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Sample records for single positive cd4

  1. Habitual physical activity levels are positively correlated with CD4 ...

    African Journals Online (AJOL)

    ... month) and functional independence as assessed from the responses to the questionnaire. There was a positive and significant correlation between the patients' length of time on ARV medication and CD4 cell counts (p < 0.0001, r = 0.45), and between CD4 cell counts and total habitual physical activity levels (p = 0.0067, ...

  2. Task-shifting of CD4 T cell count monitoring by the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration: Implication for decentralization in resource-constrained settings.

    Science.gov (United States)

    Kouabosso, André; Mossoro-Kpinde, Christian Diamant; Bouassa, Ralph-Sydney Mboumba; Longo, Jean De Dieu; Mbeko Simaleko, Marcel; Grésenguet, Gérard; Bélec, Laurent

    2018-04-01

    The accuracy of CD4 T cell monitoring by the recently developed flow cytometry-based CD4 T cell counting Muse™ Auto CD4/CD4% Assay analyzer (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany) was evaluated in trained lay providers against laboratory technicians. After 2 days of training on the Muse™ Auto CD4/CD4% analyzer, EDTA-blood samples from 6 HIV-positive and 4 HIV-negative individuals were used for CD4 T cell counting in triplicate in parallel by 12 trained lay providers as compared to 10 lab technicians. Mean number of CD4 T cells in absolute number was 829 ± 380 cells/μl by lay providers and 794 ± 409 cells/μl by technicians (P > 0.05); and in percentage 36.2 ± 14.8%CD4 by lay providers and 36.1 ± 15.0%CD4 by laboratory technician (P > 0.05). The unweighted linear regression and Passing-Bablok regression analyses on CD4 T cell results expressed in absolute count revealed moderate correlation between CD4 T cell counts obtained by lay providers and lab technicians. The mean absolute bias measured by Bland-Altman analysis between CD4 T cell/μl obtained by lay providers and lab technicians was -3.41 cells/μl. Intra-assay coefficient of variance (CV) of Muse™ Auto CD4/CD4% in absolute number was 10.1% by lay providers and 8.5% by lab technicians (P > 0.05), and in percentage 5.5% by lay providers and 4.4% by lab technicians (P > 0.05). The inter-assay CV of Muse™ Auto CD4/CD4% in absolute number was 13.4% by lay providers and 10.3% by lab technicians (P > 0.05), and in percentage 7.8% by lay providers and 6.9% by lab technicians (P > 0.05). The study demonstrates the feasibility of CD4 T cell counting using the alternative flow cytometer Muse™ Auto CD4/CD4% analyzer by trained lay providers and therefore the practical possibility of decentralization CD4 T cell counting to health community centers. Copyright © 2018. Published by Elsevier B.V.

  3. CD4+/CD8+ double-positive T cells

    DEFF Research Database (Denmark)

    Overgaard, Nana H; Jung, Ji-Won; Steptoe, Raymond J

    2015-01-01

    CD4(+)/CD8(+) DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4(+) lineage or the CD8(+) lineage is generally considered to be fixed. Nevertheless, mature CD4(+)/CD8(+) DP T cells have been described in the blood and peripheral...... cells, CD4(+)/CD8(+) T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Runx3. Considerable heterogeneity exists within the CD4(+)/CD8(+) DP T cell pool, and the function of CD4(+)/CD8(+) T cell populations remains controversial, with conflicting...... reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population....

  4. Association between red blood cell indices and CD4 count in HIV-positive reproductive women

    Science.gov (United States)

    Lumbanraja, S. N.; Siregar, D. I. S.

    2018-03-01

    Red blood cell indices, hemoglobin, and hematocrit reflect rapidity of HIV disease progression. This study aims to determine red blood cell indices and CD4 count in HIV-positive reproductive women. This study was a cross sectional study conducted at AIDS outpatient clinic at Haji Adam Malik General Hospital, Medan Indonesia. All seropositive reproductive women within antiretroviral therapy consented for blood count and CD4 examination. Data were collected and analyzed with SPSS 19. In subjects with CD4≤350 mm3, mean hemoglobin was 10.95 ± 2.01, hematocrit was 31.83 ± 5.04%, MCV was 84.17 ± 11.41, MCH was 25.98 ± 2.65, and MCHC was 32.18 ± 2.17. Mean hemoglobin, hematocrit, and MCH value was significantly lower in subjects with CD4 ≤350 mm3 (p=0.014; p=0.001; p=0.01; respectively). Lower Hb, Ht, and MCH associated with thelower CD4 count.

