptibility to human immunodeficiency virus type 1 (HIV-1 infection have been of interest for decades. We aimed to determine the contribution of large isoform of Mammalian DnaJ (MRJ-L, a HIV-1 Vpr-interacting cellular protein, to this natural variation. Expression of MRJ-L in monocyte-derived macrophages was significantly higher in HIV-infected individuals (n = 31 than their uninfected counterparts (n = 27 (p = 0.009. Fifty male homosexual subjects (20 of them are HIV-1 positive were further recruited to examine the association between MRJ-L levels and occurrence of HIV infection. Bayesian multiple logistic regression revealed that playing a receptive role and increased levels of MRJ-L in macrophages were two risk factors for HIV-1 infection. A 1% rise in MRJ-L expression was associated with a 1.13 fold (95% CrI 1.06–1.29 increase in odds of contracting HIV-1 infection. Ex vivo experiments revealed that MRJ-L facilitated Vpr-dependent nuclear localization of virus. Infection of macrophage-tropic strain is a critical step in HIV-1 transmission. MRJ-L is a critical factor in this process; hence, subjects with higher macrophage MRJ-L levels are more vulnerable to HIV-1 infection.

HIV-1 evolution, drug resistance, and host genetics: The Indian scenario

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U Shankarkumar

2009-03-01

Full Text Available U Shankarkumar, A Pawar, K GhoshNational Institute of Immunohaematology (ICMR, KEM Hospital, Parel, Mumbai, Maharashtra, IndiaAbstract: A regimen with varied side effects and compliance is of paramount importance to prevent viral drug resistance. Most of the drug-resistance studies, as well as interpretation algorithms, are based on sequence data from HIV-1 subtype B viruses. Increased resistance to antiretroviral drugs leads to poor prognosis by restricting treatment options. Due to suboptimal adherence to antiretroviral therapy there is an emergence of drug-resistant HIV-1 strains. The other factors responsible for this viral evolution are antiretroviral drug types and host genetics, especially major histocompatibility complex (MHC. Both primary and secondary drug resistances occur due to mutations in specific epitopes of viral protein regions which may influence the T cell recognition by immune system through MHC Class I and class II alleles. Mutations in viral epitopes enable the virus to escape the immune system. New drugs under clinical trials are being added but their exorbitant costs limit their access in developing countries. Thus the environmental consequences and, the impact of both viral and host genetic variations on the therapy in persons infected with HIV-1 clade C from India need to be determined.Keywords: HIV-1 C drug resistance, virus adaptation, HARRT, India

Update on HIV-1 diversity in Africa: a decade in review.

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Lihana, Raphael W; Ssemwanga, Deogratius; Abimiku, Alash'le; Ndembi, Nicaise

2012-01-01

HIV-1 strains have diversified extensively through mutation and recombination since their initial transmission to human beings many decades ago in Central Africa in the first part of the 20th Century (between 1915 and 1941). The upward trend in global HIV-1 diversity has continued unabated, with newer groups, subtypes, and unique and circulating recombinants increasingly being reported, especially in Africa. In this review, we focus on the extensive diversity of HIV-1 over a decade (2000-2011), in 51 countries of the three African geographic regions (eastern and southern, western and central, and northern Africa) as per the WHO/UNAIDS 2010 classification. References for this review were identified through searches of PubMed, conference abstracts, Google Scholar, and Springer Online Archives Collection. We retrieved 273 citations, of which 200 reported HIV-1 diversity from Africa from January, 2000 to August, 2011. Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles published in English and French were included. There has been a high diversity of HIV-1 in its epicenter, west-central Africa. A few subtypes, namely, A (A1, A2, A3, A4, A5), C, CRF02_AG, and D accounted for about 85% of new infections. Subtype A and D have been stable in East Africa; C in southern Africa; A, G, CRF02_AG, and CRF06_cpx in western Africa; and subtype B and CRF02_AG in northern Africa. Recently a new putative group, designated P, was reported to be found in two Cameroonians. The regional distributions of individual subtypes and recombinants are broadly stable, although unique/circulating recombinant forms may play an increasing role in the HIV pandemic. Understanding the kinetics and directions of this continuing adaptation and its impact on viral fitness, immunogenicity, and pathogenicity are crucial to the successful design of effective HIV vaccines. There is need for regular monitoring and review updates, such as the one

Broadly Immunogenic HLA Class I Supertype-Restricted Elite CTL Epitopes Recognized in a Diverse Population Infected with Different HIV-1 Subtypes

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Pérez, Carina L; Larsen, Mette Voldby; Gustafsson, Rasmus

2008-01-01

The genetic variations of the HIV-1 virus and its human host constitute major obstacles for obtaining potent HIV-1-specific CTL responses in individuals of diverse ethnic backgrounds infected with different HIV-1 variants. In this study, we developed and used a novel algorithm to select 184......, not previously described in the HIV-1 immunology database. In addition, we identified 21 "elite" epitopes that induced CTL responses in at least 4 of the 31 patients. A majority (27 of 31) of the study population recognized one or more of these highly immunogenic epitopes. We also found a limited set of 9...

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid.

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Fricke, Thomas; Buffone, Cindy; Opp, Silvana; Valle-Casuso, Jose; Diaz-Griffero, Felipe

2014-12-11

The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74. This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core. Overall this short-form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection.

Genetic and phylogenetic evolution of HIV-1 in a low subtype heterogeneity epidemic: the Italian example

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Tornesello Maria

2007-05-01

Full Text Available Abstract The Human Immunodeficiency Virus type 1 (HIV-1 is classified into genetic groups, subtypes and sub-subtypes which show a specific geographic distribution pattern. The HIV-1 epidemic in Italy, as in most of the Western Countries, has traditionally affected the Intra-venous drug user (IDU and Homosexual (Homo risk groups and has been sustained by the genetic B subtype. In the last years, however, the HIV-1 transmission rate among heterosexuals has dramatically increased, becoming the prevalent transmission route. In fact, while the traditional risk groups have high levels of knowledge and avoid high-risk practices, the heterosexuals do not sufficiently perceive the risk of HIV-1 infection. This misperception, linked to the growing number of immigrants from non-Western Countries, where non-B clades and circulating recombinant forms (CRFs are prevalent, is progressively introducing HIV-1 variants of non-B subtype in the Italian epidemic. This is in agreement with reports from other Western European Countries. In this context, the Italian HIV-1 epidemic is still characterized by low subtype heterogeneity and represents a paradigmatic example of the European situation. The continuous molecular evolution of the B subtype HIV-1 isolates, characteristic of a long-lasting epidemic, together with the introduction of new subtypes as well as recombinant forms may have significant implications for diagnostic, treatment, and vaccine development. The study and monitoring of the genetic evolution of the HIV-1 represent, therefore, an essential strategy for controlling the local as well as global HIV-1 epidemic and for developing efficient preventive and therapeutic strategies.

HIV-1 with multiple CCR5/CXCR4 chimeric receptor use is predictive of immunological failure in infected children.

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Cavarelli, Mariangela; Karlsson, Ingrid; Zanchetta, Marisa; Antonsson, Liselotte; Plebani, Anna; Giaquinto, Carlo; Fenyö, Eva Maria; De Rossi, Anita; Scarlatti, Gabriella

2008-09-29

HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5(broad) viruses), was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT) of HIV-1 and pediatric disease progression. Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting) and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5(narrow) phenotype (n = 20), but R5(broad) and R5X4 viruses were also found in seven and one case, respectively. The presence of R5(broad) and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3) or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5(broad) phenotype, however, the presence of the R5(broad) virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5(broad) viruses transmitted viruses with a similar broad chimeric coreceptor usage. Thus, the maternal R5(broad) phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant. Our results show that R5(broad) viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5(narrow) phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infection.

Phylogenetic analysis of HIV-1 pol gene: first subgenomic evidence of CRF29-BF among Iranian HIV-1 patients

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Kazem Baesi

2014-09-01

Full Text Available Objective: To identify the dominant subtype among the HIV-1 strains circulation in Iran. Methods: In this cross sectional study 100 HIV positive patients participated. HIV-1 RNA was extracted from plasma. RT nested-PCR was performed and the final products were sequenced and phylogenetically analyzed; reference sequences were downloaded from Los Alamos, aligned with Iranian pol sequences in the study and analyzed by neighbor-joining method. Results: The results of the phylogenetic analysis showed that HIV-1 subtype CRF-35AD was the dominant subtype among HIV-1 infected patients in Iran; this analysis also suggested a new circulating recombinant form that had not previously been identified in Iran: CRF-29BF. Conclusions: The impact of HIV diversity on pathogenesis, transmission and clinical management have been discussed in different studies; therefore, analyses of HIV genetic diversity is required to design effective antiretroviral strategies for different HIV subtypes.

The task of the HIV translator: transforming global AIDS knowledge in an awareness workshop.

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Wardlow, Holly

2012-01-01

The globalization of standardized knowledge about HIV and AIDS depends in part on local AIDS awareness educators who receive training from national and international organizations and then, ideally, disseminate what they have learned. In this article I analyze textual and observational data from a five-day introductory AIDS awareness workshop in rural Papua New Guinea. Although the instructor adhered to the handbook provided by the National AIDS Council for much of the information, she departed from it significantly when informing participants about the "root causes" of HIV's spread and in giving them advice about prevention. I explicate where her extratextual knowledge came from as well as its overall message to target audiences. I suggest that textual silences in AIDS awareness handbooks can motivate local HIV translators to embark on a kind of semiosis-the ongoing production of new, hybrid knowledge about HIV.

Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1.

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Geneviève Doyon

Full Text Available Combination antiretroviral therapy (cART can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4(+ T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy-7H-dibenzo[de,g]quinolin-7-one (57704 which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2. 57704 also increased HIV-1 expression in 3 of 4 CD8(+-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K/protein kinase B (Akt signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110α isoform, but not the p110β, δ or γ isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency.

European Union and EDCTP strategy in the global context: recommendations for preventive HIV/AIDS vaccines research

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Lehner, Thomas; Hoelscher, Michael; Clerici, Mario; Gotch, Frances; Pedneault, Louise; Tartaglia, Jim; Gray, Clive; Mestecky, Jiri; Sattentau, Quentin; van de Wijgert, Janneke; Toure, Coumba; Osmanov, Saladin; Schmidt, Reinold E.; Debre, Patrice; Romaris, Manuel; Hoeveler, Arnd; Di Fabio, Simonetta

2005-01-01

The European Commission (EC) has strong commitments and recognises the need to continue to ensure that HIV/AIDS research efforts receive global attention. The EC is facing this challenge in a global context and has made substantial investments together with European Developing Countries Clinical

German-austrian recommendations for HIV1-therapy in pregnancy and in HIV1-exposed newborn - update 2008

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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

DBR1 siRNA inhibition of HIV-1 replication

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Naidu Yathi

2005-10-01

Full Text Available Abstract Background HIV-1 and all retroviruses are related to retroelements of simpler organisms such as the yeast Ty elements. Recent work has suggested that the yeast retroelement Ty1 replicates via an unexpected RNA lariat intermediate in cDNA synthesis. The putative genomic RNA lariat intermediate is formed by a 2'-5' phosphodiester bond, like that found in pre-mRNA intron lariats and it facilitates the minus-strand template switch during cDNA synthesis. We hypothesized that HIV-1 might also form a genomic RNA lariat and therefore that siRNA-mediated inhibition of expression of the human RNA lariat de-branching enzyme (DBR1 expression would specifically inhibit HIV-1 replication. Results We designed three short interfering RNA (siRNA molecules targeting DBR1, which were capable of reducing DBR1 mRNA expression by 80% and did not significantly affect cell viability. We assessed HIV-1 replication in the presence of DBR1 siRNA and found that DBR1 knockdown led to decreases in viral cDNA and protein production. These effects could be reversed by cotransfection of a DBR1 cDNA indicating that the inhibition of HIV-1 replication was a specific effect of DBR1 underexpression. Conclusion These data suggest that DBR1 function may be needed to debranch a putative HIV-1 genomic RNA lariat prior to completion of reverse transcription.

HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E.

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Chikata, Takayuki; Tran, Giang Van; Murakoshi, Hayato; Akahoshi, Tomohiro; Qi, Ying; Naranbhai, Vivek; Kuse, Nozomi; Tamura, Yoshiko; Koyanagi, Madoka; Sakai, Sachiko; Nguyen, Dung Hoai; Nguyen, Dung Thi; Nguyen, Ha Thu; Nguyen, Trung Vu; Oka, Shinichi; Martin, Maureen P; Carrington, Mary; Sakai, Keiko; Nguyen, Kinh Van; Takiguchi, Masafumi

2018-03-01

HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control. IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1

Differential effects of sex in a West African cohort of HIV-1, HIV-2 and HIV-1/2 dually infected patients: men are worse off.

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Jespersen, Sanne; Hønge, Bo Langhoff; Esbjörnsson, Joakim; Medina, Candida; da Silva Té, David; Correira, Faustino Gomes; Laursen, Alex Lund; Østergaard, Lars; Andersen, Andreas; Aaby, Peter; Erikstrup, Christian; Wejse, Christian

2016-02-01

Several studies have reported conflicting effects of sex on HIV-1 infection. We describe differences in baseline characteristics and assess the impact of sex on HIV progression among patients at a clinic with many HIV-2 and HIV-1/2 dually infected patients. This study utilised a retrospective cohort of treatment-naïve adults at the largest HIV clinic in Guinea-Bissau from 6 June 2005 to 1 December 2013. Baseline characteristics were assessed and the patients followed until death, transfer, loss to follow-up, or 1 June 2014. We estimated the time from the first clinic visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models. A total of 5694 patients were included in the study, 3702 women (65%) and 1992 men (35%). Women were more likely than men to be infected with HIV-2 (19% vs. 15%, P < 0.01) or dually infected with HIV-1/2 (11% vs. 9%, P = 0.02). For all HIV types, women were younger (median 35 vs. 40 years), less likely to have schooling (55% vs. 77%) or to be married (46% vs. 67%), and had higher baseline CD4 cell counts (median 214 vs. 178 cells/μl). Men had a higher age-adjusted mortality rate (hazard rate ratio (HRR) 1.29, 95% confidence interval (CI) 1.09-1.52) and were more often lost to follow-up (HRR 1.27, 95% CI 1.17-1.39). Significant differences exist between HIV-infected men and women regardless of HIV type. Men seek treatment at a later stage and, despite better socio-economic status, have higher mortality and loss to follow-up than women. © 2015 John Wiley & Sons Ltd.

Living and dying to be counted: What we know about the epidemiology of the global adolescent HIV epidemic.

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Slogrove, Amy L; Mahy, Mary; Armstrong, Alice; Davies, Mary-Ann

2017-05-16

With increasing survival of vertically HIV-infected children and ongoing new horizontal HIV infections, the population of adolescents (age 10-19 years) living with HIV is increasing. This review aims to describe the epidemiology of the adolescent HIV epidemic and the ability of national monitoring systems to measure outcomes in HIV-infected adolescents through the adolescent transition to adulthood. Differences in global trends between younger (age 10-14 years) and older (age 15-19 years) adolescents in key epidemic indicators are interrogated using 2016 UNAIDS estimates. National population-based survey data in the 15 highest adolescent HIV burden countries are evaluated and examples of national case-based surveillance systems described. Finally, we consider the potential impact of adolescent-specific recommendations in the 2016 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. UNAIDS estimates indicate the population of adolescents living with HIV is increasing, new HIV infections in older adolescents are declining, and while AIDS-related deaths are beginning to decline in younger adolescents, they are still increasing in older adolescents. National population-based surveys provide valuable estimates of HIV prevalence in older adolescents and recent surveys include data on younger adolescents. Only a few countries have nationwide electronic case-based HIV surveillance, with the ability to provide population-level data on key HIV outcomes in the diagnosed population living with HIV. However, in the 15 highest adolescent HIV burden countries, there are no systems tracking adolescent transition to adulthood or healthcare transition. The strength of the 2016 WHO adolescent-specific recommendations on antiretroviral therapy and provision of HIV services to adolescents was hampered by the lack of evidence specific to this age group. Progress is being made in national surveillance and global monitoring systems

Lead Screening for HIV-1 Integrase (IN Inhibited by Traditional Chinese Medicine

Directory of Open Access Journals (Sweden)

Tzu-Chieh Hung

2014-01-01

Full Text Available Human immunodeficiency virus causes the acquired immunodeficiency syndrome (AIDS and becomes a serious world-wide problem because of this disease's rapid propagation and incurability. Integrase strand transfer inhibitors (INSTIs supports HIV have rapid drug resistance for antitreatment. Screening the traditional Chinese medicine (TCM database by simulating molecular docking and molecular dynamics may select molecular compounds to inhibit INSTIs against HIV drug resistance. (S-cathinone and (1S,2S-norpseudoephedrine are selected based on structure and ligand-based drugs are designed and then get higher bioactivity predicted score from SVM than Raltegravir and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions and hydrogen bond variations define the main regions of important amino acids in integrase. In addition to the detection of TCM compound efficacy, we suggest (1S,2S-norpseudoephedrine is better than the others based on the analysis of interaction and the effect on the structural variation.

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

International Nuclear Information System (INIS)

White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos; Knowlton, Caitlin; Kim, Baek; Sawyer, Sara L.; Diaz-Griffero, Felipe

2014-01-01

SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. - Highlights: • Human SAMHD1 single-nucleotide polymorphisms block HIV-1 and HIV-2 infection. • SAMHD1 polymorphisms do not affect its ability to block LINE-1 retrotransposition. • SAMHD1 polymorphisms decrease the cellular levels of dNTPs

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

Energy Technology Data Exchange (ETDEWEB)

White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos [Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, 1301 Morris Park – Price Center 501, New York, NY 10461 (United States); Knowlton, Caitlin; Kim, Baek [Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 (United States); Sawyer, Sara L. [Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712 (United States); Diaz-Griffero, Felipe, E-mail: Felipe.Diaz-Griffero@einstein.yu.edu [Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, 1301 Morris Park – Price Center 501, New York, NY 10461 (United States)

2014-07-15

SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. - Highlights: • Human SAMHD1 single-nucleotide polymorphisms block HIV-1 and HIV-2 infection. • SAMHD1 polymorphisms do not affect its ability to block LINE-1 retrotransposition. • SAMHD1 polymorphisms decrease the cellular levels of dNTPs.

Cyclophilin B enhances HIV-1 infection

Energy Technology Data Exchange (ETDEWEB)

DeBoer, Jason; Madson, Christian J. [Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE (United States); Belshan, Michael, E-mail: michaelbelshan@creighton.edu [Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE (United States); The Nebraska Center for Virology, University of Nebraska, Lincoln, NE (United States)

2016-02-15

Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. - Highlights: • CypB has been identified in several proteomic studies of HIV-1 infection. • CypB expression is upregulated in activated and infected T-cells. • Over-expression of CypB enhances HIV nuclear import and infection. • The N-terminus of CypB is necessary for these effects.

Cyclophilin B enhances HIV-1 infection

International Nuclear Information System (INIS)

DeBoer, Jason; Madson, Christian J.; Belshan, Michael

2016-01-01

Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. - Highlights: • CypB has been identified in several proteomic studies of HIV-1 infection. • CypB expression is upregulated in activated and infected T-cells. • Over-expression of CypB enhances HIV nuclear import and infection. • The N-terminus of CypB is necessary for these effects.

Enrichment of intersubtype HIV-1 recombinants in a dual infection system using HIV-1 strain-specific siRNAs

Science.gov (United States)

2011-01-01

Background Intersubtype HIV-1 recombinants in the form of unique or stable circulating recombinants forms (CRFs) are responsible for over 20% of infections in the worldwide epidemic. Mechanisms controlling the generation, selection, and transmission of these intersubtype HIV-1 recombinants still require further investigation. All intersubtype HIV-1 recombinants are generated and evolve from initial dual infections, but are difficult to identify in the human population. In vitro studies provide the most practical system to study mechanisms, but the recombination rates are usually very low in dual infections with primary HIV-1 isolates. This study describes the use of HIV-1 isolate-specific siRNAs to enrich intersubtype HIV-1 recombinants and inhibit the parental HIV-1 isolates from a dual infection. Results Following a dual infection with subtype A and D primary HIV-1 isolates and two rounds of siRNA treatment, nearly 100% of replicative virus was resistant to a siRNA specific for an upstream target sequence in the subtype A envelope (env) gene as well as a siRNA specific for a downstream target sequence in the subtype D env gene. Only 20% (10/50) of the replicating virus had nucleotide substitutions in the siRNA-target sequence whereas the remaining 78% (39/50) harbored a recombination breakpoint that removed both siRNA target sequences, and rendered the intersubtype D/A recombinant virus resistant to the dual siRNA treatment. Since siRNAs target the newly transcribed HIV-1 mRNA, the siRNAs only enrich intersubtype env recombinants and do not influence the recombination process during reverse transcription. Using this system, a strong bias is selected for recombination breakpoints in the C2 region, whereas other HIV-1 env regions, most notably the hypervariable regions, were nearly devoid of intersubtype recombination breakpoints. Sequence conservation plays an important role in selecting for recombination breakpoints, but the lack of breakpoints in many conserved

Characteristics of HIV-1 discordant couples enrolled in a trial of HSV-2 suppression to reduce HIV-1 transmission: the partners study.

Directory of Open Access Journals (Sweden)

Jairam R Lingappa

Full Text Available The Partners HSV-2/HIV-1 Transmission Study (Partners Study is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2 suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort.HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count >or=250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed.Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2-9 with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (500 relative to <350, respectively, p<0.001.The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission.ClinicalTrials.gov NCT00194519.

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013

NARCIS (Netherlands)

C.J.L. Murray (Christopher); K.F. Ortblad (Katrina F); C. Guinovart (Caterina); S.S. Lim (Stephen); T.M. Wolock (Timothy M); D.A. Roberts (D Allen); E.A. Dansereau (Emily A); N. Graetz (Nicholas); R.M. Barber (Ryan); J.C. Brown (Jonathan C); H. Wang (Haidong); H.C. Duber (Herbert C); M. Naghavi (Morteza); D. Dicker (Daniel); L. Dandona (Lalit); J.A. Salomon (Joshua); K.R. Heuton (Kyle R); K. Foreman (Kyle); D.E. Phillips (David E); T.D. Fleming (Thomas D); A.D. Flaxman (Abraham D); B.K. Phillips (Bryan K); E.M. Johnson (Elizabeth); M.S. Coggeshall (Megan S); F. Abd-Allah (Foad); S.F. Abera (Semaw Ferede); J.P. Abraham (Jerry); I. Abubakar (Ibrahim); L.J. Abu-Raddad (Laith J); N.M. Abu-Rmeileh (Niveen Me); T. Achoki (Tom); A. Adeyemo (Adebowale); A.K. Adou (Arsène Kouablan); J.C. Adsuar (José C); E.E. Agardh (Emilie Elisabet); D. Akena (Dickens); M.J. Al Kahbouri (Mazin J); D. Alasfoor (Deena); M.I. Albittar (Mohammed I); G. Alcalá-Cerra (Gabriel); M.A. Alegretti (Miguel Angel); G. Alemu (Getnet ); R. Alfonso-Cristancho (Rafael); S. Alhabib (Samia); R. Ali (Raghib); F. Alla (Francois); P.J. Allen (Peter); U. Alsharif (Ubai); E. Alvarez (Elena); N. Alvis-Guzman (Nelson); A.A. Amankwaa (Adansi A); A.T. Amare (Azmeraw T); H. Amini (Hassan); K.A. Ammar; B.O. Anderson (Benjamin); C.A.T. Antonio (Carl Abelardo T); P. Anwari (Palwasha); J. Ärnlöv (Johan); V.S.A. Arsenijevic (Valentina S Arsic); A. Artaman (Ali); R.J. Asghar (Rana J); R. Assadi (Reza); L.S. Atkins (Lydia S); A.F. Badawi (Alaa); A. Banerjee (Amitava); S. Basu (Saonli); J. Beardsley (Justin); T. Bekele (Tolesa); M.L. Bell (Michelle Lee); E. Bernabe (Eduardo); T.J. Beyene (Tariku Jibat); N. Bhala (Neeraj); P.L. Bhalla (Pankaj); Z.A. Bhutta (Zulfiqar A); A.B. Abdulhak (Aref Bin); A. Binagwaho (Agnes); J.D. Blore (Jed D); D. Bose (Dipan); M. Brainin (Michael); N. Breitborde (Nicholas); C.A. Castañeda-Orjuela (Carlos A); F. Catalá-López (Ferrán); D. Chadha; J.-C. Chang (Jung-Chen); Y.T. Chiang; T.-W. Chuang (Ting-Wu); M. Colomar (Mercedes); L.T. Cooper Jr. (Leslie Trumbull); C. Cooper (Charles); K.J. Courville (Karen J); M.R. Cowie (Martin R.); M. Criqui (Michael); R. Dandona (Rakhi); A. Dayama (Anand); D. de Leo (Diego); F. Degenhardt; B. Del Pozo-Cruz (Borja); K. Deribe (Kebede); D.C. Des Jarlais (Don C); M. Dessalegn (Muluken); S.D. Dharmaratne (Samath D); U. Dilmen (Uǧur); E.L. Ding (Eric); J.M. Driscoll; Z. Durrani; R.G. Ellenbogen (Richard G); S. Ermakov (Sergey); A. Esteghamati (Alireza); E.J.A. Faraon (Emerito Jose A); F. Farzadfar (Farshad); S.-M. Fereshtehnejad (Seyed-Mohammad); D.O. Fijabi (Daniel Obadare); M.H. Forouzanfar (Mohammad H); U. Fra.Paleo (Urbano); L. Gaffikin (Lynne); A. Gamkrelidze (Amiran); F.G. Gankpé (Fortuné Gbètoho); J.M. Geleijnse (Marianne); B.D. Gessner (Bradford D); K.B. Gibney (Katherine B); I.A.M. Ginawi (Ibrahim Abdelmageem Mohamed); E.L. Glaser (Elizabeth L); P. Gona (Philimon); A. Goto (Akimoto); H.N. Gouda (Hebe N); H.C. Gugnani (Harish Chander); R. Gupta (Rajeev); R. Gupta (Rajeev); N. Hafezi-Nejad (Nima); R.R. Hamadeh (Randah Ribhi); M. Hammami (Mouhanad); G.J. Hankey (Graeme); H.L. Harb (Hilda L); J.M. Haro (Josep Maria); R. Havmoeller (Rasmus); S.I. Hay (Simon I); M.T. Hedayati (Mohammad T); I.B.H. Pi (Ileana B Heredia); H.W. Hoek (Hans); J.C. Hornberger (John C); H.D. Hosgood (H Dean); P.J. Hotez (Peter); D.G. Hoy (Damian G); J. Huang (Jian); K.M. Iburg (Kim M); B.T. Idrisov (Bulat T); K. Innos (Kaire); K.H. Jacobsen (Kathryn H); P. Jeemon (Panniyammakal); P.N. Jensen (Paul N); V. Jha (Vivekanand); G. Jiang (Guohong); J.B. Jonas; K. Juel (Knud); H. Kan (Haidong); I. Kankindi (Ida); V. Karam (Vincent); F. Karch (Francois); C.K. Karema (Corine Kakizi); A. Kaul (Anil); N. Kawakami (Norito); D.S. Kazi (Dhruv S); A.H. Kemp (Andrew H); A.P. Kengne (Andre Pascal); A. Keren (Andre); M. Kereselidze (Maia); Y.S. Khader (Yousef Saleh); S.E.A.H. Khalifa (Shams Eldin Ali Hassan); E.A. Khan (Ejaz Ahmed); Y.-H. Khang (Young-Ho); I. Khonelidze (Irma); Y. Kinfu (Yohannes); J.M. Kinge (Jonas M); L. Knibbs (Luke); Y. Kokubo (Yoshihiro); S. Kosen (Soewarta); B.K. Defo (Barthelemy Kuate); V.S. Kulkarni (Veena S); C. Kulkarni (Chanda); K. Kumar (Kuldeep); R.B. Kumar (Ravi B); G.A. Kumar (G Anil); G.F. Kwan (Gene F); T. Lai (Taavi); A.L. Balaji (Arjun Lakshmana); H. Lam (Hilton); Q. Lan (Qing); V.C. Lansingh (Van C); H.J. Larson (Heidi J); A. Larsson (Anders); J.-T. Lee (Jong-Tae); P.N. Leigh (Nigel); M. Leinsalu (Mall); R. Leung (Ricky); Y. Li (Yichong); Y. Li (Yongmei); G.M.F. de Lima (Graça Maria Ferreira); H.-H. Lin (Hsien-Ho); S.E. Lipshultz (Steven); S. Liu (Simin); Y. Liu (Yang); B.K. Lloyd (Belinda K); P.A. Lotufo (Paulo A); V.M.P. Machado (Vasco Manuel Pedro); J.H. Maclachlan (Jennifer H); C. Magis-Rodriguez (Carlos); M. Majdan (Marek); C.C. Mapoma (Christopher Chabila); W. Marcenes (Wagner); M.B. Marzan (Melvin Barrientos); J.R. Masci (Joseph R); R. Mashal; A.J. Mason-Jones (Amanda J); B.M. Mayosi (Bongani); T.T. Mazorodze (Tasara T); M.J. Mckay (Michael); M.J. Meaney; M.M. Mehndiratta (Man Mohan); F. Mejia-Rodriguez (Fabiola); Y.A. Melaku (Yohannes Adama); Z.A. Memish (Ziad); W. Mendoza (Walter); T.R. Miller (Ted R); E.J. Mills (Edward J); K.A. Mohammad (Karzan Abdulmuhsin); A.H. Mokdad (Ali H); G.L. Mola (Glen Liddell); L. Monasta (Lorenzo); M. Montico (Marcella); A.R. Moore (Ami R); R. Mori (Riccardo); W.N. Moturi (Wilkister Nyaora); M. Mukaigawara (Mitsuru); A.C. Murthy (Adeline C.); A. Naheed (Aliya); K.S. Naidoo (Kovin S); L. Naldi; M. Nangia (Monika); K.M.V. Narayan (Venkat); J.H.E. Nash (John); C. Nejjari (Chakib); R.D. Nelson (Robert); S.P. Neupane (Sudan Prasad); C. Newton (Cameron); M. Ng (Marie); M.I. Nisar (Muhammad Imran); S. Nolte (Sandra); O.F. Norheim (Ole F); V. Nowaseb (Vincent); L. Nyakarahuka (Luke); I.-H. Oh (In-Hwan); T. Ohkubo (Takayoshi); B.O. Olusanya (Bolajoko O); S.B. Omer (Saad B); J.N. Opio (John Nelson); O.E. Orisakwe (Orish Ebere); N.G. Pandian (Natesa); C. Papachristou; M.S. Caicedo (Marco); J. Patten; V.K. Paul (Vinod K); B.I. Pavlin (Boris Igor); N. Pearce (Neil); D.M. Pereira (David M); Z. Pervaiz (Zahid); K. Pesudovs (Konrad); M. Petzold (Max); F. Pourmalek (Farshad); D. Qato (Dima); A.D. Quezada (Amado D); D.A. Quistberg (D Alex); A. Rafay (Anwar); K. Rahimi (Kazem); V. Rahimi-Movaghar (Vafa); S.U. Rahman (Sajjad Ur); M. Raju (Murugesan); S.M. Rana (Saleem M); H. Razavi (Homie); R.Q. Reilly (Robert Quentin); G. Remuzzi (Giuseppe); J.H. Richardus (Jan Hendrik); L. Ronfani (Luca); N. van Roy (Nadine); M.L. Sabin (Miriam Lewis); M.Y. Saeedi (Mohammad Yahya); M.A. Sahraian (Mohammad Ali); G.M.J. Samonte (Genesis May J); M.S. Sawhney (Monika); I.J.C. Schneider (Ione J C); D.C. Schwebel (David C); S. Seedat (Soraya); S.G. Sepanlou (Sadaf G); E.E. Servan-Mori (Edson E); S. Sheikhbahaei (Sara); K. Shibuya (Kenji); H.H. Shin (Hwashin Hyun); I. Shiue (Ivy); R. Shivakoti (Rupak); I.D. Sigfusdottir (Inga Dora); D.H. Silberberg (Donald H); A.P. Silva (Andrea P); J. Simard (Jacques); J.A. Singh (Jasvinder); V. Skirbekk (Vegard); K. Sliwa (Karen); S. Soneji (Samir); S.S. Soshnikov (Sergey S); C.T. Sreeramareddy (Chandrashekhar T); V.K. Stathopoulou (Vasiliki Kalliopi); K. Stroumpoulis (Konstantinos); S. Swaminathan; B.C. Sykes (Bryan); K.M. Tabb (Karen M); R.T. Talongwa (Roberto Tchio); E.Y. Tenkorang (Eric Yeboah); A.S. Terkawi (Abdullah Sulieman); A.J. Thomson (Alan J); A.L. Thorne-Lyman (Andrew L); J.A. Towbin (Jeffrey A); J. Traebert (Jefferson); B.X. Tran (Bach X); Z.T. Dimbuene (Zacharie Tsala); M. Tsilimbaris (Miltiadis); U.S. Uchendu (Uche S); K.N. Ukwaja (Kingsley N); S.R. Vallely (Stephen); T.J. Vasankari (Tommi J); N. Venketasubramanian (Narayanaswamy); F.S. Violante (Francesco S); V.V. Vlassov (Vasiliy Victorovich); P. Waller (Patrick); M.T. Wallin (Mitchell T); L. Wang (Linhong); S.X. Wang; Y. Wang (Yanping); S. Weichenthal (Scott); E. Weiderpass (Elisabete); R.G. Weintraub (Robert G); R. Westerman (Ronny); R.G. White (Richard); J.D. Wilkinson (James D); T.N. Williams (Thomas Neil); S.M. Woldeyohannes (Solomon Meseret); J.B. Wong (John); G. Xu (Gelin); Y.C. Yang (Yang C); K.-I. Yano; P. Yip (Paul); N. Yonemoto (Naohiro); S.-J. Yoon (Seok-Jun); M. Younis (Mustafa); C. Yu (Chuanhua); K.Y. Jin (Kim Yun); M. El Sayed Zaki (Maysaa); Y. Zhao (Yong); Y. Zheng (Yuhui); K. Balakrishnan (Kalpana); M. Zhou (Ming); J. Zhu (Jun); X.N. Zou (Xiao Nong); A.D. Lopez (Alan D); T. Vos (Theo)

2014-01-01

markdownabstract__Abstract__ Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach

Synergy against drug-resistant HIV-1 with the microbicide antiretrovirals, dapivirine and tenofovir, in combination.

Science.gov (United States)

Schader, Susan M; Colby-Germinario, Susan P; Schachter, Jordana R; Xu, Hongtao; Wainberg, Mark A

2011-08-24

To evaluate the candidate antiretroviral microbicide compounds, dapivirine (DAP) and tenofovir (TFV), alone and in combination against the transmission of wild-type and nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 from different subtypes. We determined single-drug efficacy of the RTIs, DAP and TFV, against subtype B and non-B wild-type and NNRTI-resistant HIV-1 in vitro. To assess breadth of activity, compounds were tested alone and in combination against wild-type and NNRTI-resistant subtype C primary HIV-1 isolates and complimentary clonal HIV-1 from subtypes B, C and CRF02_AG to control for viral variation. Early infection was quantified by counting light units emitted from TZM-bl cells less than 48-h postinfection. Combination ratios were based on drug inhibitory concentrations (IC(50)s) and combined effects were determined by calculating combination indices. Both candidate microbicide antiretrovirals demonstrated potent anti-NNRTI-resistant HIV-1 activity in vitro, albeit the combination protected better than the single-drug treatments. Of particular interest, the DAP with TFV combination exhibited synergy (50% combination index, CI(50) = 0.567) against subtype C NNRTI-resistant HIV-1, whereas additivity (CI(50) = 0.987) was observed against the wild-type counterpart from the same patient. The effect was not compounded by the presence of subdominant viral fractions, as experiments using complimentary clonal subtype C wild-type (CI(50) = 0.968) and NNRTI-resistant (CI(50) = 0.672) HIV-1, in lieu of the patient quasispecies, gave similar results. This study supports the notion that antiretroviral drug combinations may retain antiviral activity against some drug-resistant HIV-1 despite subtype classification and quasispecies diversity.

Mother-to-Child HIV-1 Transmission Events Are Differentially Impacted by Breast Milk and Its Components from HIV-1-Infected Women.