  5. The relationship between skin manifestations and CD4 counts among hiv positive patients

    International Nuclear Information System (INIS)

    Rad, F.; Ghaderi, E.; Moradi, G.; Mafakheri, L.

    2008-01-01

    Skin manifestations are common clinical features among HIV positive patients. The aim of this study was to document skin manifestations and their relationships with CD4 cell counts among HIV positive patients in Sanandaj. This was a descriptive study. The patients were examined for skin disorders by a dermatologist and CD4 counts were obtained from the patient's medical records. Independent samples T test were used for data analysis. In this study 66 (94.3%) patients had at least one skin problem. Fungal infections were the most common cause. The eight most common types of mucocutaneous problems were gingivitis, pallor, itching, photosensitivity, seborrheic dermatitis, candidiasis, folliculitis and tinea versicolor. The most common manifestation was gingivitis. Mean CD4 cell counts were lower in individuals with viral and bacterial skin diseases (P <0.05). The results of this study indicated that skin problems were common among HIV positive patients. Patients with advanced stages of skin disorders had relatively lower CD4 counts. Therefore examination of skin is recommended for all HIV positive patients for early detection of skin disorders, as early diagnosis and management of dermatologic problems will improve the quality of life in HIV positive patients. (author)

  6. A Positive Control for Detection of Functional CD4 T Cells in PBMC: The CPI Pool.

    Science.gov (United States)

    Schiller, Annemarie; Zhang, Ting; Li, Ruliang; Duechting, Andrea; Sundararaman, Srividya; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

    2017-12-07

    Testing of peripheral blood mononuclear cells (PBMC) for immune monitoring purposes requires verification of their functionality. This is of particular concern when the PBMC have been shipped or stored for prolonged periods of time. While the CEF (Cytomegalo-, Epstein-Barr and Flu-virus) peptide pool has become the gold standard for testing CD8 cell functionality, a positive control for CD4 cells is so far lacking. The latter ideally consists of proteins so as to control for the functionality of the antigen processing and presentation compartments, as well. Aiming to generate a positive control for CD4 cells, we first selected 12 protein antigens from infectious/environmental organisms that are ubiquitous: Varicella, Influenza, Parainfluenza, Mumps, Cytomegalovirus, Streptococcus , Mycoplasma , Lactobacillus , Neisseria , Candida , Rubella, and Measles. Of these antigens, three were found to elicited interferon (IFN)-γ-producing CD4 cells in the majority of human test subjects: inactivated cytomegalo-, parainfluenza-, and influenza virions (CPI). While individually none of these three antigens triggered a recall response in all donors, the pool of the three (the 'CPI pool'), did. One hundred percent of 245 human donors tested were found to be CPI positive, including Caucasians, Asians, and African-Americans. Therefore, the CPI pool appears to be suitable to serve as universal positive control for verifying the functionality of CD4 and of antigen presenting cells.

  7. Gender differences in mortality and CD4 count response among virally suppressed HIV-positive patients.

    Science.gov (United States)

    Maskew, Mhairi; Brennan, Alana T; Westreich, Daniel; McNamara, Lynne; MacPhail, A Patrick; Fox, Matthew P

    2013-02-01

    Treatment outcomes for antiretroviral therapy (ART) patients may vary by gender, but estimates from current evidence may be confounded by disease stage and adherence. We investigated the gender differences in treatment response among HIV-positive patients virally suppressed within 6 months of treatment initiation. We analyzed data from 7,354 patients initiating ART between April 2004 and April 2010 at Themba Lethu Clinic, a large urban public sector treatment facility in South Africa. We estimated the relations among gender, mortality, and mean CD4 response in HIV-infected adults virally suppressed within 6 months of treatment initiation and used inverse probability of treatment weights to correct estimates for loss to follow-up. Male patients had a 20% greater risk of death at both 24 months and 36 months of follow-up compared to females. Older patients and those with a low hemoglobin level or low body mass index (BMI) were at increased risk of mortality throughout follow-up. Men gained fewer CD4 cells after treatment initiation than did women. The mean differences in CD4 count gains made by women and men between baseline and 12, 24, and 36 months were 28.2 cells/mm(3) (95% confidence interval [CI] 22.2-34.3), 60.8 cells/mm(3) (95% CI 71.1-50.5 cells/mm(3)), and 83.0 cells/mm(3) (95% CI 97.1-68.8 cells/mm(3)), respectively. Additionally, patients with a current detectable viral load (>400 copies/mL) and older patients had a lower mean CD4 increase at the same time points. In this initially virally suppressed population, women showed consistently better immune response to treatment than did men. Promoting earlier uptake of HIV treatment among men may improve their immunologic outcomes.