Directory of Open Access Journals (Sweden)

Ruizhong Shen

Full Text Available Breast milk is a vehicle of infection and source of protection in post-natal mother-to-child HIV-1 transmission (MTCT. Understanding the mechanism by which breast milk limits vertical transmission will provide critical insight into the design of preventive and therapeutic approaches to interrupt HIV-1 mucosal transmission. However, characterization of the inhibitory activity of breast milk in human intestinal mucosa, the portal of entry in postnatal MTCT, has been constrained by the limited availability of primary mucosal target cells and tissues to recapitulate mucosal transmission ex vivo. Here, we characterized the impact of skimmed breast milk, breast milk antibodies (Igs and non-Ig components from HIV-1-infected Ugandan women on the major events of HIV-1 mucosal transmission using primary human intestinal cells and tissues. HIV-1-specific IgG antibodies and non-Ig components in breast milk inhibited the uptake of Ugandan HIV-1 isolates by primary human intestinal epithelial cells, viral replication in and transport of HIV-1- bearing dendritic cells through the human intestinal mucosa. Breast milk HIV-1-specific IgG and IgA, as well as innate factors, blocked the uptake and transport of HIV-1 through intestinal mucosa. Thus, breast milk components have distinct and complementary effects in reducing HIV-1 uptake, transport through and replication in the intestinal mucosa and, therefore, likely contribute to preventing postnatal HIV-1 transmission. Our data suggests that a successful preventive or therapeutic approach would require multiple immune factors acting at multiple steps in the HIV-1 mucosal transmission process.

HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

DEFF Research Database (Denmark)

Vanangamudi, Murugesan; Poongavanam, Vasanthanathan; Namasivayam, Vigneshwaran

2017-01-01

BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising......: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine...

Variations and determinants of carbon content in plants: a global synthesis

Science.gov (United States)

Ma, Suhui; He, Feng; Tian, Di; Zou, Dongting; Yan, Zhengbing; Yang, Yulong; Zhou, Tiancheng; Huang, Kaiyue; Shen, Haihua; Fang, Jingyun

2018-02-01

Plant carbon (C) content is one of the most important plant traits and is critical to the assessment of global C cycle and ecological stoichiometry; however, the global variations in plant C content remain poorly understood. In this study, we conducted a global analysis of the plant C content by synthesizing data from 4318 species to document specific values and their variation of the C content across plant organs and life forms. Plant organ C contents ranged from 45.0 % in reproductive organs to 47.9 % in stems at global scales, which were significantly lower than the widely employed canonical value of 50 %. Plant C content in leaves (global mean of 46.9 %) was higher than that in roots (45.6 %). Across life forms, woody plants exhibited higher C content than herbaceous plants. Conifers, relative to broad-leaved woody species, had higher C content in roots, leaves, and stems. Plant C content tended to show a decrease with increasing latitude. The life form explained more variation of the C content than climate. Our findings suggest that specific C content values of different organs and life forms developed in our study should be incorporated into the estimations of regional and global vegetation biomass C stocks.

Variations and determinants of carbon content in plants: a global synthesis

Directory of Open Access Journals (Sweden)

S. Ma

2018-02-01

Full Text Available Plant carbon (C content is one of the most important plant traits and is critical to the assessment of global C cycle and ecological stoichiometry; however, the global variations in plant C content remain poorly understood. In this study, we conducted a global analysis of the plant C content by synthesizing data from 4318 species to document specific values and their variation of the C content across plant organs and life forms. Plant organ C contents ranged from 45.0 % in reproductive organs to 47.9 % in stems at global scales, which were significantly lower than the widely employed canonical value of 50 %. Plant C content in leaves (global mean of 46.9 % was higher than that in roots (45.6 %. Across life forms, woody plants exhibited higher C content than herbaceous plants. Conifers, relative to broad-leaved woody species, had higher C content in roots, leaves, and stems. Plant C content tended to show a decrease with increasing latitude. The life form explained more variation of the C content than climate. Our findings suggest that specific C content values of different organs and life forms developed in our study should be incorporated into the estimations of regional and global vegetation biomass C stocks.

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990—2013: a systematic analysis for the Global Burden of Disease Study 2013

DEFF Research Database (Denmark)

J L Murray, Christopher; F Ortblad, Katrina; Guinovart, Caterina

2014-01-01

Background The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between...... with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data...... and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble...

HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe

DEFF Research Database (Denmark)

Zinyama-Gutsire, Rutendo B L; Chasela, Charles; Kallestrup, Per

2015-01-01

HIV infection remains a major global health burden since its discovery in 1983. Sub-Saharan Africa is the region hardest hit by the HIV/AIDS pandemic where 63% of the 33 million infected people live. While there is marked person-to-person variability in susceptibility, progression, and survival...

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013

NARCIS (Netherlands)

Murray, Christopher J. L.; Ortblad, Katrina F.; Guinovart, Caterina; Lim, Stephen S.; Wolock, Timothy M.; Roberts, D. Allen; Dansereau, Emily A.; Graetz, Nicholas; Barber, Ryan M.; Brown, Jonathan C.; Wang, Haidong; Duber, Herbert C.; Naghavi, Mohsen; Dicker, Daniel; Dandona, Lalit; Salomon, Joshua A.; Heuton, Kyle R.; Foreman, Kyle; Phillips, David E.; Fleming, Thomas D.; Flaxman, Abraham D.; Phillips, Bryan K.; Johnson, Elizabeth K.; Coggeshall, Megan S.; Abd-Allah, Foad; Abera, Semaw Ferede; Abraham, Jerry P.; Abubakar, Ibrahim; Abu-Raddad, Laith J.; Abu-Rmeileh, Niveen Me; Achoki, Tom; Adeyemo, Austine Olufemi; Adou, Arsene Kouablan; Adsuar, Jose C.; Agardh, Emilie Elisabet; Akena, Dickens; Al Kahbouri, Mazin J.; Alasfoor, Deena; Albittar, Mohammed I.; Alcala-Cerra, Gabriel; Angel Alegretti, Miguel; Alemu, Zewdie Aderaw; Alfonso-Cristancho, Rafael; Alhabib, Samia; Ali, Raghib; Alla, Francois; Allen, Peter J.; Alsharif, Ubai; Alvarez, Elena; Alvis-Guzman, Nelson; Amankwaa, Adansi A.; Amare, Azmeraw T.; Amini, Hassan; Ammar, Walid; Anderson, Benjamin O.; Antonio, Carl Abelardo T.; Anwari, Palwasha; Arnlov, Johan; Arsenijevic, Valentina S. Arsic; Artaman, Ali; Asghar, Rana J.; Assadi, Reza; Atkins, Lydia S.; Badawi, Alaa; Balakrishnan, Kalpana; Banerjee, Amitava; Basu, Sanjay; Beardsley, Justin; Bekele, Tolesa; Bell, Michelle L.; Bernabe, Eduardo; Beyene, Tariku Jibat; Bhala, Neeraj; Bhalla, Ashish; Bhutta, Zulfiqar A.; Bin Abdulhak, Aref; Binagwaho, Agnes; Blore, Jed D.; Basara, Berrak Bora; Bose, Dipan; Brainin, Michael; Breitborde, Nicholas; Castaneda-Orjuela, Carlos A.; Catala-Lopez, Ferran; Chadha, Vineet K.; Chang, Jung-Chen; Chiang, Peggy Pei-Chia; Chuang, Ting-Wu; Colomar, Mercedes; Cooper, Leslie Trumbull; Cooper, Cyrus; Courville, Karen J.; Cowie, Benjamin C.; Criqui, Michael H.; Dandona, Rakhi; Dayama, Anand; De Leo, Diego; Degenhardt, Louisa; Del Pozo-Cruz, Borja; Deribe, Kebede; Des Jarlais, Don C.; Dessalegn, Muluken; Dharmaratne, Samath D.; Dilmen, Ugur; Ding, Eric L.; Driscoll, Tim R.; Durrani, Adnan M.; Ellenbogen, Richard G.; Ermakov, Sergey Petrovich; Esteghamati, Alireza; Faraon, Emerito Jose A.; Farzadfar, Farshad; Fereshtehnejad, Seyed-Mohammad; Fijabi, Daniel Obadare; Forouzanfar, Mohammad H.; Paleo, Urbano Fra; Gaffikin, Lynne; Gamkrelidze, Amiran; Gankpe, Fortune Gbetoho; Geleijnse, Johanna M.; Gessner, Bradford D.; Gibney, Katherine B.; Ginawi, Ibrahim Abdelmageem Mohamed; Glaser, Elizabeth L.; Gona, Philimon; Goto, Atsushi; Gouda, Hebe N.; Gugnani, Harish Chander; Gupta, Rajeev; Gupta, Rahul; Hafezi-Nejad, Nima; Hamadeh, Randah Ribhi; Hammami, Mouhanad; Hankey, Graeme J.; Harb, Hilda L.; Maria Haro, Josep; Havmoeller, Rasmus; Hay, Simon I.; Hedayati, Mohammad T.; Heredia Pi, Ileana B.; Hoek, Hans W.; Hornberger, John C.; Hosgood, H. Dean; Hotez, Peter J.; Hoy, Damian G.; Huang, John J.; Iburg, Kim M.; Idrisov, Bulat T.; Innos, Kaire; Jacobsen, Kathryn H.; Jeemon, Panniyammakal; Jensen, Paul N.; Jha, Vivekanand; Jiang, Guohong; Jonas, Jost B.; Juel, Knud; Kan, Haidong; Kankindi, Ida; Karam, Nadim E.; Karch, Andre; Karema, Corine Kakizi; Kaul, Anil; Kawakami, Norito; Kazi, Dhruv S.; Kemp, Andrew H.; Kengne, Andre Pascal; Keren, Andre; Kereselidze, Maia; Khader, Yousef Saleh; Khalifa, Shams Eldin Ali Hassan; Khan, Ejaz Ahmed; Khang, Young-Ho; Khonelidze, Irma; Kinfu, Yohannes; Kinge, Jonas M.; Knibbs, Luke; Kokubo, Yoshihiro; Kosen, S.; Defo, Barthelemy Kuate; Kulkarni, Veena S.; Kulkarni, Chanda; Kumar, Kaushalendra; Kumar, Ravi B.; Kumar, G. Anil; Kwan, Gene F.; Lai, Taavi; Balaji, Arjun Lakshmana; Lam, Hilton; Lan, Qing; Lansingh, Van C.; Larson, Heidi J.; Larsson, Anders; Lee, Jong-Tae; Leigh, James; Leinsalu, Mall; Leung, Ricky; Li, Yichong; Li, Yongmei; Ferreira De Lima, Graca Maria; Lin, Hsien-Ho; Lipshultz, Steven E.; Liu, Shiwei; Liu, Yang; Lloyd, Belinda K.; Lotufo, Paulo A.; Pedro Machado, Vasco Manuel; Maclachlan, Jennifer H.; Magis-Rodriguez, Carlos; Majdan, Marek; Mapoma, Christopher Chabila; Marcenes, Wagner; Barrieotos Marzan, Melvin; Masci, Joseph R.; Mashal, Mohammad Taufiq; Mason-Jones, Amanda J.; Mayosi, Bongani M.; Mazorodze, Tasara T.; Mckay, Abigail Cecilia; Meaney, Peter A.; Mehndiratta, Man Mohan; Mejia-Rodriguez, Fabiola; Melaku, Yohannes Adama; Memish, Ziad A.; Mendoza, Walter; Miller, Ted R.; Mills, Edward J.; Mohammad, Karzan Abdulmuhsin; Mokdad, Ali H.; Mola, Glen Liddell; Monasta, Lorenzo; Montico, Marcella; Moore, Ami R.; Mori, Rintaro; Moturi, Wilkister Nyaora; Mukaigawara, Mitsuru; Murthy, Kinnari S.; Naheed, Aliya; Naidoo, Kovin S.; Naldi, Luigi; Nangia, Vinay; Narayan, K. M. Venkat; Nash, Denis; Nejjari, Chakib; Nelson, Robert G.; Neupane, Sudan Prasad; Newton, Charles R.; Ng, Marie; Nisar, Muhammad Imran; Nolte, Sandra; Norheim, Ole F.; Nowaseb, Vincent; Nyakarahuka, Luke; Oh, In-Hwan; Ohkubo, Takayoshi; Olusanya, Bolajoko O.; Omer, Saad B.; Opio, John Nelson; Orisakwe, Orish Ebere; Pandian, Jeyaraj D.; Papachristou, Christina; Paternina Caicedo, Angel J.; Patten, Scott B.; Paul, Vinod K.; Pavlin, Boris Igor; Pearce, Neil; Pereira, David M.; Pervaiz, Aslam; Pesudovs, Konrad; Petzold, Max; Pourmalek, Farshad; Qato, Dima; Quezada, Amado D.; Quistberg, D. Alex; Rafay, Anwar; Rahimi, Kazem; Rahimi-Movaghar, Vafa; Rahman, Sajjad Ur; Raju, Murugesan; Rana, Saleem M.; Razavi, Homie; Reilly, Robert Quentin; Remuzzi, Giuseppe; Richardus, Jan Hendrik; Ronfani, Luca; Roy, Nobhojit; Sabin, Nsanzimana; Saeedi, Mohammad Yahya; Sahraian, Mohammad Ali; Samonte, Genesis May J.; Sawhney, Monika; Schneider, Ione J. C.; Schwebel, David C.; Seedat, Soraya; Sepanlou, Sadaf G.; Servan-Mori, Edson E.; Sheikhbahaei, Sara; Shibuya, Kenji; Shin, Hwashin Hyun; Shiue, Ivy; Shivakoti, Rupak; Sigfusdottir, Inga Dora; Silberberg, Donald H.; Silva, Andrea P.; Simard, Edgar P.; Singh, Jasvinder A.; Skirbekk, Vegard; Sliwa, Karen; Soneji, Samir; Soshnikov, Sergey S.; Sreeramareddy, Chandrashekhar T.; Stathopoulou, Vasiliki Kalliopi; Stroumpoulis, Konstantinos; Swaminathan, Soumya; Sykes, Bryan L.; Tabb, Karen M.; Talongwa, Roberto Tchio; Tenkorang, Eric Yeboah; Terkawi, Abdullah Sulieman; Thomson, Alan J.; Thorne-Lyman, Andrew L.; Towbin, Jeffrey A.; Traebert, Jefferson; Tran, Bach X.; Dimbuene, Zacharie Tsala; Tsilimbaris, Miltiadis; Uchendu, Uche S.; Ukwaja, Kingsley N.; Uzun, Selen Begum; Vallely, Andrew J.; Vasankari, Tommi J.; Venketasubramanian, N.; Violante, Francesco S.; Vlassov, Vasiliy Victorovich; Vollset, Stein Emil; Waller, Stephen; Wallin, Mitchell T.; Wang, Linhong; Wang, XiaoRong; Wang, Yanping; Weichenthal, Scott; Weiderpass, Elisabete; Weintraub, Robert G.; Westerman, Ronny; White, Richard A.; Wilkinson, James D.; Williams, Thomas Neil; Woldeyohannes, Solomon Meseret; Wong, John Q.; Xu, Gelin; Yang, Yong C.; Yano, Yuichiro; Yentur, Gokalp Kadri; Yip, Paul; Yonemoto, Naohiro; Yoon, Seok-Jun; Younis, Mustafa; Yu, Chuanhua; Jin, Kim Yun; Zaki, Maysaa El Sayed; Zhao, Yong; Zheng, Yingfeng; Zhou, Maigeng; Zhu, Jun; Zou, Xiao Nong; Lopez, Alan D.; Vos, Theo

2014-01-01

Background The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between

The cytosolic exonuclease TREX1 inhibits the innate immune response to HIV-1

Science.gov (United States)

Yan, Nan; Regalado-Magdos, Ashton D.; Stiggelbout, Bart; Lee-Kirsch, Min Ae; Lieberman, Judy

2010-01-01

Viral infection triggers innate immune sensors to produce type I interferons (IFN). However, HIV infection of T cells and macrophages does not trip these alarms. How HIV avoids activating nucleic acid sensors is unknown. The cytosolic exonuclease TREX1 suppressed IFN triggered by HIV. In Trex1−/− mouse cells and human CD4+ T cells and macrophages in which TREX1 was inhibited by RNA interference, cytosolic HIV DNA accumulated, and HIV infection induced type I IFN that inhibited HIV replication and spreading. TREX1 bound to cytosolic HIV DNA and digested excess HIV DNA that would otherwise activate IFN expression via a TBK1, STING and IRF3 dependent pathway. HIV-stimulated IFN production in cells deficient in TREX1 did not involve known nucleic acid sensors. PMID:20871604

Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients

Science.gov (United States)

Addai, Amma B.; Pandhare, Jui; Paromov, Victor; Mantri, Chinmay K.; Pratap, Siddharth; Dash, Chandravanu

2015-01-01

Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4+ T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM–100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4+ T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4+ T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4+ T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients. PMID:25691383

Development of an HIV-1 Subtype Panel in China: Isolation and Characterization of 30 HIV-1 Primary Strains Circulating in China.

Directory of Open Access Journals (Sweden)

Jingwan Han

Full Text Available The complex epidemic and significant diversity of HIV-1 strains in China pose serious challenges for surveillance and diagnostic assays, vaccine development and clinical management. There is a lack of HIV-1 isolates in current canonical HIV-1 subtype panels that can represent HIV-1 diversity in China; an HIV-1 subtype panel for China is urgently needed.Blood samples were collected from HIV-1 infected patients participating in the drug-resistance surveillance program in China. The samples were isolated, cultured and stored as neat culture supernatant. The HIV-1 isolates were fully characterized. The panel was used to compare 2 viral load assays and 2 p24 assays as the examples of how this panel could be used.An HIV-1 subtype panel for China composed of 30 HIV-1 primary strains of four subtypes (B [including Thai-B], CRF01_AE, CRF07_BC and G was established. The samples were isolated and cultured to a high-titer (10(6-10(9 copies/ml/high-volume (40 ml. The HIV-1 isolates were fully characterized by the final viral load, p24 concentration, gag-pol and envC2V3 sequencing, co-receptor prediction, determination of the four amino acids at the tip of the env V3-loop, glycosylation sites in the V3 loop and the drug-resistance mutations. The comparison of two p24 assays and two viral load assays on the isolates illustrated how this panel may be used for the evaluation of diagnostic assay performance. The Pearson value between p24 assays were 0.938. The viral load results showed excellent concordance and agreement for samples of Thai-B, but lower correlations for samples of CRF01_AE.The current panel of 30 HIV-1 isolates served as a basis for the development of a comprehensive panel of fully characterized viral isolates, which could reflect the current dynamic and complex HIV-1 epidemic in China. This panel will be available to support HIV-1 research, assay evaluation, vaccine and drug development.

HIV-1 Reservoir Association with Immune Activation

Directory of Open Access Journals (Sweden)

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.

CCR2, CCR5, and CXCL12 variation and HIV/AIDS in Papua New Guinea.

Science.gov (United States)

Mehlotra, Rajeev K; Hall, Noemi B; Bruse, Shannon E; John, Bangan; Zikursh, Melinda J Blood; Stein, Catherine M; Siba, Peter M; Zimmerman, Peter A

2015-12-01

Polymorphisms in chemokine receptors, serving as HIV co-receptors, and their ligands are among the well-known host genetic factors associated with susceptibility to HIV infection and/or disease progression. Papua New Guinea (PNG) has one of the highest adult HIV prevalences in the Asia-Pacific region. However, information regarding the distribution of polymorphisms in chemokine receptor (CCR5, CCR2) and chemokine (CXCL12) genes in PNG is very limited. In this study, we genotyped a total of nine CCR2-CCR5 polymorphisms, including CCR2 190G >A, CCR5 -2459G >A and Δ32, and CXCL12 801G >A in PNG (n=258), North America (n=184), and five countries in West Africa (n=178). Using this data, we determined previously characterized CCR5 haplotypes. In addition, based on the previously reported associations of CCR2 190, CCR5 -2459, CCR5 open reading frame, and CXCL12 801 genotypes with HIV acquisition and/or disease progression, we calculated composite full risk scores, considering both protective as well as susceptibility effects of the CXCL12 801 AA genotype. We observed a very high frequency of the CCR5 -2459A allele (0.98) in the PNG population, which together with the absence of Δ32 resulted in a very high frequency of the HHE haplotype (0.92). These frequencies were significantly higher than in any other population (all P-valuesnew insights regarding CCR5 variation in the PNG population, and suggest that the collective variation in CCR2, CCR5, and CXCL12 may increase the risk of HIV/AIDS in a large majority of Papua New Guineans. Copyright © 2015 Elsevier B.V. All rights reserved.

HIV-1 with multiple CCR5/CXCR4 chimeric receptor use is predictive of immunological failure in infected children.

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Mariangela Cavarelli

Full Text Available BACKGROUND: HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5(broad viruses, was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT of HIV-1 and pediatric disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5(narrow phenotype (n = 20, but R5(broad and R5X4 viruses were also found in seven and one case, respectively. The presence of R5(broad and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3 or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5(broad phenotype, however, the presence of the R5(broad virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5(broad viruses transmitted viruses with a similar broad chimeric coreceptor usage. Thus, the maternal R5(broad phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant. CONCLUSIONS/SIGNIFICANCE: Our results show that R5(broad viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5(narrow phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infection.

Hepatitis B Virus Vaccination in HIV-1-Infected Young Adults: A Tool to Reduce the Size of HIV-1 Reservoirs?

Science.gov (United States)

Bekele, Yonas; Graham, Rebecka Lantto; Soeria-Atmadja, Sandra; Nasi, Aikaterini; Zazzi, Maurizio; Vicenti, Ilaria; Naver, Lars; Nilsson, Anna; Chiodi, Francesca

2017-01-01

During anti-retroviral therapy (ART) HIV-1 persists in cellular reservoirs, mostly represented by CD4+ memory T cells. Several approaches are currently being undertaken to develop a cure for HIV-1 infection through elimination (or reduction) of these reservoirs. Few studies have so far been conducted to assess the possibility of reducing the size of HIV-1 reservoirs through vaccination in virologically controlled HIV-1-infected children. We recently conducted a vaccination study with a combined hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccine in 22 HIV-1-infected children. We assessed the size of the virus reservoir, measured as total HIV-1 DNA copies in blood cells, pre- and postvaccination. In addition, we investigated by immunostaining whether the frequencies of CD4+ and CD8+ T cells and parameters of immune activation and proliferation on these cells were modulated by vaccination. At 1 month from the last vaccination dose, we found that 20 out of 22 children mounted a serological response to HBV; a majority of children had antibodies against HAV at baseline. The number of HIV-1 DNA copies in blood at 1 month postvaccination was reduced in comparison to baseline although this reduction was not statistically significant. A significant reduction of HIV-1 DNA copies in blood following vaccination was found in 12 children. The frequencies of CD4+ (naïve, effector memory) and CD8+ (central memory) T-cell subpopulations changed following vaccinations and a reduction in the activation and proliferation pattern of these cells was also noticed. Multivariate linear regression analysis revealed that the frequency of CD8+ effector memory T cells prior to vaccination was strongly predictive of the reduction of HIV-1 DNA copies in blood following vaccination of the 22 HIV-1-infected children. The results of this study suggest a beneficial effect of vaccination to reduce the size of virus reservoir in HIV-1-infected children receiving ART. A reduced frequency of

Hepatitis B Virus Vaccination in HIV-1-Infected Young Adults: A Tool to Reduce the Size of HIV-1 Reservoirs?

Directory of Open Access Journals (Sweden)

Yonas Bekele

2018-01-01

Full Text Available During anti-retroviral therapy (ART HIV-1 persists in cellular reservoirs, mostly represented by CD4+ memory T cells. Several approaches are currently being undertaken to develop a cure for HIV-1 infection through elimination (or reduction of these reservoirs. Few studies have so far been conducted to assess the possibility of reducing the size of HIV-1 reservoirs through vaccination in virologically controlled HIV-1-infected children. We recently conducted a vaccination study with a combined hepatitis A virus (HAV and hepatitis B virus (HBV vaccine in 22 HIV-1-infected children. We assessed the size of the virus reservoir, measured as total HIV-1 DNA copies in blood cells, pre- and postvaccination. In addition, we investigated by immunostaining whether the frequencies of CD4+ and CD8+ T cells and parameters of immune activation and proliferation on these cells were modulated by vaccination. At 1 month from the last vaccination dose, we found that 20 out of 22 children mounted a serological response to HBV; a majority of children had antibodies against HAV at baseline. The number of HIV-1 DNA copies in blood at 1 month postvaccination was reduced in comparison to baseline although this reduction was not statistically significant. A significant reduction of HIV-1 DNA copies in blood following vaccination was found in 12 children. The frequencies of CD4+ (naïve, effector memory and CD8+ (central memory T-cell subpopulations changed following vaccinations and a reduction in the activation and proliferation pattern of these cells was also noticed. Multivariate linear regression analysis revealed that the frequency of CD8+ effector memory T cells prior to vaccination was strongly predictive of the reduction of HIV-1 DNA copies in blood following vaccination of the 22 HIV-1-infected children. The results of this study suggest a beneficial effect of vaccination to reduce the size of virus reservoir in HIV-1-infected children receiving ART. A reduced

Hepatitis B Virus Vaccination in HIV-1-Infected Young Adults: A Tool to Reduce the Size of HIV-1 Reservoirs?

Science.gov (United States)

Bekele, Yonas; Graham, Rebecka Lantto; Soeria-Atmadja, Sandra; Nasi, Aikaterini; Zazzi, Maurizio; Vicenti, Ilaria; Naver, Lars; Nilsson, Anna; Chiodi, Francesca

2018-01-01

During anti-retroviral therapy (ART) HIV-1 persists in cellular reservoirs, mostly represented by CD4+ memory T cells. Several approaches are currently being undertaken to develop a cure for HIV-1 infection through elimination (or reduction) of these reservoirs. Few studies have so far been conducted to assess the possibility of reducing the size of HIV-1 reservoirs through vaccination in virologically controlled HIV-1-infected children. We recently conducted a vaccination study with a combined hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccine in 22 HIV-1-infected children. We assessed the size of the virus reservoir, measured as total HIV-1 DNA copies in blood cells, pre- and postvaccination. In addition, we investigated by immunostaining whether the frequencies of CD4+ and CD8+ T cells and parameters of immune activation and proliferation on these cells were modulated by vaccination. At 1 month from the last vaccination dose, we found that 20 out of 22 children mounted a serological response to HBV; a majority of children had antibodies against HAV at baseline. The number of HIV-1 DNA copies in blood at 1 month postvaccination was reduced in comparison to baseline although this reduction was not statistically significant. A significant reduction of HIV-1 DNA copies in blood following vaccination was found in 12 children. The frequencies of CD4+ (naïve, effector memory) and CD8+ (central memory) T-cell subpopulations changed following vaccinations and a reduction in the activation and proliferation pattern of these cells was also noticed. Multivariate linear regression analysis revealed that the frequency of CD8+ effector memory T cells prior to vaccination was strongly predictive of the reduction of HIV-1 DNA copies in blood following vaccination of the 22 HIV-1-infected children. The results of this study suggest a beneficial effect of vaccination to reduce the size of virus reservoir in HIV-1-infected children receiving ART. A reduced frequency of

Curcumin derivatives as HIV-1 protease inhibitors

Energy Technology Data Exchange (ETDEWEB)

Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

1993-12-31

Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

The global security perspective on the effects of executive cognitive function on complex behavioral screening intervention and HIV/AIDS.

Science.gov (United States)

Kim, Suk-Hee

2010-11-01

The purpose of this quantitative study is to understand the global security perspective on the effects of executive cognitive function (ECF) on Complex Behavioral Screening Intervention and HIV/AIDS. The HIV/AIDS pandemic is as much a social, political, economic, and cultural problem as a biomedical one. HIV/AIDS is associated centrally with the collapse not just of communities and families but potentially of states, with some of the largest public health interventions ever and enormous questions about governance, a huge population of orphans, and deep questions about intergenerational relations and cultural transmission. This study also is to develop a screening instrument that improves quality of life for individuals with executive cognitive impairments and behavior problems in our communities and the global society.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

Directory of Open Access Journals (Sweden)

Amy L Slogrove

2018-03-01

Full Text Available Globally, the population of adolescents living with perinatally acquired HIV (APHs continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER, individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG, and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs. Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR] duration of

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

Science.gov (United States)

Slogrove, Amy L; Schomaker, Michael; Davies, Mary-Ann; Williams, Paige; Balkan, Suna; Ben-Farhat, Jihane; Calles, Nancy; Chokephaibulkit, Kulkanya; Duff, Charlotte; Eboua, Tanoh François; Kekitiinwa-Rukyalekere, Adeodata; Maxwell, Nicola; Pinto, Jorge; Seage, George; Teasdale, Chloe A; Wanless, Sebastian; Warszawski, Josiane; Wools-Kaloustian, Kara; Yotebieng, Marcel; Timmerman, Venessa; Collins, Intira J; Goodall, Ruth; Smith, Colette; Patel, Kunjal; Paul, Mary; Gibb, Diana; Vreeman, Rachel; Abrams, Elaine J; Hazra, Rohan; Van Dyke, Russell; Bekker, Linda-Gail; Mofenson, Lynne; Vicari, Marissa; Essajee, Shaffiq; Penazzato, Martina; Anabwani, Gabriel; Q Mohapi, Edith; N Kazembe, Peter; Hlatshwayo, Makhosazana; Lumumba, Mwita; Goetghebuer, Tessa; Thorne, Claire; Galli, Luisa; van Rossum, Annemarie; Giaquinto, Carlo; Marczynska, Magdalena; Marques, Laura; Prata, Filipa; Ene, Luminita; Okhonskaia, Liubov; Rojo, Pablo; Fortuny, Claudia; Naver, Lars; Rudin, Christoph; Le Coeur, Sophie; Volokha, Alla; Rouzier, Vanessa; Succi, Regina; Sohn, Annette; Kariminia, Azar; Edmonds, Andrew; Lelo, Patricia; Ayaya, Samuel; Ongwen, Patricia; Jefferys, Laura F; Phiri, Sam; Mubiana-Mbewe, Mwangelwa; Sawry, Shobna; Renner, Lorna; Sylla, Mariam; Abzug, Mark J; Levin, Myron; Oleske, James; Chernoff, Miriam; Traite, Shirley; Purswani, Murli; Chadwick, Ellen G; Judd, Ali; Leroy, Valériane

2018-03-01

Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow

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.

The dual action of poly(ADP-ribose polymerase -1 (PARP-1 inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity

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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.

Accumulation of MxB/Mx2-resistant HIV-1 Capsid Variants During Expansion of the HIV-1 Epidemic in Human Populations.

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Wei, Wei; Guo, Haoran; Ma, Min; Markham, Richard; Yu, Xiao-Fang

2016-06-01

Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution. Copyright © 2016. Published by Elsevier B.V.

The HIV-1 Rev/RRE system is required for HIV-1 5' UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles

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Ma Hong

2011-06-01

Full Text Available Abstract Background The process of HIV-1 genomic RNA (gRNA encapsidation is governed by a number of viral encoded components, most notably the Gag protein and gRNA cis elements in the canonical packaging signal (ψ. Also implicated in encapsidation are cis determinants in the R, U5, and PBS (primer binding site from the 5' untranslated region (UTR. Although conventionally associated with nuclear export of HIV-1 RNA, there is a burgeoning role for the Rev/RRE in the encapsidation process. Pleiotropic effects exhibited by these cis and trans viral components may confound the ability to examine their independent, and combined, impact on encapsidation of RNA into HIV-1 viral particles in their innate viral context. We systematically reconstructed the HIV-1 packaging system in the context of a heterologous murine leukemia virus (MLV vector RNA to elucidate a mechanism in which the Rev/RRE system is central to achieving efficient and specific encapsidation into HIV-1 viral particles. Results We show for the first time that the Rev/RRE system can augment RNA encapsidation independent of all cis elements from the 5' UTR (R, U5, PBS, and ψ. Incorporation of all the 5' UTR cis elements did not enhance RNA encapsidation in the absence of the Rev/RRE system. In fact, we demonstrate that the Rev/RRE system is required for specific and efficient encapsidation commonly associated with the canonical packaging signal. The mechanism of Rev/RRE-mediated encapsidation is not a general phenomenon, since the combination of the Rev/RRE system and 5' UTR cis elements did not enhance encapsidation into MLV-derived viral particles. Lastly, we show that heterologous MLV RNAs conform to transduction properties commonly associated with HIV-1 viral particles, including in vivo transduction of non-dividing cells (i.e. mouse neurons; however, the cDNA forms are episomes predominantly in the 1-LTR circle form. Conclusions Premised on encapsidation of a heterologous RNA into

Forced sexual initiation, sexual intimate partner violence and HIV risk in women: A global review of the literature

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Stockman, Jamila K.; Lucea, Marguerite B.; Campbell, Jacquelyn C.

2012-01-01

Coerced or forced sexual initiation and sexual intimate partner violence (sexual IPV) contribute significantly to a woman’s risk for HIV infection. This review systematically examines global research (n=21 studies) published since 2000 on the role of coerced/forced sexual initiation and sexual IPV on HIV risk in women. In predominantly low- and middle-income countries, coerced/forced sexual initiation was associated with HIV/STIs, multiple and high-risk sex partners, and no condom use. Most studies using behaviorally specific terms for sexual IPV found strong associations between sexual IPV and HIV risk behaviors. In contrast, studies using less specific definitions often failed to find these significant associations. To develop more comprehensive HIV prevention programs, future efforts should integrate behaviorally specific terms into assessing prevalence of sexual IPV and its association with HIV risk, consider cultural differences, and identify causal pathways between coerced or forced sexual initiation, HIV risk behaviors and HIV/STI infection. PMID:23143750

Environmental variation and population responses to global change

NARCIS (Netherlands)

Lawson, Callum R.; Vindenes, Yngvild; Bailey, Liam; van de Pol, Martijn

2015-01-01

Species' responses to environmental changes such as global warming are affected not only by trends in mean conditions, but also by natural and human-induced environmental fluctuations. Methods are needed to predict how such environmental variation affects ecological and evolutionary processes, in

[HIV-1 genetic variability in non Spaniard infected children].

Science.gov (United States)

Piñeiro Pérez, R; Mellado Peña, M J; Holguín, A; Cilleruelo, M J; García Hortelano, M; Villota, J; Martín Fontelos, P

2009-01-01

The prevalence of HIV-1 non-B subtypes (HIV-NBS) is increasing in Europe, because of emigration from countries where genetic variants are endemic. Although HIV-NBS could have a different clinical evolution and could respond differently to antiretrovirals (AR) than B-subtypes, these variant's response remain undocumented. To identify HIV-1 genetic variants and to determine clinical evolution in a non-Spaniard children infected with HIV-1. Children with HIV-1 infection from endemic countries were tested for HIV-1 subtypes between 1-1-1988 and 31-12-2006. Twelve children less than 18 years old and born abroad were selected. HIV-NBS were isolated in 5 children (42%): CRF2_AG recombinant in 3 cases (Equatorial Guinea), Subtype C in one (Equatorial Guinea) and CRF13_cpx in last one (India). Because of the increasing frequency of patients with HIV-NBS and their unknown long-term evolution, all children from endemic countries should be tested for HIV subtypes. We believe new studies with more patients during longer times could reveal differences in these patient's clinical, immunological and virological evolution.

Comprehensive Cross-Clade Characterization of Antibody-Mediated Recognition, Complement-Mediated Lysis, and Cell-Mediated Cytotoxicity of HIV-1 Envelope-Specific Antibodies toward Eradication of the HIV-1 Reservoir.

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Mujib, Shariq; Liu, Jun; Rahman, A K M Nur-Ur; Schwartz, Jordan A; Bonner, Phil; Yue, Feng Yun; Ostrowski, Mario A

2017-08-15

eradication of HIV-1 in infected humans remains uncertain. In this study, we tested the ability of bnAbs to directly recognize and eliminate primary human CD4 T cells infected with diverse HIV-1 strains representative of the global epidemic by antibody-dependent pathways. We also tested several combinations of bnAbs in our assays in order to maximize the clearance of infected cells. We show that the ability of bnAbs to identify and kill infected cells is highly variable and that only a few of them are able to exert this function. Our data will help guide the formulation of bnAbs to test in future human trials aimed at the development of a cure. Copyright © 2017 American Society for Microbiology.

Comparison of the RealTime HIV-1, COBAS TaqMan 48 v1.0, Easy Q v1.2, and Versant v3.0 assays for Determination of HIV-1 Viral Loads in a Cohort of Canadian Patients with Diverse HIV Subtype Infections▿

OpenAIRE

Church, Deirdre; Gregson, Daniel; Lloyd, Tracie; Klein, Marina; Beckthold, Brenda; Laupland, Kevin; Gill, M. John

2010-01-01

HIV clinics in Canada provide care to an increasing number of patients born outside of Canada with HIV-1 non-B subtype infections. Because the Easy Q HIV-1 v1.2 assay (EQ; bioMérieux) failed to detect some non-B subtype infections, a multiassay HIV-1 viral load (VL) study was conducted with patients with diverse HIV subtype infections. Patients were enrolled from the Southern Alberta HIV Clinic (SAC), Calgary, Alberta, Canada (n = 349) and the McGill HIV Clinic (MHC), Montreal, Quebec, Canada...

HIV-1 viral load measurement in venous blood and fingerprick blood using Abbott RealTime HIV-1 DBS assay.