  8. Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women.

    Science.gov (United States)

    Engström, Karin; Wojdacz, Tomasz K; Marabita, Francesco; Ewels, Philip; Käller, Max; Vezzi, Francesco; Prezza, Nicola; Gruselius, Joel; Vahter, Marie; Broberg, Karin

    2017-05-01

    Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 μg/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (>80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.

  9. The frequency of double-positive thymocytes expressing an αβ TCR clonotype regulates peripheral CD4 T cell compartment homeostasis

    Science.gov (United States)

    Reed, Amy J; Zarrabi, Yasaman; Perate, Alison L; Jeganathan, Arjun; Naji, Ali; Noorchashm, Hooman

    2005-01-01

    The present study aimed to determine whether the frequency of double positive (DP) thymocytes expressing αβ T-cell receptor (TCR) clonotypes at the time of selection regulates peripheral CD4 T-cell compartment size. Scid recipients were inoculated with various ratios of TCR Cα0/0 and wild-type bone marrow (BM) stem cells. Increasing the frequency of TCR Cα0/0 thymocytes at steady-state introduced a graded decrease in the maturation probability of the total DP thymocyte pool. At 12–14 weeks following BM inoculation, the frequency of TCR Cα0/0 DP thymocytes was inversely correlated with that of CD4 single positive (SP) thymocytes. Notwithstanding, a decreased frequency of wild-type DP thymocytes led to a marked increase in their transit efficiency from the DP to SP compartments. The frequency-dependent increase in thymocyte transit efficiency was associated with a CD4 SP cell surface phenotype indicative of increased antigenic experience. Importantly, the frequency of DP thymocytes capable of expressing TCR clonotypes dictated the steady-state size of the peripheral CD4 T cell compartment and its potential for homeostatic proliferation. Collectively, these results indicate that the efficiency of DP to CD4 SP transit is a frequency dependent process, which determines (1) the steady-state size of the peripheral T cell compartment and (2) the threshold for homeostatic expansion of peripheral CD4 T cells. PMID:16236130

  10. Single Particle Tracking reveals two distinct environments for CD4 receptors at the surface of living T lymphocytes

    International Nuclear Information System (INIS)

    Mascalchi, Patrice; Lamort, Anne Sophie; Salomé, Laurence; Dumas, Fabrice

    2012-01-01

    Highlights: ► We studied the diffusion of single CD4 receptors on living lymphocytes. ► This study reveals that CD4 receptors have either a random or confined diffusion. ► The dynamics of unconfined CD4 receptors was accelerated by a temperature raise. ► The dynamics of confined CD4 receptors was unchanged by a temperature raise. ► Our results suggest the existence of two different environments for CD4 receptors. -- Abstract: We investigated the lateral diffusion of the HIV receptor CD4 at the surface of T lymphocytes at 20 °C and 37 °C by Single Particle Tracking using Quantum Dots. We found that the receptors presented two major distinct behaviors that were not equally affected by temperature changes. About half of the receptors showed a random diffusion with a diffusion coefficient increasing upon raising the temperature. The other half of the receptors was permanently or transiently confined with unchanged dynamics on raising the temperature. These observations suggest that two distinct subpopulations of CD4 receptors with different environments are present at the surface of living T lymphocytes.

  11. CD4 Cell Count in HIV positive subjects in Asaba, South South Nigeria

    African Journals Online (AJOL)

    Most of the subjects (61.8%) were aged 40 years and below and most had a low literacy level [92.1% attained a maximum educational status of secondary education or less]. Their CD4 cell count ranged from 8 to 566 cells/mm3, with a mean of 98.1 ± 106.22. Most of the subjects [86.9%] had CD4 cell count of 200 or less.