Science.gov (United States)

Tang, Ning; Pahalawatta, Vihanga; Frank, Andrea; Bagley, Zowie; Viana, Raquel; Lampinen, John; Leckie, Gregor; Huang, Shihai; Abravaya, Klara; Wallis, Carole L

2017-07-01

HIV RNA suppression is a key indicator for monitoring success of antiretroviral therapy. From a logistical perspective, viral load (VL) testing using Dried Blood Spots (DBS) is a promising alternative to plasma based VL testing in resource-limited settings. To evaluate the analytical and clinical performance of the Abbott RealTime HIV-1 assay using a fully automated one-spot DBS sample protocol. Limit of detection (LOD), linearity, lower limit of quantitation (LLQ), upper limit of quantitation (ULQ), and precision were determined using serial dilutions of HIV-1 Virology Quality Assurance stock (VQA Rush University), or HIV-1-containing armored RNA, made in venous blood. To evaluate correlation, bias, and agreement, 497 HIV-1 positive adult clinical samples were collected from Ivory Coast, Uganda and South Africa. For each HIV-1 participant, DBS-fingerprick, DBS-venous and plasma sample results were compared. Correlation and bias values were obtained. The sensitivity and specificity were analyzed at a threshold of 1000 HIV-1 copies/mL generated using the standard plasma protocol. The Abbott HIV-1 DBS protocol had an LOD of 839 copies/mL, a linear range from 500 to 1×10 7 copies/mL, an LLQ of 839 copies/mL, a ULQ of 1×10 7 copies/mL, and an inter-assay SD of ≤0.30 log copies/mL for all tested levels within this range. With clinical samples, the correlation coefficient (r value) was 0.896 between DBS-fingerprick and plasma and 0.901 between DBS-venous and plasma, and the bias was -0.07 log copies/mL between DBS-fingerprick and plasma and -0.02 log copies/mL between DBS-venous and plasma. The sensitivity of DBS-fingerprick and DBS-venous was 93%, while the specificity of both DBS methods was 95%. The results demonstrated that the Abbott RealTime HIV-1 assay with DBS sample protocol is highly sensitive, specific and precise across a wide dynamic range and correlates well with plasma values. The Abbott RealTime HIV-1 assay with DBS sample protocol provides an

Stimulation of HIV-1-specific cytolytic T-lymphocytes facilitates elimination of latent viral reservoir after virus reactivation

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Shan, Liang; Deng, Kai; Shroff, Neeta S.; Durand, Christine; Rabi, S. Alireza.; Yang, Hung-Chih; Zhang, Hao; Margolick, Joseph B.; Blankson, Joel N.; Siliciano, Robert F.

2012-01-01

Summary Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia. Life-long treatment is therefore required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T-cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4+ T cells survived despite viral cytopathic effects, even in the presence of autologous cytolytic T-lymphocytes (CTL) from most patients on HAART. Antigen-specific stimulation of patient CTLs led to efficient killing of infected cells. These results demonstrate that stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials. PMID:22406268

Sexually transmitted infections among HIV-1-discordant couples.

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Brandon L Guthrie

2009-12-01

Full Text Available More new HIV-1 infections occur within stable HIV-1-discordant couples than in any other group in Africa, and sexually transmitted infections (STIs may increase transmission risk among discordant couples, accounting for a large proportion of new HIV-1 infections. Understanding correlates of STIs among discordant couples will aid in optimizing interventions to prevent HIV-1 transmission in these couples.HIV-1-discordant couples in which HIV-1-infected partners were HSV-2-seropositive were tested for syphilis, chlamydia, gonorrhea, and trichomoniasis, and HIV-1-uninfected partners were tested for HSV-2. We assessed sociodemographic, behavioral, and biological correlates of a current STI.Of 416 couples enrolled, 16% were affected by a treatable STI, and among these both partners were infected in 17% of couples. A treatable STI was found in 46 (11% females and 30 (7% males. The most prevalent infections were trichomoniasis (5.9% and syphilis (2.6%. Participants were 5.9-fold more likely to have an STI if their partner had an STI (P<0.01, and STIs were more common among those reporting any unprotected sex (OR = 2.43; P<0.01 and those with low education (OR = 3.00; P<0.01. Among HIV-1-uninfected participants with an HSV-2-seropositive partner, females were significantly more likely to be HSV-2-seropositive than males (78% versus 50%, P<0.01.Treatable STIs were common among HIV-1-discordant couples and the majority of couples affected by an STI were discordant for the STI, with relatively high HSV-2 discordance. Awareness of STI correlates and treatment of both partners may reduce HIV-1 transmission.ClinicalTrials.gov NCT00194519.

Community study of the relative impact of HIV-1 and HIV-2 on intrathoracic tuberculosis

DEFF Research Database (Denmark)

Seng, R; Gustafson, P; Gomes, VF

2002-01-01

BACKGROUND: HIV-1 infection is associated with an increased incidence of and mortality from tuberculosis. Few community studies have examined the effect of HIV-2 on tuberculosis. METHODS: We investigated the association between HIV-1, HIV-2 and active tuberculosis in four districts (population 42...

Structural Study of a New HIV-1 Entry Inhibitor and Interaction with the HIV-1 Fusion Peptide in Dodecylphosphocholine Micelles.

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Pérez, Yolanda; Gómara, Maria José; Yuste, Eloísa; Gómez-Gutierrez, Patricia; Pérez, Juan Jesús; Haro, Isabel

2017-08-25

Previous studies support the hypothesis that the envelope GB virus C (GBV-C) E1 protein interferes the HIV-1 entry and that a peptide, derived from the region 139-156 of this protein, has been defined as a novel HIV-1 entry inhibitor. In this work, we firstly focus on the characterization of the structural features of this peptide, which are determinant for its anti-HIV-1 activity and secondly, on the study of its interaction with the proposed viral target (i.e., the HIV-1 fusion peptide). We report the structure of the peptide determined by NMR spectroscopy in dodecylphosphocholine (DPC) micelles solved by using restrained molecular dynamics calculations. The acquisition of different NMR experiments in DPC micelles (i.e., peptide-peptide titration, diffusion NMR spectroscopy, and addition of paramagnetic relaxation agents) allows a proposal of an inhibition mechanism. We conclude that a 18-mer peptide from the non-pathogenic E1 GBV-C protein, with a helix-turn-helix structure inhibits HIV-1 by binding to the HIV-1 fusion peptide at the membrane level, thereby interfering with those domains in the HIV-1, which are critical for stabilizing the six-helix bundle formation in a membranous environment. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Correlation between HIV-1 genotype and clinical progression in HIV/AIDS patients in Surabaya, Indonesia

Science.gov (United States)

Rachman, B. E.; Khairunisa, S. Q.; Witaningrum, A. M.; Yunifiar, M. Q.; Nasronudin

2018-03-01

Several factors such as host and viral factors can affect the progression of HIV/AIDS. This study aims to identify the correlation viral factors, especially the HIV-1 subtype with HIV/AIDS progression. Inpatient HIV/AIDS during the period March to September 2017 and willing to participate are included in the study. Historical data of disease and treatment was taken by medical record. Blood samples were amplified, sequenced and undergone phylogenetic analysis. Linear regression analysis was used to estimate beta coefficient (β) and 95%CI of HIV/AIDS progression (measured by the CD4 change rate, ΔCD4 cell count/time span in months).This study has 17 samples. The HIV-1 subtype was dominated by CRF01_AE (81.8%) followed by subtype B (18.2%). There was significant correlation between subtype HIV-1 (p = 0.04) and body mass index (p = 0.038) with HIV/AIDS clinical stage. Many factors were assumed to be correlated with increased rate of CD4, but we only subtype HIV-1 had a significant correlation (p = 0.024) with it. From multivariate analysis, we also found that subtype HIV-1 had a significant correlation (β = 0.788, 95%CI: 17.5-38.6, p = 0.004).

Impact of global health governance on country health systems: the case of HIV initiatives in Nigeria.

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Chima, Charles Chikodili; Homedes, Nuria

2015-06-01

Three global health initiatives (GHIs) - the US President's Emergency Plan for AIDS Relief, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the World Bank Multi-Country HIV/AIDS Program - finance most HIV services in Nigeria. Critics assert that GHIs burden fragile health systems in resource-poor countries and that health system limitations in these countries constrain the achievement of the objectives of GHIs. This study analyzed interactions between HIV GHIs and the Nigerian Health System and explored how the impact of the GHIs could be optimized. A country case study was conducted using qualitative methods, including: semi-structured interviews, direct observation, and archival review. Semi-structured interviews were held with key informants selected to reach a broad range of stakeholders including policymakers, program managers, service providers, representatives of donor agencies and their implementing partners; the WHO country office in Nigeria; independent consultants; and civil society organizations involved in HIV work. The fieldwork was conducted between June and August 2013. HIV GHIs have had a mixed impact on the health system. They have enhanced availability of and access to HIV services, improved quality of services, and strengthened health information systems and the role of non-state actors in health care. On the negative end, HIV donor funding has increased dependency on foreign aid, widened disparities in access to HIV services, done little to address the sustainability of the services, crowded out non-HIV health services, and led to the development of a parallel supply management system. They have also not invested significantly in the production of new health workers and have not addressed maldistribution problems, but have rather contributed to internal brain drain by luring health workers from the public sector to non-governmental organizations and have increased workload for existing health workers. There is poor policy direction

Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota

Science.gov (United States)

Nunn, Kenetta L.; Wang, Ying-Ying; Harit, Dimple; Humphrys, Michael S.; Ma, Bing; Cone, Richard; Ravel, Jacques

2015-01-01

ABSTRACT Cervicovaginal mucus (CVM) can provide a barrier that precludes HIV and other sexually transmitted virions from reaching target cells in the vaginal epithelium, thereby preventing or reducing infections. However, the barrier properties of CVM differ from woman to woman, and the causes of these variations are not yet well understood. Using high-resolution particle tracking of fluorescent HIV-1 pseudoviruses, we found that neither pH nor Nugent scores nor total lactic acid levels correlated significantly with virus trapping in unmodified CVM from diverse donors. Surprisingly, HIV-1 was generally trapped in CVM with relatively high concentrations of d-lactic acid and a Lactobacillus crispatus-dominant microbiota. In contrast, a substantial fraction of HIV-1 virions diffused rapidly through CVM with low concentrations of d-lactic acid that had a Lactobacillus iners-dominant microbiota or significant amounts of Gardnerella vaginalis, a bacterium associated with bacterial vaginosis. Our results demonstrate that the vaginal microbiota, including specific species of Lactobacillus, can alter the diffusional barrier properties of CVM against HIV and likely other sexually transmitted viruses and that these microbiota-associated changes may account in part for the elevated risks of HIV acquisition linked to bacterial vaginosis or intermediate vaginal microbiota. PMID:26443453

Molecular docking of (5E)-3-(2-aminoethyl)-5-(2- thienylmethylene)-1, 3-thiazolidine-2, 4-dione on HIV-1 reverse transcriptase: novel drug acting on enzyme.

Science.gov (United States)

Seniya, Chandrabhan; Yadav, Ajay; Uchadia, Kuldeep; Kumar, Sanjay; Sagar, Nitin; Shrivastava, Priyanka; Shrivastava, Shilpi; Wadhwa, Gulshan

2012-01-01

The study of Human immunodeficiency virus (HIV) in humans and animal models in last 31 years suggested that it is a causative agent of AIDS. This causes serious pandemic public health concern globally. It was reported that the HIV-1 reverse transcriptase (RT) played a critical role in the life cycle of HIV. Therefore, inhibition of HIV-1RT enzyme is one of the major and potential targets in the treatment of AIDS. The enzyme (HIV-1RT) was successfully targeted by non nucleotide reverse transcriptase inhibitors (NNRTIs). But frequent application of NNRTIs led drug resistance mutation on HIV infections. Therefore, there is a need to search new NNRTIs with appropriate pharmacophores. For the purpose, a virtually screened 3D model of unliganded HIV-1RT (1DLO) was explored. The unliganded HIV-1RT (1DLO) was docked with 4-thiazolidinone and its derivatives (ChemBank Database) by using AutoDock4. The best seven docking solutions complex were selected and analyzed by Ligplot. The analysis showed that derivative (5E)-3-(2- aminoethyl)-5-(2- thienylmethylene)-1, 3-thiazolidine-2, 4-dione (CID 3087795) has maximum potential against unliganded HIV-1RT (1DLO). The analysis was done on the basis of scoring and binding ability. The derivative (5E)-3-(2- aminoethyl)-5-(2- thienylmethylene)-1, 3-thiazolidine-2, 4-dione (CID 3087795) indicated minimum energy score and highest number of interactions with active site residue and could be a promising inhibitor for HIV-1 RT as Drug target.

Cyclophilin B enhances HIV-1 infection.

Science.gov (United States)

DeBoer, Jason; Madson, Christian J; Belshan, Michael

2016-02-01

Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. Copyright © 2015 Elsevier Inc. All rights reserved.

Standardization of a cytometric p24-capture bead-assay for the detection of main HIV-1 subtypes.

Science.gov (United States)

Merbah, Mélanie; Onkar, Sayali; Grivel, Jean-Charles; Vanpouille, Christophe; Biancotto, Angélique; Bonar, Lydia; Sanders-Buell, Eric; Kijak, Gustavo; Michael, Nelson; Robb, Merlin; Kim, Jerome H; Tovanabutra, Sodsai; Chenine, Agnès-Laurence

2016-04-01

The prevailing method to assess HIV-1 replication and infectivity is to measure the production of p24 Gag protein by enzyme-linked immunosorbent assay (ELISA). Since fluorescent bead-based technologies offer a broader dynamic range and higher sensitivity, this study describes a p24 capture Luminex assay capable of detecting HIV-1 subtypes A-D, circulating recombinant forms (CRF) CRF01_AE and CRF02_AG, which together are responsible for over 90% of HIV-1 infections worldwide. The success of the assay lies in the identification and selection of a cross-reactive capture antibody (clone 183-H12-5C). Fifty-six isolates that belonged to six HIV-1 subtypes and CRFs were successfully detected with p-values below 0.021; limits of detection ranging from 3.7 to 3 × 104 pg/ml. The intra- and inter-assay variation gave coefficient of variations below 6 and 14%, respectively. The 183-bead Luminex assay also displayed higher sensitivity of 91% and 98% compared to commercial p24 ELISA and a previously described Luminex assay. The p24 concentrations measured by the 183-bead Luminex assay showed a significant correlation (R=0.92, passay leverages the advantages of the Luminex platform, which include smaller sample volume and simultaneous detection of up to 500 analytes in a single sample, and delivers a valuable tool for the field. Copyright © 2016 Elsevier B.V. All rights reserved.

Appreciating HIV-1 diversity: subtypic differences in ENV

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Gnanakaran, S [Los Alamos National Laboratory; Shen, Tongye [Los Alamos National Laboratory; Lynch, Rebecca M [NON LANL; Derdeyn, Cynthia A [NON LANL

2008-01-01

Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of inter-subtype diversity. Recent studies have revealed that the HIV-1 subtypes exhibit phenotypic differences that result from subtle differences in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtypic differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most prevalent subtype globally.

HIV-1 gp120 and drugs of abuse: interactions in the central nervous system.

Science.gov (United States)

Silverstein, Peter S; Shah, Ankit; Weemhoff, James; Kumar, Santosh; Singh, D P; Kumar, Anil

2012-07-01

HIV-1 infection is a global public health problem with more than 34 million people living with HIV infection. Although great strides have been made in treating this epidemic with therapeutic agents, the increase in patient life span has been coincident with an increase in the prevalence of HIV-associated neurocognitive disorders (HAND). HAND is thought to result from the neurotoxic effects of viral proteins that are shed from HIV-infected microglial cells. One of the primary neurotoxins responsible for this effect is the HIV-1 glycoprotein gp120. Exposure of neurons to gp120 has been demonstrated to cause apoptosis in neurons, as well as numerous indirect effects such as an increase in inflammatory cytokines, an increase in oxidative stress, and an increase in permeability of the blood-brain barrier. In many patients, the use of drugs of abuse (DOA) exacerbates the neurotoxic effects of gp120. Cocaine, methamphetamine and morphine are three DOAs that are commonly used by those infected with HIV-1. All three of these DOAs have been demonstrated to increase oxidative stress in the CNS as well as to increase permeability of the blood-brain barrier. Numerous model systems have demonstrated that these DOAs have the capability of exacerbating the neurotoxic effects of gp120. This review will summarize the neurotoxic effects of gp120, the deleterious effects of cocaine, methamphetamine and morphine on the CNS, and the combined effects of gp120 in the context of these drugs.

The Case for Adolescent HIV Vaccination in South Africa: A Cost-Effectiveness Analysis.

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Moodley, Nishila; Gray, Glenda; Bertram, Melanie

2016-01-01

Despite comprising 0.7% of the world population, South Africa is home to 18% of the global human immunodeficiency virus (HIV) prevalence. Unyielding HIV subepidemics among adolescents threaten national attempts to curtail the disease burden. Should an HIV vaccine become available, establishing its point of entry into the health system becomes a priority. This study assesses the impact of school-based HIV vaccination and explores how variations in vaccine characteristics affect cost-effectiveness. The cost per quality adjusted life year (QALY) gained associated with school-based adolescent HIV vaccination services was assessed using Markov modeling that simulated annual cycles based on national costing data. The estimation was based on a life expectancy of 70 years and employs the health care provider perspective. The simultaneous implementation of HIV vaccination services with current HIV management programs would be cost-effective, even at relatively higher vaccine cost. At base vaccine cost of US$ 12, the incremental cost effectiveness ratio (ICER) was US$ 43 per QALY gained, with improved ICER values yielded at lower vaccine costs. The ICER was sensitive to duration of vaccine mediated protection and variations in vaccine efficacy. Data from this work demonstrate that vaccines offering longer duration of protection and at lower cost would result in improved ICER values. School-based HIV vaccine services of adolescents, in addition to current HIV prevention and treatment health services delivered, would be cost-effective.

The private sector role in HIV/AIDS in the context of an expanded global response: expenditure trends in five sub-Saharan African countries.

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Sulzbach, Sara; De, Susna; Wang, Wenjuan

2011-07-01

Global financing for the HIV response has reached unprecedented levels in recent years. Over US$10 billion were mobilized in 2007, an effort credited with saving the lives of millions of people living with HIV (PLHIV). A relatively unexamined aspect of the global HIV response is the role of the private sector in financing HIV/AIDS services. As the nature of the response evolves from emergency relief to long-term sustainability, understanding current and potential contributions from the private sector is critical. This paper examines trends in private sector financing, management and resource consumption related to HIV/AIDS in five sub-Saharan African countries, with a particular emphasis on the effects of recently scaled-up donor funding on private sector contributions. We analysed National Health Accounts HIV/AIDS subaccount data for Kenya, Malawi, Rwanda, Tanzania and Zambia between 2002 and 2006. HIV subaccounts provide comparable data on the flow of HIV/AIDS funding from source to use. Findings indicate that private sector contributions decreased in all countries except Tanzania. With regards to managing HIV/AIDS funds, non-governmental organizations are increasingly controlling the largest share of resources relative to other stakeholders, whereas private for-profit entities are managing fewer HIV/AIDS resources since the donor influx. The majority of HIV/AIDS funds were spent in the public sector, although a considerable amount was spent at private facilities, largely fuelled by out-of-pocket (OOP) payments. On the whole, OOP spending by PLHIV decreased over the 4-year period, with the exception of Malawi, demonstrating that PLHIV have increased access to free or subsidized HIV/AIDS services. Our findings suggest that the influx of donor funding has led to decreased private contributions for HIV/AIDS. The reduction in private sector investment and engagement raises concerns about the sustainability of HIV/AIDS programmes over the long term, particularly in

Field evaluation of an open and polyvalent universal HIV-1/SIVcpz/SIVgor quantitative RT-PCR assay for HIV-1 viral load monitoring in comparison to Abbott RealTime HIV-1 in Cameroon.

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Guichet, Emilande; Aghokeng, Avelin; Eymard-Duvernay, Sabrina; Vidal, Nicole; Ayouba, Ahidjo; Mpoudi Ngole, Eitel; Delaporte, Eric; Ciaffi, Laura; Peeters, Martine

2016-11-01

With the increasing demand of HIV viral load (VL) tests in resource-limited countries (RLCs) there is a need for assays at affordable cost and able to quantify all known HIV-1 variants. VLs obtained with a recently developed open and polyvalent universal HIV-1/SIVcpz/SIVgor RT-qPCR were compared to Abbott RealTime HIV-1 assay in Cameroon. On 474 plasma samples, characterized by a wide range of VLs and a broad HIV-1 group M genetic diversity, 97.5% concordance was observed when using the lower detection limit of each assay. When using the threshold of 3.00 log 10 copies/mL, according to WHO guidelines to define virological failure (VF) in RLCs, the concordance was 94.7%, 360/474 versus 339/474 patients were identified with VF with the new assay and Abbott RealTime HIV-1, respectively. Higher VLs were measured with the new assay, +0.47 log 10 copies/mL (95% CI; 0.42-0.52) as shown with Bland-Altman analysis. Eleven samples from patients on VF with drug resistance were not detected by Abbott RealTime HIV-1 versus two only with the new assay. Overall, our study showed that the new assay can be easily implemented in a laboratory in RLCs with VL experience and showed good performance on a wide diversity of HIV-1 group M variants. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression.

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Peter Messiaen

Full Text Available BACKGROUND: As Lens epithelium-derived growth factor (LEDGF/p75 is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs. Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs. METHODS: Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs in the coding region, flanking intronic regions and full 3'UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC using RT-qPCR. RESULTS: 325 samples were investigated from patients of Caucasian (n = 291 and African (n = 34 origin, including Elite (n = 49 and Viremic controllers (n = 62. 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3'UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828 was significantly under-represented in Caucasian patients (P<0.0001 compared to healthy controls (HapMap. Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression. CONCLUSIONS: LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further

Evaluation of four rapid tests for diagnosis and differentiation of HIV-1 and HIV-2 infections in Guinea-Conakry, West Africa.

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Chaillet, Pascale; Tayler-Smith, Katie; Zachariah, Rony; Duclos, Nanfack; Moctar, Diallo; Beelaert, Greet; Fransen, Katrien

2010-09-01

With both HIV-1 and HV-2 prevalent in Guinea-Conakry, accurate diagnosis and differentiation is crucial for treatment purposes. Thus, four rapid HIV tests were evaluated for their HIV-1 and HIV-2 diagnostic and discriminative capacity for use in Guinea-Conakry. These included SD Bioline HIV 1/2 3.0 (Standard Diagnostics Inc.), Genie II HIV1/HIV2 (Bio-Rad), First Response HIV Card Test 1-2.0 (PMC Medical) and Immunoflow HIV1-HIV2 (Core Diagnostics). Results were compared with gold standard tests (INNO-LIA HIV-I/II Score) and NEW LAV BLOT II (Bio-Rad). Four hundred and forty three sequential stored HIV-positive serum samples, of known HIV-type, were evaluated. Genie II HIV1/HIV2, Immunoflow HIV1-HIV2 and SD Bioline HIV 1/2 3.0 had 100% sensitivity (95% CI, 98.9-100%) while for First Response HIV Card Test 1-2.0 this was 99.5% (95% CI, 98.2%-99.9%). In terms of discriminatory capacity, Genie II HIV1/HIV2 identified 382/ 384(99.5%) HIV-1 samples, 49/ 52(95%) HIV-2 and 7/7(100%) HIV-positive untypable samples. Immunoflow HIV1-HIV2 identified 99% HIV-1, 67% HIV-2 and all HIV-positive untypable samples. First Response HIV Card Test 1-2.0 identified 94% HIV-1, 64% HIV-2 and 57% HIV-positive untypable samples. SD-Bioline HIV 1/2 3.0 was the worst overall performer identifying 65% HIV-1, 69% HIV-2 and all HIV-positive untypable samples. The use of SD Bioline HIV 1/2 3.0 (the current standard in Guinea-Conakry) as a discriminatory HIV test is poor and may be best replaced by Immunoflow HIV1-HIV2. Copyright 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Role of sex hormones and the vaginal microbiome in susceptibility and mucosal immunity to HIV-1 in the female genital tract.

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Vitali, Danielle; Wessels, Jocelyn M; Kaushic, Charu

2017-09-12

While the prevalence of Human immunodeficiency virus-1 (HIV-1) infection has stabilized globally, it continues to be the leading cause of death among women of reproductive age. The majority of new infections are transmitted heterosexually, and women have consistently been found to be more susceptible to HIV-1 infection during heterosexual intercourse compared to men. This emphasizes the need for a deeper understanding of how the microenvironment in the female genital tract (FGT) could influence HIV-1 acquisition. This short review focuses on our current understanding of the interplay between estrogen, progesterone, and the cervicovaginal microbiome and their immunomodulatory effects on the FGT. The role of hormonal contraceptives and bacterial vaginosis on tissue inflammation, T cell immunity and HIV-1 susceptibility is discussed. Taken together, this review provides valuable information for the future development of multi-purpose interventions to prevent HIV-1 infection in women.

Introduction to a Special Issue of the Journal of Immunological Methods: Building global resource programs to support HIV/AIDS clinical trial studies.

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Sanchez, Ana M; Denny, Thomas N; O'Gorman, Maurice

2014-07-01

This Special Issue of the Journal of Immunological Methods includes 16 manuscripts describing quality assurance activities related to virologic and immunologic monitoring of six global laboratory resource programs that support international HIV/AIDS clinical trial studies: Collaboration for AIDS Vaccine Discovery (CAVD); Center for HIV/AIDS Vaccine Immunology (CHAVI); External Quality Assurance Program Oversight Laboratory (EQAPOL); HIV Vaccine Trial Network (HVTN); International AIDS Vaccine Initiative (IAVI); and Immunology Quality Assessment (IQA). The reports from these programs address the many components required to develop comprehensive quality control activities and subsequent quality assurance programs for immune monitoring in global clinical trials including: all aspects of processing, storing, and quality assessment of PBMC preparations used ubiquitously in HIV clinical trials, the development and optimization of assays for CD8 HIV responses and HIV neutralization, a comprehensive global HIV virus repository, and reports on the development and execution of novel external proficiency testing programs for immunophenotyping, intracellular cytokine staining, ELISPOT and luminex based cytokine measurements. In addition, there are articles describing the implementation of Good Clinical Laboratory Practices (GCLP) in a large quality assurance laboratory, the development of statistical methods specific for external proficiency testing assessment, a discussion on the ability to set objective thresholds for measuring rare events by flow cytometry, and finally, a manuscript which addresses a framework for the structured reporting of T cell immune function based assays. It is anticipated that this series of manuscripts covering a wide range of quality assurance activities associated with the conduct of global clinical trials will provide a resource for individuals and programs involved in improving the harmonization, standardization, accuracy, and sensitivity of

Cross-country Association of Press Freedom and LGBT freedom with prevalence of persons living with HIV: implication for global strategy against HIV/AIDS.

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Chen, Xinguang; Elliott, Amy L; Wang, Shuang

2018-01-01

Human behaviors are affected by attitudes and beliefs, which in turn are shaped by higher-level values to which we have ascribed. In this study, we explore the relationship between two higher-level values, press freedom and LGBT freedom, and HIV infection with national data at the population level. Data were the number of persons living with HIV (PLWH, n  = 35,468,911) for 148 countries during 2011-15, press freedom index (PFI) determined by the Reporters Without Borders, and LGBT freedom index (LGBT-FI) based on laws regulating same-sex relationships and expression. PLWH prevalence (1/1000), PFI and LGBT-FI were mapped first. Multiple regression was thus used to associate the logarithm of PLWH prevalence with PFI, LGBT-FI and PFI × LGBT-FI interaction, controlling for per capita GDP and weighted by population size. Global prevalence of PLWH during 2011-15 was 0.51 per 1000 population. The prevalence showed a geographic pattern moving from high at the south and west ends of the world map to low at the north and east. Both PFI and LGBT-FI were positively associated with PLWH prevalence with a negative interaction between the two. More people are infected with HIV in countries with higher press freedom and higher LGBT freedom. Furthermore, press freedom can attenuate the positive association between levels of LGBT freedom and risk of HIV infection. This study demonstrated the urgency for and provided data supporting further research to investigate potential cultural and socioecological mechanisms underpinning the complex relationship among press freedom, LGBT freedom and HIV infection, with data collected at the individual level.

HIV-1 proteins dysregulate motivational processes and dopamine circuitry.

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Bertrand, Sarah J; Mactutus, Charles F; Harrod, Steven B; Moran, Landhing M; Booze, Rosemarie M

2018-05-18

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1-30%, w/v) and cocaine (0.01-1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC 50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

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.

Fibroblast growth factors 1 and 2 in cerebrospinal fluid are associated with HIV disease, methamphetamine use, and neurocognitive functioning

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Bharti AR

2016-04-01

Full Text Available Ajay R Bharti,1 Steven Paul Woods,2 Ronald J Ellis,3 Mariana Cherner,2 Debra Rosario,3 Michael Potter,3 Robert K Heaton,2 Ian P Everall,4 Eliezer Masliah,5 Igor Grant,2 Scott L Letendre1 On behalf of the Translational Methamphetamine AIDS Research Center Group 1Department of Medicine, 2Department of Psychiatry, 3Department of Neurosciences, University of California San Diego, San Diego, CA, USA; 4Department of Psychiatry, University of Melbourne, Victoria, Australia; 5Department of Pathology, University of Californa San Diego, San Diego, CA, USA Background: Human immunodeficiency virus (HIV and methamphetamine use commonly affect neurocognitive (NC functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD. Methods: A total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin. Comprehensive NC testing was summarized by global and domain impairment ratings. Results: Sixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV– and MAD– controls (P=0.003. Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R2=0.09, P=0.01: higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use strengthened the model (model R2=0.18, P=0.004 but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment

Sieve analysis in HIV-1 vaccine efficacy trials.

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Edlefsen, Paul T; Gilbert, Peter B; Rolland, Morgane

2013-09-01

The genetic characterization of HIV-1 breakthrough infections in vaccine and placebo recipients offers new ways to assess vaccine efficacy trials. Statistical and sequence analysis methods provide opportunities to mine the mechanisms behind the effect of an HIV vaccine. The release of results from two HIV-1 vaccine efficacy trials, Step/HVTN-502 (HIV Vaccine Trials Network-502) and RV144, led to numerous studies in the last 5 years, including efforts to sequence HIV-1 breakthrough infections and compare viral characteristics between the vaccine and placebo groups. Novel genetic and statistical analysis methods uncovered features that distinguished founder viruses isolated from vaccinees from those isolated from placebo recipients, and identified HIV-1 genetic targets of vaccine-induced immune responses. Studies of HIV-1 breakthrough infections in vaccine efficacy trials can provide an independent confirmation to correlates of risk studies, as they take advantage of vaccine/placebo comparisons, whereas correlates of risk analyses are limited to vaccine recipients. Through the identification of viral determinants impacted by vaccine-mediated host immune responses, sieve analyses can shed light on potential mechanisms of vaccine protection.

Constitutively Active MAVS Inhibits HIV-1 Replication via Type I Interferon Secretion and Induction of HIV-1 Restriction Factors.

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Sachin Gupta

Full Text Available Type I interferon is known to inhibit HIV-1 replication through the induction of interferon stimulated genes (ISG, including a number of HIV-1 restriction factors. To better understand interferon-mediated HIV-1 restriction, we constructed a constitutively active form of the RIG-I adapter protein MAVS. Constitutive MAVS was generated by fusion of full length MAVS to a truncated form of the Epstein Barr virus protein LMP1 (ΔLMP1. Supernatant from ΔLMP1-MAVS-transfected 293T cells contained high levels of type I interferons and inhibited HIV replication in both TZM-bl and primary human CD4+ T cells. Supernatant from ΔLMP1-MAVS-transfected 293T cells also inhibited replication of VSV-G pseudotyped single cycle SIV in TZM-bl cells, suggesting restriction was post-entry and common to both HIV and SIV. Gene array analysis of ΔLMP1-MAVS-transfected 293T cells and trans-activated CD4+ T cells showed significant upregulation of ISG, including previously characterized HIV restriction factors Viperin, Tetherin, MxB, and ISG56. Interferon blockade studies implicated interferon-beta in this response. In addition to direct viral inhibition, ΔLMP1-MAVS markedly enhanced secretion of IFN-β and IL-12p70 by dendritic cells and the activation and maturation of dendritic cells. Based on this immunostimulatory activity, an adenoviral vector (Ad5 expressing ΔLMP1-MAVS was tested as a molecular adjuvant in an HIV vaccine mouse model. Ad5-Gag antigen combined with Ad5-ΔLMP1-MAVS enhanced control of vaccinia-gag replication in a mouse challenge model, with 4/5 animals showing undetectable virus following challenge. Overall, ΔLMP1-MAVS is a promising reagent to inhibit HIV-1 replication in infected tissues and enhance vaccine-mediated immune responses, while avoiding toxicity associated with systemic type I interferon administration.

Timing is everything: international variations in historical sexual partnership concurrency and HIV prevalence.

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Martina Morris

Full Text Available BACKGROUND: Higher prevalence of concurrent partnerships is one hypothesis for the severity of the HIV epidemic in the countries of Southern Africa. But measures of the prevalence of concurrency alone do not adequately capture the impact concurrency will have on transmission dynamics. The importance of overlap duration and coital exposure are examined here. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a comparison of data from three studies of sexual behavior carried out in the early 1990s in Uganda, Thailand and the US. Using cumulative concurrency measures, the three countries appeared somewhat similar. Over 50% of both Thai and Ugandan men reported a concurrency within the last three partnerships and over 20% reported a concurrency in the last year, the corresponding rates among US men were nearly 20% for Blacks and Hispanics, and about 10% for other racial/ethnic groups. Concurrency measures that were more sensitive to overlap duration, however, showed large differences. The point prevalence of concurrency on the day of interview was over 10% among Ugandan men compared to 1% for Thai men. Ugandan concurrencies were much longer duration - a median of about two years - than either the Thai (1 day or US concurrencies (4-9 months across all groups, and involved 5-10 times more coital risk exposure with the less frequent partner. In the US, Blacks and Hispanics reported higher prevalence, longer duration and greater coital exposure than Whites, but were lower than Ugandans on nearly every measure. Together, the differences in the prevalence, duration and coital exposure of concurrent partnerships observed align with the HIV prevalence differentials seen in these populations at the time the data were collected. CONCLUSIONS/SIGNIFICANCE: There were substantial variations in the patterns of concurrent partnerships within and between populations. More long-term overlapping partnerships, with regular coital exposure, were found in populations with

Optimization and validation of a neutralizing antibody assay for HIV-1 in A3R5 cells.

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Sarzotti-Kelsoe, Marcella; Daniell, Xiaoju; Todd, Christopher A; Bilska, Miroslawa; Martelli, Amanda; LaBranche, Celia; Perez, Lautaro G; Ochsenbauer, Christina; Kappes, John C; Rountree, Wes; Denny, Thomas N; Montefiori, David C

2014-07-01

A3R5 is a human CD4(+) lymphoblastoid cell line that was engineered to express CCR5 and is useful for the detection of weak neutralizing antibody responses against tier 2 strains of HIV-1. Here we describe the optimization and validation of the HIV-1 neutralizing antibody assay that utilizes A3R5 cells, performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines. The assay utilizes Renilla luciferase-expressing replication competent infectious molecular clones (IMC) encoding heterologous env genes from different HIV-1 clades. Key assay validation parameters tested included specificity, accuracy, precision, limit of detection and quantitation, specificity, linearity and range, and robustness. Plasma samples demonstrated higher non-specific activity than serum samples in the A3R5 assay. This assay can tolerate a wide range of virus input but is more sensitive to cell concentration. The higher sensitivity of the A3R5 assay in neutralization responses to tier 2 strains of HIV-1 makes it complementary to, but not a substitute for the TZM-bl assay. The validated A3R5 assay is employed as an endpoint immunogenicity test for vaccine-elicited neutralizing antibodies against tier 2 strains of HIV-1, and to identify correlates of protection in HIV-1 vaccine trials conducted globally. Copyright © 2014 Elsevier B.V. All rights reserved.

CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals.

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Kulkarni, Hemant; Agan, Brian K; Marconi, Vincent C; O'Connell, Robert J; Camargo, Jose F; He, Weijing; Delmar, Judith; Phelps, Kenneth R; Crawford, George; Clark, Robert A; Dolan, Matthew J; Ahuja, Sunil K

2008-09-08

Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management

Frequency and site mapping of HIV-1/SIVcpz, HIV- 2/SIVsmm and ...

African Journals Online (AJOL)

out to analyze the effects of various restriction enzymes on the HIV genome. A computer simulated model using Web cutter Version 2.0, and cytogenetic analysis. 339 restriction enzymes from Promega database, 10 HIV-1/SIVcpz genes, 10 HIV-2/SIVsmm genes and 10 other SIV genes. Gene sequences were fed into Web ...

Reduced HIV symptoms and improved health-related quality of life correlate with better access to care for HIV-1 infected women: the ELLA study.