  12. The role of CD4 in antigen-independent activation of isolated single T lymphocytes

    DEFF Research Database (Denmark)

    Kelso, A; Owens, T

    1988-01-01

    The membrane molecule CD4 (L3T4) is thought to facilitate activation of Class II H-2-restricted T cells by binding to Ia determinants on antigen-presenting cells. Recent reports suggest that CD4 can also contribute to antigen-independent activation by anti-T cell receptor (TCR) antibodies. An assay...

  13. CD52 expression on CD4+ T cells in HIV-positive individuals on cART

    DEFF Research Database (Denmark)

    Vojdeman, Fie Juhl; Gaardbo, Julie Christine; Hartling, Hans Jakob

    2018-01-01

    BACKGROUND: Human immune defect virus (HIV) persists in a latent state in quiescent CD4+ T cells preventing eradication of HIV. CD52 is a surface molecule modulated by HIV. We aimed at examining factors related to CD52 expression on CD4+ T cells in HIV-positive individuals and the impact...... of initiation of combination antiretroviral therapy (cART). METHODS: Peripheral blood mononuclear cells (PBMC) from 18 HIV-positive individuals and 10 uninfected age and gender matched controls were examined by flow cytometry for CD38 and CD52 expression on CD4+ T cells. Stimulation assays were performed on 8...... healthy blood donors to determine a cut-off for CD52 expression. RESULTS: All examined CD4+ T cells expressed CD52. However, both CD4+ T cells with higher (CD52++) and with lower CD52 expression (CD52dim) were found in HIV-positive individuals compared to uninfected controls. Two % CD52dim cells defined...

  14. Seroprevalence of Epstein-Barr virus among HIV positive patients moreover and its association with CD4 positive lymphocyte count.

    Directory of Open Access Journals (Sweden)

    Alireza Abdollahi

    2014-12-01

    Full Text Available Opportunistic infections are the leading cause of hospitalization and morbidity in human immunodeficiency virus (HIV positive patients and are the most common cause of death between them. We aimed to measure IgG antibody against EBV viral capsid antigen (EBV-VCA IgG to determine the seroprevalence of this infection in HIV-positive population. A case-control study between September 2011 and October 2012 was conducted in a teaching hospital enrolling 114 HIV-positive patients as case group and 114 healthy individuals as control with similar age and sex. Enzyme-linked immunosurbant assay (ELISA technique was used for determination of EBV-VAC IgG in obtained samples. Of 114 serum samples obtained from HIV-positive patients, 103 (90.4% samples were found positive for EBV-VCA IgG antibody. There was no significant difference in seroprevalence of EBV VCA IgG antibody between patients received antiretroviral therapy and naive patients (91.5% vs. 87.5%, P>0.05. There was no statistically significant difference in EBV-VCA IgG seroprevalence between three groups of CD4+ in HIV positive group. In conclusion current study showed that seroprevalence of EBV in HIV-positive patients is higher than HIV-negative healthy participants; however, administration of HAART and CD4+ lymphocyte count did not reveal a significant effect in seroprevalence of EBV. Due to the significance of this virus in mortality and morbidity and causing certain malignancies in patients with AIDS, these patients are strongly recommended to be tested for this virus.

  15. Single N277A substitution in C2 of simian immunodeficiency virus envelope influences vaccine-elicited CD4i neutralizing and anti-V2 antibody responses.

    Science.gov (United States)

    Tang, Xian; Guo, Jia; Cheng, Lin; Sun, Caijun; Liu, Li; Zuo, Teng; Wang, Hui; Chen, Ling; Zhang, Linqi; Chen, Zhiwei

    2017-05-02

    An effective HIV vaccine remains elusive, and immunogens capable of eliciting protective host humoral immunity have not yet been identified. Although HIV/SIV infections result in the abundant production of CD4-induced (CD4i) antibodies (Abs), these Abs are not protective due to steric restrictions following gp120 binding to CD4 on target cells. Here we report that both DNA- and vaccinia-based vaccines encoding SIV mac239 gp160 readily elicited high levels of CD4i Abs in experimental animals. We identified a highly conserved N-linked glycosylation site N277 in the C2 region which strongly affected the immunogenicity of the CD4i Ab domain. Moreover, a single N277A substitution significantly enhanced the immunogenicity of the V2 domain yielding higher titers and frequency of anti-V2 Ab responses as determined by ELISA and yeast antigen display mapping, respectively. Importantly, immune sera elicited by the N277A-mutated gp160 exhibited elevated antibody-dependent cellular cytotoxicity (ADCC) activity. ADCC activity correlated positively with the anti-V2 Ab titer yet, inversely with CD4i Ab titer. Thus, we identified a determinant of the CD4i domain that might affect vaccine-elicited anti-V2 Ab and ADCC responses to SIV mac239 . Our findings may have implications for design of immunogens to direct B cell recognition in the development of an Ab-based HIV vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. cd4 changes in haart-naïve hiv positive pregnant women on haart

    African Journals Online (AJOL)

    boaz

    PURPOSE: PMTCT interventions, especially initiation of Highly active antiretroviral therapy (HAART) has modified the ... a period of 2 months in pregnancy. CD4 counts ... women on antiretroviral drugs. Thus it becomes highly imperative for such, considering the hitherto immunologic changes expected of normal pregnancy.

  17. Primary Cutaneous CD4-Positive Small/Medium Pleomorphic T-cell Lymphoma – A Case Report

    Directory of Open Access Journals (Sweden)

    Micković Milena

    2016-12-01

    Full Text Available Primary cutaneous CD4-positive small- to medium-sized pleomorphic T-cell lymphoma is a provisional entity in the 2005 WHO-EORTC classification for cutaneous lymphomas. It is a rare condition and, in most cases, it has a favorable clinical course and prognosis. Primary cutaneous CD4-positive small/medium pleomorphic T-cell lymphoma (PCSM-TCL is defined as a cutaneous T-cell lymphoma with predominantly small- to medium-sized CD4-positive pleomorphic T-cells without a history of patches and plaques typical of mycosis fungoides. PCSM-TCL usually presents as a solitary plaque or tumor on the head, neck, trunk or upper extremities and it is considered to have indolent clinical behavior. Histologically, it is characterized by a dense infiltration of small/medium-sized pleomorphic T-cells that involves the entire dermal thickness, often with nodular extension into the hypodermis. Using immunohistochemical staining, the majority of the reported cases proved to be CD3, CD4 positive and CD8, CD30 negative. However, due to the rarity and heterogeneity of the PCSM-TCL, precise clinicopathologic characteristics of PCSM-TCL have not been well characterized and the optimal treatment for this group of lymphomas is yet to be defined. Dermatologists and pathologists should be aware of this entity in order to avoid unnecessary aggressive treatments.

  18. Factors influencing CD4 cell count in HIV-positive pregnant women in a secondary health center in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Akinbami AA

    2015-04-01

    Full Text Available Akinsegun A Akinbami,1 Abidoye Gbadegesin,2 Sarah O Ajibola,3 Ebele I Uche,1 Adedoyin O Dosunmu,1 Adewumi Adediran,4 Adekunle Sobande2 1Department of Haematology and Blood Transfusion, 2Department Of Obstetrics and Gynaecology, College of Medicine, Lagos State University, Ikeja, Lagos, Nigeria; 3Department of Haematology and Immunology, Ben-Carson School of Medicine, Babcock University, Ilisan, Ogun State, Nigeria; 4Department of Haematology and Blood Transfusion, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria Background: Immunity in pregnancy is physiologically compromised, and this may affect CD4 count levels. It is well-established that several factors affect CD4 count level in pregnancy. This study aimed to determine the mean and reference range of CD4 count in human immunodeficiency virus (HIV-positive pregnant women in Lagos, Nigeria. Methods: A retrospective study was carried out at antenatal clinics of the Maternal and Child Center of a secondary health center in Lagos State, Nigeria. Records of HIV-positive pregnant women at various gestational ages, including CD4+ cell count at booking, packed cell volume (PCV at booking and labor, gestational age at delivery, and infant weight and sex were retrieved. The descriptive data was given as mean ± standard deviation (SD. Pearson's chi-squared test and correlation were used for analytical assessment. Results: Data were retrieved for a total of 143 patients. The mean age was 31.15±3.78 years. The mean PCV was 31.01%±3.79% at booking and 30.49%±4.80% during labor. The mean CD4 count was 413.87±212.09 cells/µL, with a range of 40 to 1,252 cells/µL. The mean infant weight was 3.05±0.45 kg, with a range of 2 to 5 kg. Age of the mother, gestational age, and PCV at booking were not statistically significantly associated with CD4 count. Conclusion: Maternal age, gestational age, and PCV at booking had no significant effects on CD4+ cell count levels in