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Baran, Robert; Mulcahy, Fiona; Krznaric, Ivanka; Monforte, Antonella d'Arminio; Samarina, Anna; Xi, He; Cassetti, Isabel; Madruga, Jose Valdez; Zachry, Woodie; van Wyk, Jean; Martinez, Marisol

2014-01-01

Global HIV-1 prevalence is 35.3 million [1]; women comprise >50% of those infected. The majority of women may lack regular care and only one-fourth are virologically suppressed [2]. ELLA is a cross-sectional, non-interventional study conducted across Europe, Latin America, Canada and Asia that describes barriers to care for HIV-infected women and associations with disease stage, symptoms and health-related quality of life (HRQoL). HIV-infected women eligible for ELLA (≥18 years) completed: Barrier to Care Scale (BACS) comprising 12 items in four domains (Index range 0-12, Overall range 1-4, greater=more barriers, Overall score ≥2 considered severe); AIDS Clinical Trials Group (ACTG) Health Status Assessment comprising 21 items assessing 9 HRQoL domains (range 0-100, greater=better); and ACTG Symptom Distress Module comprising 20 symptoms rated on bother (range 0-4, greater=more bother). Healthcare providers documented medical history and HIV clinical data. Correlations of BACS response and last reported VL/CD4 count with HIV symptoms and HRQoL were analyzed. Spearman rank order was used to test correlations with statistical significance set at p50 years); 47.7% education HIV was acquired heterosexually in 83.0%; 88.2% of subjects were on ART; 57.5% had VLsymptom count and less symptom bother (psymptom count and less symptom bother correlated with better HRQoL on all nine domains (pHIV symptoms and less bother (pHIV-infected women, reduced barriers to care correlated with fewer symptoms, less symptom bother and better HRQoL. Improved HRQoL may be mediated by greater CD4 counts and fewer symptoms. Better access to care may improve HRQoL outcomes in this population.

Global Health Diplomacy, "San Francisco Values," and HIV/AIDS: From the Local to the Global.

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Kevany, Sebastian

2015-01-01

San Francisco has a distinguished history as a cosmopolitan, progressive, and international city, including extensive associations with global health. These circumstances have contributed to new, interdisciplinary scholarship in the field of global health diplomacy (GHD). In the present review, we describe the evolution and history of GHD at the practical and theoretical levels within the San Francisco medical community, trace related associations between the local and the global, and propose a range of potential opportunities for further development of this dynamic field. We provide a historical overview of the development of the "San Francisco Model" of collaborative, community-owned HIV/AIDS treatment and care programs as pioneered under the "Ward 86" paradigm of the 1980s. We traced the expansion and evolution of this model to the national level under the Ryan White Care Act, and internationally via the President's Emergency Plan for AIDS Relief. In parallel, we describe the evolution of global health diplomacy practices, from the local to the global, including the integration of GHD principles into intervention design to ensure social, political, and cultural acceptability and sensitivity. Global health programs, as informed by lessons learned from the San Francisco Model, are increasingly aligned with diplomatic principles and practices. This awareness has aided implementation, allowed policymakers to pursue related and progressive social and humanitarian issues in conjunction with medical responses, and elevated global health to the realm of "high politics." In the 21st century, the integration between diplomatic, medical, and global health practices will continue under "smart global health" and GHD paradigms. These approaches will enhance intervention cost-effectiveness by addressing and optimizing, in tandem with each other, a wide range of (health and non-health) foreign policy, diplomatic, security, and economic priorities in a synergistic manner

The utility of protein structure as a predictor of site-wise dN/dS varies widely among HIV-1 proteins.

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Meyer, Austin G; Wilke, Claus O

2015-10-06

Protein structure acts as a general constraint on the evolution of viral proteins. One widely recognized structural constraint explaining evolutionary variation among sites is the relative solvent accessibility (RSA) of residues in the folded protein. In influenza virus, the distance from functional sites has been found to explain an additional portion of the evolutionary variation in the external antigenic proteins. However, to what extent RSA and distance from a reference site in the protein can be used more generally to explain protein adaptation in other viruses and in the different proteins of any given virus remains an open question. To address this question, we have carried out an analysis of the distribution and structural predictors of site-wise dN/dS in HIV-1. Our results indicate that the distribution of dN/dS in HIV follows a smooth gamma distribution, with no special enrichment or depletion of sites with dN/dS at or above one. The variation in dN/dS can be partially explained by RSA and distance from a reference site in the protein, but these structural constraints do not act uniformly among the different HIV-1 proteins. Structural constraints are highly predictive in just one of the three enzymes and one of three structural proteins in HIV-1. For these two proteins, the protease enzyme and the gp120 structural protein, structure explains between 30 and 40% of the variation in dN/dS. Finally, for the gp120 protein of the receptor-binding complex, we also find that glycosylation sites explain just 2% of the variation in dN/dS and do not explain gp120 evolution independently of either RSA or distance from the apical surface. © 2015 The Author(s).

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.

Dual-mixed HIV-1 coreceptor tropism and HIV-associated neurocognitive deficits.

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Morris, Sheldon R; Woods, Steven Paul; Deutsch, Reena; Little, Susan J; Wagner, Gabriel; Morgan, Erin E; Heaton, Robert K; Letendre, Scott L; Grant, Igor; Smith, Davey M

2013-10-01

HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described. This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to four sequential neurocognitive assessments over a median of 160 days (IQR, 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count, and problematic methamphetamine use. Six subjects (8.3 %) had DM at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR, 7.2–12.2). There were 44 (61.1 %) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio, 4.4; 95 % CI, 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier; 95 % CI, 1.0–1.2). This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together, these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.

Are slum dwellers at heightened risk of HIV infection than other urban residents? Evidence from population-based HIV prevalence surveys in Kenya.

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Madise, Nyovani J; Ziraba, Abdhalah K; Inungu, Joseph; Khamadi, Samoel A; Ezeh, Alex; Zulu, Eliya M; Kebaso, John; Okoth, Vincent; Mwau, Matilu

2012-09-01

In 2008, the global urban population surpassed the rural population and by 2050 more than 6 billion will be living in urban centres. A growing body of research has reported on poor health outcomes among the urban poor but not much is known about HIV prevalence among this group. A survey of nearly 3000 men and women was conducted in two Nairobi slums in Kenya between 2006 and 2007, where respondents were tested for HIV status. In addition, data from the 2008/2009 Kenya Demographic and Health Survey were used to compare HIV prevalence between slum residents and those living in other urban and rural areas. The results showed strong intra-urban differences. HIV was 12% among slum residents compared with 5% and 6% among non-slum urban and rural residents, respectively. Generally, men had lower HIV prevalence than women although in the slums the gap was narrower. Among women, sexual experience before the age of 15 compared with after 19 years was associated with 62% higher odds of being HIV positive. There was ethnic variation in patterns of HIV infection although the effect depended on the current place of residence. Copyright © 2012 Elsevier Ltd. All rights reserved.

HIV/HTLV-1 co-infection

African Journals Online (AJOL)

result of a lymphoproliferative disorder. In the context of HIV co-infection, lympho- cytosis has been described during early sero- conversion associated with CMV, as well as in HIV/HTLV-1 co-infection where CD4+ lymphocytosis can be caused by both a reactive or clonal expansion. Consequently, patients with untreated ...

Gender inequality and HIV transmission: a global analysis

OpenAIRE

Richardson, Eugene T; Collins, Sean E; Kung, Tiffany; Jones, James H; Tram, Khai Hoan; Boggiano, Victoria L; Bekker, Linda-Gail; Zolopa, Andrew R

2014-01-01

Introduction: The HIV pandemic disproportionately impacts young women. Worldwide, young women aged 15–24 are infected with HIV at rates twice that of young men, and young women alone account for nearly a quarter of all new HIV infections. The incommensurate HIV incidence in young – often poor – women underscores how social and economic inequalities shape the HIV epidemic. Confluent social forces, including political and gender violence, poverty, racism, and sexism impede equal access to thera...

Responses to the global HIV and AIDS pandemic: a study of the role of faith-based organisations in Lesotho.

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Olowu, Dejo

2015-01-01

This article attempts to establish the key contribution by people of faith to the global HIV pandemic response, using Lesotho as a case study. Particular focus is paid to the work of selected religious organisations in Lesotho in this context, assessing their capacities to coordinate an effective HIV and AIDS action at the grassroots levels through education, health care, development, and social service activities. Empirical evaluations and findings regarding the level and quality of faith-based engagement in this field establish the basic premise of this article, namely, that faith-based organisations are contributing energy, expertise, and experience in order to achieve the commitment of the global commitment to advance universal access to HIV prevention, treatment, and support. Although the article is particularly focused on the Lesotho context, its tremendous implications for simulated studies and approaches across Sub-Saharan Africa are accentuated.

Herpes simplex virus type 2 (HSV-2) genital shedding in HSV-2-/HIV-1-co-infected women receiving effective combination antiretroviral therapy.

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Péré, Héléne; Rascanu, Aida; LeGoff, Jérome; Matta, Mathieu; Bois, Frédéric; Lortholary, Olivier; Leroy, Valériane; Launay, Odile; Bélec, Laurent

2016-03-01

The dynamics of genital shedding of HSV-2 DNA was assessed in HIV-1-infected women taking combination antiretroviral therapy (cART). HIV-1 RNA, HIV-1 DNA and HSV DNA loads were measured during 12-18 months using frozen plasma, PBMC and cervicovaginal lavage samples from 22 HIV-1-infected women, including 17 women naive for antiretroviral therapy initiating cART and 5 women with virological failure switching to a new regimen. Nineteen (86%) women were HSV-2-seropositive. Among HSV-2-/HIV-1-co-infected women, HIV-1 RNA loads showed a rapid fall from baseline after one month of cART, in parallel in paired plasma and cervicovaginal secretions. In contrast, HIV-1 DNA loads did not show significant variations from baseline up to 18 months of treatment in both systemic and genital compartments. HSV DNA was detected at least once in 12 (63%) of 19 women during follow up: HSV-2 shedding in the genital compartment was observed in 11% of cervicovaginal samples at baseline and in 16% after initiating or switching cART. Cervicovaginal HIV-1 RNA loads were strongly associated with plasma HIV-1 RNA loads over time, but not with cervicovaginal HSV DNA loads. Reactivation of genital HSV-2 replication frequently occurred despite effective cART in HSV-2-/HIV-1-co-infected women. Genital HSV-2 replication under cART does not influence cervicovaginal HIV-1 RNA or DNA shedding. © The Author(s) 2015.

Cis elements and trans-acting factors involved in the RNA dimerization of the human immunodeficiency virus HIV-1.

Science.gov (United States)

Darlix, J L; Gabus, C; Nugeyre, M T; Clavel, F; Barré-Sinoussi, F

1990-12-05

The retroviral genome consists of two identical RNA molecules joined at their 5' ends by the Dimer Linkage Structure (DLS). To study the mechanism of dimerization and the DLS of HIV-1 RNA, large amounts of bona fide HIV-1 RNA and of mutants have been synthesized in vitro. We report that HIV-1 RNA forms dimeric molecules and that viral nucleocapsid (NC) protein NCp15 greatly activates dimerization. Deletion mutagenesis in the RNA 5' 1333 nucleotides indicated that a small domain of 100 nucleotides, located between positions 311 to 415 from the 5' end, is necessary and sufficient to promote HIV-1 RNA dimerization. This dimerization domain encompasses an encapsidation element located between the 5' splice donor site and initiator AUG of gag and shows little sequence variations in different strains of HIV-1. Furthermore, cross-linking analysis of the interactions between NC and HIV-1 RNA (311 to 415) locates a major contact site in the encapsidation element of HIV-1 RNA. The genomic RNA dimer is tightly associated with nucleocapsid protein molecules in avian and murine retroviruses, and this ribonucleoprotein structure is believed to be the template for reverse transcription. Genomic RNA-protein interactions have been analyzed in human immunodeficiency virus (HIV) virions and results showed that NC protein molecules are tightly bound to the genomic RNA dimer. Since retroviral RNA dimerization and packaging appear to be under the control of the same cis element, the encapsidation sequences, and trans-acting factor, the NC protein, they are probably related events in the course of virion assembly.

Correlates of HIV-1 genital shedding in Tanzanian women.

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Clare Tanton

2011-03-01

Full Text Available Understanding the correlates of HIV shedding is important to inform strategies to reduce HIV infectiousness. We examined correlates of genital HIV-1 RNA in women who were seropositive for both herpes simplex virus (HSV-2 and HIV-1 and who were enrolled in a randomised controlled trial of HSV suppressive therapy (aciclovir 400 mg b.i.d vs. placebo in Tanzania.Samples, including a cervico-vaginal lavage, were collected and tested for genital HIV-1 and HSV and reproductive tract infections (RTIs at randomisation and 6, 12 and 24 months follow-up. Data from all women at randomisation and women in the placebo arm during follow-up were analysed using generalised estimating equations to determine the correlates of cervico-vaginal HIV-1 RNA detection and load.Cervico-vaginal HIV-1 RNA was detected at 52.0% of 971 visits among 482 women, and was independently associated with plasma viral load, presence of genital ulcers, pregnancy, bloody cervical or vaginal discharge, abnormal vaginal discharge, cervical ectopy, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, an intermediate bacterial vaginosis score and HSV DNA detection. Similar factors were associated with genital HIV-1 RNA load.RTIs were associated with increased presence and quantity of genital HIV-1 RNA in this population. These results highlight the importance of integrating effective RTI treatment into HIV care services.

Frequent intra-subtype recombination among HIV-1 circulating in Tanzania.

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Ireen E Kiwelu

Full Text Available The study estimated the prevalence of HIV-1 intra-subtype recombinant variants among female bar and hotel workers in Tanzania. While intra-subtype recombination occurs in HIV-1, it is generally underestimated. HIV-1 env gp120 V1-C5 quasispecies from 45 subjects were generated by single-genome amplification and sequencing (median (IQR of 38 (28-50 sequences per subject. Recombination analysis was performed using seven methods implemented within the recombination detection program version 3, RDP3. HIV-1 sequences were considered recombinant if recombination signals were detected by at least three methods with p-values of ≤0.05 after Bonferroni correction for multiple comparisons. HIV-1 in 38 (84% subjects showed evidence for intra-subtype recombination including 22 with HIV-1 subtype A1, 13 with HIV-1 subtype C, and 3 with HIV-1 subtype D. The distribution of intra-patient recombination breakpoints suggested ongoing recombination and showed selective enrichment of recombinant variants in 23 (60% subjects. The number of subjects with evidence of intra-subtype recombination increased from 29 (69% to 36 (82% over one year of follow-up, although the increase did not reach statistical significance. Adjustment for intra-subtype recombination is important for the analysis of multiplicity of HIV infection. This is the first report of high prevalence of intra-subtype recombination in the HIV/AIDS epidemic in Tanzania, a region where multiple HIV-1 subtypes co-circulate. HIV-1 intra-subtype recombination increases viral diversity and presents additional challenges for HIV-1 vaccine design.

Regional gene expression of LOX-1, VCAM-1, and ICAM-1 in aorta of HIV-1 transgenic rats.

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Anne Mette Fisker Hag

Full Text Available BACKGROUND: Increased prevalence of atherosclerotic cardiovascular disease in HIV-infected patients has been observed. The cause of this accelerated atherosclerosis is a matter of controversy. As clinical studies are complicated by a multiplicity of risk-factors and a low incidence of hard endpoints, studies in animal models could be attractive alternatives. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated gene expression of lectin-like oxidized-low-density-lipoprotein receptor-1 (LOX-1, vascular cell adhesion molecule-1 (VCAM-1, and intercellular adhesion molecule-1 (ICAM-1 in HIV-1 transgenic (HIV-1Tg rats; these genes are all thought to play important roles in early atherogenesis. Furthermore, the plasma level of sICAM-1 was measured. We found that gene expressions of LOX-1 and VCAM-1 were higher in the aortic arch of HIV-1Tg rats compared to controls. Also, the level of sICAM-1 was elevated in the HIV-1Tg rats compared to controls, but the ICAM-1 gene expression profile did not show any differences between the groups. CONCLUSIONS/SIGNIFICANCE: HIV-1Tg rats have gene expression patterns indicating endothelial dysfunction and accelerated atherosclerosis in aorta, suggesting that HIV-infection per se may cause atherosclerosis. This transgenic rat model may be a very promising model for further studies of the pathophysiology behind HIV-associated cardiovascular disease.

HIV epidemiology. The early spread and epidemic ignition of HIV-1 in human populations.

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Faria, Nuno R; Rambaut, Andrew; Suchard, Marc A; Baele, Guy; Bedford, Trevor; Ward, Melissa J; Tatem, Andrew J; Sousa, João D; Arinaminpathy, Nimalan; Pépin, Jacques; Posada, David; Peeters, Martine; Pybus, Oliver G; Lemey, Philippe

2014-10-03

Thirty years after the discovery of HIV-1, the early transmission, dissemination, and establishment of the virus in human populations remain unclear. Using statistical approaches applied to HIV-1 sequence data from central Africa, we show that from the 1920s Kinshasa (in what is now the Democratic Republic of Congo) was the focus of early transmission and the source of pre-1960 pandemic viruses elsewhere. Location and dating estimates were validated using the earliest HIV-1 archival sample, also from Kinshasa. The epidemic histories of HIV-1 group M and nonpandemic group O were similar until ~1960, after which group M underwent an epidemiological transition and outpaced regional population growth. Our results reconstruct the early dynamics of HIV-1 and emphasize the role of social changes and transport networks in the establishment of this virus in human populations. Copyright © 2014, American Association for the Advancement of Science.

Consistency of Estimated Global Water Cycle Variations Over the Satellite Era

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Robertson, F. R.; Bosilovich, M. G.; Roberts, J. B.; Reichle, R. H.; Adler, R.; Ricciardulli, L.; Berg, W.; Huffman, G. J.

2013-01-01

Motivated by the question of whether recent indications of decadal climate variability and a possible "climate shift" may have affected the global water balance, we examine evaporation minus precipitation (E-P) variability integrated over the global oceans and global land from three points of view-remotely sensed retrievals / objective analyses over the oceans, reanalysis vertically-integrated moisture convergence (MFC) over land, and land surface models forced with observations-based precipitation, radiation and near-surface meteorology. Because monthly variations in area-averaged atmospheric moisture storage are small and the global integral of moisture convergence must approach zero, area-integrated E-P over ocean should essentially equal precipitation minus evapotranspiration (P-ET) over land (after adjusting for ocean and land areas). Our analysis reveals considerable uncertainty in the decadal variations of ocean evaporation when integrated to global scales. This is due to differences among datasets in 10m wind speed and near-surface atmospheric specific humidity (2m qa) used in bulk aerodynamic retrievals. Precipitation variations, all relying substantially on passive microwave retrievals over ocean, still have uncertainties in decadal variability, but not to the degree present with ocean evaporation estimates. Reanalysis MFC and P-ET over land from several observationally forced diagnostic and land surface models agree best on interannual variations. However, upward MFC (i.e. P-ET) reanalysis trends are likely related in part to observing system changes affecting atmospheric assimilation models. While some evidence for a low-frequency E-P maximum near 2000 is found, consistent with a recent apparent pause in sea-surface temperature (SST) rise, uncertainties in the datasets used here remain significant. Prospects for further reducing uncertainties are discussed. The results are interpreted in the context of recent climate variability (Pacific Decadal

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.