  19. Perfect count: a novel approach for the single platform enumeration of absolute CD4+ T-lymphocytes.

    Science.gov (United States)

    Storie, Ian; Sawle, Alex; Goodfellow, Karen; Whitby, Liam; Granger, Vivian; Ward, Rosalie Y; Peel, Janet; Smart, Theresa; Reilly, John T; Barnett, David

    2004-01-01

    The derivation of reliable CD4(+) T lymphocyte counts is vital for the monitoring of disease progression and therapeutic effectiveness in HIV(+) individuals. Flow cytometry has emerged as the method of choice for CD4(+) T lymphocyte enumeration, with single-platform technology, coupled with reference counting beads, fast becoming the "gold standard." However, although single-platform, bead-based, sample acquisition requires the ratio of beads to cells to remain unchanged, there is no available method, until recently, to monitor this. Perfect Count beads have been developed to address this issue and to incorporate two bead populations, with different densities, to allow the detection of inadequate mixing. Comparison of the relative proportions of both beads with the manufacture's defined limits enables an internal QC check during sample acquisition. In this study, we have compared CD4(+) T lymphocyte counts, obtained from 104 HIV(+) patients, using TruCount beads with MultiSet software (defined as the predicated method) and the new Perfect Count beads, incorporating an in house sequential gating strategy. We have demonstrated an excellent degree of correlation between the predicate method and the Perfect Count system (r(2) = 0.9955; Bland Altman bias +27 CD4(+) T lymphocytes/microl). The Perfect Count system is a robust method for performing single platform absolute counts and has the added advantage of having internal QC checks. Such an approach enables the operator to identify potential problems during sample preparation, acquisition and analysis. Copyright 2003 Wiley-Liss, Inc.

  20. Secondary syphilis in HIV positive individuals: correlation with histopathologic findings, CD4 counts, and quantity of treponemes in microscopic sections.

    Science.gov (United States)

    Rosa, Gabriela; Procop, Gary W; Schold, Jesse D; Piliang, Melissa P

    2016-10-01

    Although syphilis is uncommon, infection rates are much higher in HIV-infected individuals than the general population. A proposed explanation is impaired cellular immunity with HIV infection. A search of one institution yielded 10 patients with a diagnosis of secondary syphilis on skin biopsy, positive syphilis serology and available CD4 counts. We evaluated 11 biopsies from the 10 patients. We correlated the patients' CD4 counts with the histologic findings and with the number of treponemes on skin biopsies, highlighted by immunohistochemistry (IHC). We also compared the detection of spirochetes in silver stained sections (e.g. Warthin-Starry) with T. pallidum IHC. All biopsies were assessed for various histologic features. The sensitivity of IHC to detect treponemes was 64% and of silver stain was 9% (p-value 0.04). The number of treponemes on the biopsies was determined by IHC. High numbers of spirochetes (i.e. >100 per 10 hpf) were only seen in patients with CD4 counts less than 250 cells/ml. The most consistent histologic finding was a moderate to severe lymphoplasmacytic infiltrate. Although the study is small, it appears that a higher number of spirochetes is associated with CD4 counts less than 250 cell/ml. The T. pallidum IHC stain was vastly superior to the Warthin-Starry stain. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. [Analysis on dynamic variations of CD4-Positive T-Lymphocytes counts and influencing factors among patients receiving highly active antiretroviral therapy in Guangxi Zhuang autonomous region].