The Epidemiology of HIV-1 Transmitted Drug Resistance

NARCIS (Netherlands)

D. Frentz (Dineke)

2012-01-01

textabstractThe human immunodeficiency virus (HIV) was first discovered in 1983. In 2009, it was estimated that 33.3 (31.4 -35.3) million individuals are infected with HIV worldwide. In that year 1.8 (1.6-2.1) million people died from HIV. Although the virus continues to spread, the number of new

The socio-cultural context of the transmission of HIV in Thailand.

Science.gov (United States)

Ford, N; Koetsawang, S

1991-01-01

At a global level there are considerable differences between regions in the levels of prevalence, and rate of transmission, of the Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS). Furthermore there are differences between regions in the social and demographic characteristics of HIV carriers/AIDS sufferers (e.g. heterosexuals, homosexuals, injecting drug users, infants). It is notable that Asia has generally lagged behind other regions in the spread of HIV. However recently Thailand has acknowledged rapidly increasing levels of infection. This paper is structured in terms of three broad sections. (1) An outline of some basic epidemiological principles concerning the transmission of HIV which help account for the regional variations in prevalence; (2) a description of the emerging awareness of HIV as a public health problem within Thailand; (3) a review of the social characteristics of HIV carriers in Thailand, interpreted by reference to the wider social context, chiefly in terms of; the commercial sex industry/sexual lifestyles, international tourism, and injecting drug dependency. Reference is also made to impressions of the personal response of individuals learning of their HIV seropositive status. A brief comment compares the sexual culture and sex industry in Thailand to that of other South East Asian countries (most notably the Philippines). The paper highlights the importance of considering the particular social and historical factors which shape and sustain the transmission of HIV within a particular country.

Increased Risk of Female HIV-1 Acquisition Throughout Pregnancy and Postpartum: A Prospective Per-coital Act Analysis Among Women with HIV-1 Infected Partners.

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Thomson, Kerry A; Hughes, James; Baeten, Jared M; John-Stewart, Grace; Celum, Connie; Cohen, Craig R; Ngure, Kenneth; Kiarie, James; Mugo, Nelly; Heffron, Renee

2018-03-05

Understanding the absolute and relative risk of HIV-1 acquisition during pregnancy and postpartum can inform HIV-1 prevention strategies for women. We used a complementary log-log model and data from 2,751 HIV-1 serodiscordant couples to compare the probability of women's HIV-1 acquisition risk per sex act during early pregnancy, late pregnancy, postpartum, and non-pregnant periods. At total of 686 pregnancies were identified and 82 incident HIV-1 infections occurred. After adjustment for condom use, age, PrEP use, and HIV-1 viral load, the per act probability of HIV-1 acquisition was higher in late pregnancy (aRR 2.82, p=0.01) and postpartum (aRR 3.97, p=0.01) compared to non-pregnant periods. The HIV-1 acquisition probability per condomless sex act for a 25 year old woman not taking PrEP with an HIV-1 infected male partner with viral load of 10,000 copies/ml was 0.0011 (95% CI: 0.005, 0.0019), 0.0022 (95% CI: 0.0004, 0.0093), 0.0030 (95% CI: 0.0007, 0.0108), and 0.0042 (95% CI: 0.0007, 0.0177) in the non-pregnant, early pregnant, late pregnant, and postpartum periods, respectively. The HIV-1 acquisition probability per condomless sex act steadily increased through pregnancy and was highest during the postpartum period, suggesting that biological changes during pregnancy and postpartum increase female HIV-1 susceptibility.

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

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Ole S Søgaard

2015-09-01

Full Text Available Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03. Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04. Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2 were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.clinicaltrials.gov NTC02092116.

HIV type 2 epidemic in Spain: challenges and missing opportunities.

Science.gov (United States)

de Mendoza, Carmen; Cabezas, Teresa; Caballero, Estrella; Requena, Silvia; Amengual, María J; Peñaranda, María; Sáez, Ana; Tellez, Raquel; Lozano, Ana B; Treviño, Ana; Ramos, José M; Pérez, José L; Barreiro, Pablo; Soriano, Vicente

2017-06-19

: HIV type 2 (HIV-2) is a neglected virus despite estimates of 1-2 million people infected worldwide. HIV-2 is less efficiently transmitted than HIV-1 by sex and from mother to child. Although AIDS may develop in HIV-2 carriers, it takes longer than in HIV-1-infected patients. In contrast with HIV-1 infection, there is no global pandemic caused by HIV-2, as the virus is largely confined to West Africa. In a less extent and due to socioeconomic ties and wars, HIV-2 is prevalent in Portugal and its former colonies in Brazil, India, Mozambique and Angola. Globally, HIV-2 infections are steadily declining over time. A total of 338 cases of HIV-2 infection had been reported at the Spanish HIV-2 registry until December 2016, of whom 63% were men. Overall 72% were sub-Saharan Africans, whereas 16% were native Spaniards. Dual HIV-1 and HIV-2 coinfection was found in 9% of patients. Heterosexual contact was the most likely route of HIV-2 acquisition in more than 90% of cases. Roughly one-third presented with CD4 cell counts less than 200 cells/μl and/or AIDS clinical events. Plasma HIV-2 RNA was undetectable at baseline in 40% of patients. To date, one-third of HIV-2 carriers have received antiretroviral therapy, using integrase inhibitors 32 individuals. New diagnoses of HIV-2 in Spain have remained stable since 2010 with an average of 15 cases yearly. Illegal immigration from Northwestern African borders accounts for over 75% of new HIV-2 diagnoses. Given the relatively large community of West Africans already living in Spain and the continuous flux of immigration from endemic regions, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded once in all HIV-seroreactive persons, especially when showing atypical HIV serological profiles, immunovirological disconnect (CD4 cell count loss despite undetectable HIV-1 viremia) and/or high epidemiological risks (birth in or sex partners from endemic regions).

HIV Testing, Care, and Treatment Among Women Who Use Drugs From a Global Perspective: Progress and Challenges.

Science.gov (United States)

Metsch, Lisa; Philbin, Morgan M; Parish, Carrigan; Shiu, Karen; Frimpong, Jemima A; Giang, Le Minh

2015-06-01

The article reviews data on HIV testing, treatment, and care outcomes for women who use drugs in 5 countries across 5 continents. We chose countries in which the HIV epidemic has, either currently or historically, been fueled by injection and non-injection drug use and that have considerable variation in social structural and drug policies: Argentina, Vietnam, Australia, Ukraine, and the United States. There is a dearth of available HIV care continuum outcome data [ie, testing, linkage, retention, antiretroviral therapy (ART) provision, viral suppression] among women drug users, particularly among noninjectors. Although some progress has been made in increasing HIV testing in this population, HIV-positive women drug users in 4 of the 5 countries have not fully benefitted from ART nor are they regularly engaged in HIV care. Issues such as the criminalization of drug users, HIV-specific criminal laws, and the lack of integration between substance use treatment and HIV primary care play a major role. Strategies that effectively address the pervasive factors that prevent women drug users from engaging in HIV care and benefitting from ART and other prevention services are critical. Future success in enhancing the HIV continuum for women drug users should consider structural and contextual level barriers and promote social, economic, and legal policies that overhaul the many years of discrimination and stigmatization faced by women drug users worldwide. Such efforts must emphasis the translation of policies into practice and approaches to implementation that can help HIV-infected women who use drugs engage at all points of the HIV care continuum.

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy.

Science.gov (United States)

Tan, Suiyi; Duan, Heng; Xun, Tianrong; Ci, Wei; Qiu, Jiayin; Yu, Fei; Zhao, Xuyan; Wu, Linxuan; Li, Lin; Lu, Lu; Jiang, Shibo; Liu, Shuwen

2014-07-01

The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope.

Directory of Open Access Journals (Sweden)

Art F Y Poon

2007-11-01

Full Text Available The third variable loop (V3 of the human immunodeficiency virus type 1 (HIV-1 envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1 that founder effects in the evolutionary history of the sequences can be ignored, and; (2 that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%-40%. Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to

Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990–2009

Science.gov (United States)

Heitzinger, K; Sow, P S; Badiane, N M Dia; Gottlieb, G S; N’Doye, I; Toure, M; Kiviat, N B; Hawes, S E

2013-01-01

Summary We assessed trends in the relative prevalences of HIV-1, HIV-2 and dual HIV-1/HIV-2 infection in 10,321 women attending outpatient clinics in Senegal between 1990 and 2009. The relative prevalence of HIV-1 (defined as the proportion of seropositive subjects having HIV-1) rose sharply from 38% in 1990 until 1993 (P Senegal. From 1993 to 2009, the relative prevalence of HIV-1 increased at a slower rate, while the relative prevalences of HIV-2 and dual infection decreased. These results confirm trends in HIV prevalence observed in other West African populations and provide a critical update on HIV transmission risk among women in Senegal. PMID:23104745

Harnessing Novel Imaging Approaches to Guide HIV Prevention and Cure Discoveries-A National Institutes of Health and Global HIV Vaccine Enterprise 2017 Meeting Report.

Science.gov (United States)

Sanders-Beer, Brigitte E; Voronin, Yegor; McDonald, David; Singh, Anjali

2018-01-01

Advances in imaging technologies have greatly increased our understanding of cellular and molecular interactions in humans and their corresponding animal models of infectious diseases. In the HIV/SIV field, imaging has provided key insights into mucosal viral transmission, local and systemic virus spread, host-virus dynamics, and chronic inflammation/immune activation and the resultant immunopathology. Recent developments in imaging applications are yielding physical, spatial, and temporal measurements to enhance insight into biological functions and disease processes, while retaining important cellular, microenvironmental, organ, and intact organism contextual details. Taking advantage of the latest advancements in imaging technologies may help answer important questions in the HIV field. The Global HIV Vaccine Enterprise in collaboration with the National Institutes of Health (NIH) sponsored a meeting on May 8 and 9, 2017 to provide a platform to review state-of-the-art imaging technologies and to foster multidisciplinary collaborations in HIV/AIDS research. The meeting covered applications of imaging in studies of early events and pathogenesis, reservoirs, and cure, as well as in vaccine development. In addition, presentations and discussions of imaging applications from non-HIV biomedical research areas were included. This report summarizes the presentations and discussions at the meeting.

Structure of HIV-1 protease determined by neutron crystallography

International Nuclear Information System (INIS)

Adachi, Motoyasu; Kuroki, Ryota

2009-01-01

HIV-1 protease is an aspartic protease, and plays an essential role in replication of HIV. To develop HIV-1 protease inhibitors through structure-based drug design, it is necessary to understand the catalytic mechanism and inhibitor recognition of HIV-1 protease. We have determined the crystal structure of HIV-1 protease in complex with KNI-272 to 1.9 A resolution by neutron crystallography in combination with 1.4 A resolution X-ray diffraction data. The results show that the carbonyl group of hydroxymethylcarbonyl (HMC) in KNI-272 forms a hydrogen bonding interaction with protonated Asp 25 and the hydrogen atom from the hydroxyl group of HMC forms a hydrogen bonding interaction with the deprotonated Asp125. This is the first neutron report for HIV-1/inhibitor complex and shows directly the locations of key hydrogen atoms in catalysis and in the binding of a transition-state analog. The results confirm key aspect of the presumed catalytic mechanism of HIV-1 protease and will aid in the further development of protease inhibitors. (author)

Global, regional, and country-level coverage of interventions to prevent and manage HIV and hepatitis C among people who inject drugs: a systematic review.

Science.gov (United States)

Larney, Sarah; Peacock, Amy; Leung, Janni; Colledge, Samantha; Hickman, Matthew; Vickerman, Peter; Grebely, Jason; Dumchev, Kostyantyn V; Griffiths, Paul; Hines, Lindsey; Cunningham, Evan B; Mattick, Richard P; Lynskey, Michael; Marsden, John; Strang, John; Degenhardt, Louisa

2017-12-01

People who inject drugs (PWID) are a key population affected by the global HIV and hepatitis C virus (HCV) epidemics. HIV and HCV prevention interventions for PWID include needle and syringe programmes (NSP), opioid substitution therapy (OST), HIV counselling and testing, HIV antiretroviral therapy (ART), and condom distribution programmes. We aimed to produce country-level, regional, and global estimates of coverage of NSP, OST, HIV testing, ART, and condom programmes for PWID. We completed searches of peer-reviewed (MEDLINE, Embase, and PsycINFO), internet, and grey literature databases, and disseminated data requests via social media and targeted emails to international experts. Programme and survey data on each of the named interventions were collected. Programme data were used to derive country-level estimates of the coverage of interventions in accordance with indicators defined by WHO, UNAIDS, and the UN Office on Drugs and Crime. Regional and global estimates of NSP, OST, and HIV testing coverage were also calculated. The protocol was registered on PROSPERO, number CRD42017056558. In 2017, of 179 countries with evidence of injecting drug use, some level of NSP services were available in 93 countries, and there were 86 countries with evidence of OST implementation. Data to estimate NSP coverage were available for 57 countries, and for 60 countries to estimate OST coverage. Coverage varied widely between countries, but was most often low according to WHO indicators (200 needle-syringes distributed per PWID and >40 OST recipients per 100 PWID). Coverage of HIV and HCV prevention interventions for PWID remains poor and is likely to be insufficient to effectively prevent HIV and HCV transmission. Scaling up of interventions for PWID remains a crucial priority for halting the HIV and HCV epidemics. Open Society Foundations, The Global Fund, WHO, UNAIDS, United Nations Office on Drugs and Crime, Australian National Drug and Alcohol Research Centre, University of

Molecular Basis for Drug Resistance in HIV-1 Protease

Directory of Open Access Journals (Sweden)

Celia A. Schiffer

2010-11-01

Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

A sensitive HIV-1 envelope induced fusion assay identifies fusion enhancement of thrombin

International Nuclear Information System (INIS)

Cheng, De-Chun; Zhong, Guo-Cai; Su, Ju-Xiang; Liu, Yan-Hong; Li, Yan; Wang, Jia-Ye; Hattori, Toshio; Ling, Hong; Zhang, Feng-Min

2010-01-01

To evaluate the interaction between HIV-1 envelope glycoprotein (Env) and target cell receptors, various cell-cell-fusion assays have been developed. In the present study, we established a novel fusion system. In this system, the expression of the sensitive reporter gene, firefly luciferase (FL) gene, in the target cells was used to evaluate cell fusion event. Simultaneously, constitutively expressed Renilla luciferase (RL) gene was used to monitor effector cell number and viability. FL gave a wider dynamic range than other known reporters and the introduction of RL made the assay accurate and reproducible. This system is especially beneficial for investigation of potential entry-influencing agents, for its power of ruling out the false inhibition or enhancement caused by the artificial cell-number variation. As a case study, we applied this fusion system to observe the effect of a serine protease, thrombin, on HIV Env-mediated cell-cell fusion and have found the fusion enhancement activity of thrombin over two R5-tropic HIV strains.

Comparison of glycerolisation with cryopreservation methods on HIV-1 inactivation

International Nuclear Information System (INIS)

Van Baare, J.; Pagnon, J.; Cameron, P.; Vardaxis, N.; Middlekoop, E.; Crowe, S.

1999-01-01

Cryopreservation and glycerolisation are two successful long-term preservation methods for human cadaveric donor skin, which is used in the treatment of bum patients. High concentrations of glycerol has been shown to be antibacterial and virucidal. Because fear of possible transmission of HIV-1 following allograft transplantation, this study was undertaken to investigate whether HIV can be effectively eliminated from skin explants. HIV-1 Ba-L, which has been shown to infect monocytes in skin explants and also dendritic cells, was. For the experiments we used cell-free virus, exogenously HIV infected peripheral blood mononuclear cells (PBMCs) and exogenously HIV infected cadaver split skin. Different concentrations of glycerol at various temperatures and the glycerolisation procedure as used by the Euro Skin Bank were used to determine the effects on HIV-1 Ba-L infectivity. For the cryopreservation technique we used 10% DMSO and a controlled rate freezer. HIV-1 Ba-L transfer was determined by adding uninfected PBMCs to the infected material and reverse transcriptase was measured. Cell-free HIV-1 Ba-L was not inactivated by 50% glycerol but was effectively inactivated within 30 minutes by 70% and 85% glycerol at 4 degree C, room temperature and 37 degree C. In contrast, cell-free HIV-1 Ba-L was not inactivated by cryopreservation. Most importantly, we have shown that HIV-1 Ba-L present in split skin is inactivated by incubating skin in 70% glycerol for three hours at 37-C. HIV in exogenously infected skin was not inactivated by cryopreservation. High concentrations of glycerol effectively inactivates free HIV-1 Ba-L and intracellular HIV-1 Ba-L. Also the current glycerolisation procedure carried out by the Euro Skin Bank effectively inactivates infectious virus. However, the cryopreservation technique did not show any reduction in HIV-1 Ba-L infectivity

Designing global collective action in population and HIV/AIDS programs, 1983-2002: has anything changed?

NARCIS (Netherlands)

van Dalen, H.P.

2008-01-01

The 1994 International Conference of Population and Development (ICPD) in Cairo established goals for the expansion of assistance in matters of reproductive health and HIV/AIDS. This global effort marked a structural break in principle from the past, but did it also change funding behavior? Panel

An anti-HIV microbicide engineered in commensal bacteria: secretion of HIV-1 fusion inhibitors by lactobacilli

NARCIS (Netherlands)

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

Exosomes from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells License Quiescent CD4+ T Lymphocytes To Replicate HIV-1 through a Nef- and ADAM17-Dependent Mechanism

OpenAIRE

Arenaccio, Claudia; Chiozzini, Chiara; Columba-Cabezas, Sandra; Manfredi, Francesco; Affabris, Elisabetta; Baur, Andreas; Federico, Maurizio

2014-01-01

Resting CD4+ T lymphocytes resist human immunodeficiency virus (HIV) infection. Here, we provide evidence that exosomes from HIV-1-infected cells render resting human primary CD4+ T lymphocytes permissive to HIV-1 replication. These results were obtained with transwell cocultures of HIV-1-infected cells with quiescent CD4+ T lymphocytes in the presence of inhibitors of exosome release and were confirmed using exosomes purified from supernatants of HIV-1-infected primary CD4+ T lymphocytes. We...