    Science.gov (United States)

    Jiang, He; Zhu, Qiuying; Lan, Guanghua; Liu, Wei; Zhou, Chongxing; Shen, Zhiyong

    2015-10-01

    To understand dynamic variation of CD4-Positive T-Lymphocytes counts and influencing factors among patients receiving highly active anti-retroviral therapy (HAART) in Guangxi. Adult patients who received antiviral treatment for the first time after 1 January 2013 were selected. Their CD4-Positive T-Lymphocytes counts at baseline, 6 months and 12 months after treatment were analyzed. By using the general linear model repeated measures ANOVA, CD4-Positive T-Lymphocytes dynamic variations and influencing factors were described and analyzed. The average CD4 cell counts of 4 082 patients at baseline, 6(th) months and 12(th) months were (195.3 ± 155.7) cells/mm³, (331.9 ± 202.6) cells/mm³ and (380.9 ± 221.3) cells/mm³, respectively. The time specific differences in CD4-Positive T-Lymphocytes count among them were statistically significant (F=3 161.124, P=0.000). CD4-Positive T-Lymphocytes counts increased over time after treatment. The main influencing factors were sex, age, baseline CD4 cell count, medication, discontinuation of treatment or dose miss. Influenced by sex, age, medication, discontinuation of treatment or dose miss, the increased CD4-Positive T-Lymphocytes count showed a linear trend. Influenced by baseline CD4-Positive T-Lymphocytes counts and dose miss, the increase of CD4-Positive T-Lymphocytes count showed a trend which was conformed to quadratic curvilinear equation. CD4-Positive T-Lymphocytes counts among patients receiving HAART in Guangxi were influenced by many factors. It is necessary to select the time to start treatment according to patient's characteristics to get good outcome.

  2. CD4+CD8β+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr; Cruz, Jazmina L.; Bridge, Jennifer A.

    2017-01-01

    CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily...... detectable in the blood, spleen, and peripheral lymph nodes of naïve C57BL/6 mice. DP T cells were also present in Jα-/- and CD1d-/- mice, indicating that these cells are not NK-T cells. After skin administration of CASAC adjuvant, but not Quil A adjuvant, both total DP T cells and skin-infiltrating DP T...... cells increased in number. We explored the possibility that DP T cells could represent aggregates between CD4+ and CD8+ single-positive T cells and found strong evidence that a large proportion of apparent DP T cells were indeed aggregates. However, the existence of true CD4+CD8+ DP T cells...

  3. lon-beam analysis of plasma of HIV-Aids positive individual patients and comparison to CD4 counts

    International Nuclear Information System (INIS)

    Mars, J.A.; Kunsevi-Kilola, C.; Maqutu, M.L.; Kunsevi-Kilola, C; Mohammed, A.; Tarr, S.

    2013-01-01

    Full text: HIV-Aids related diseases have claimed the lives of many individuals, especially those that are economically active. This economic burden has crippled many economies since many of the lives claimed are those of individuals with special skills. However, the pathogenesis of human immuno-deficiency virus (HIV) infection is until present not fully understood. Elements such as Ca, Mg, Fe, Cu, Zn and Se are incorporated into the structure of many enzymes and are therefore essential to the enzyme function. The focus of this study is the correlation of trace element concentrations, determined by IBA, and the CD4 count. Blood obtained from 100 HIV sero-positive males and females attending clinics at the National Health Training College in Maseru metropolis, Lesotho. The CD4 cells of the samples were determined by flow cytometry (Cytoflow SL - S using CD4/CD45 monoclonal antibody and SSC/F12 getting strategy). Afterwards the plasma specimens were freeze dried and then pulverized into palettes. The palettes were coated with carbon and then irradiated with a proton beam of 3 MeV energy. X-ray emission and backscattering data were obtained and then quantified with various computational software. (author)

  4. lon-beam analysis of plasma of HIV-Aids positive individual patients and comparison to CD4 counts

    Energy Technology Data Exchange (ETDEWEB)

    Mars, J.A.; Kunsevi-Kilola, C. [Department of Biomedical Sciences, Cape Peninsula University of Technology, PO Box 1906. Bellville, 7535 (South Africa); Maqutu, M.L.; Kunsevi-Kilola, C; Mohammed, A. [HIV-Aids Unit, Cape Peninsula Universily of Technology, PO Box 1906, Bellville, 7535, (South Africa); Tarr, S. [National Health Training College, Private Bag A18, Maseru, Lesotho (South Africa)

    2013-07-01

    Full text: HIV-Aids related diseases have claimed the lives of many individuals, especially those that are economically active. This economic burden has crippled many economies since many of the lives claimed are those of individuals with special skills. However, the pathogenesis of human immuno-deficiency virus (HIV) infection is until present not fully understood. Elements such as Ca, Mg, Fe, Cu, Zn and Se are incorporated into the structure of many enzymes and are therefore essential to the enzyme function. The focus of this study is the correlation of trace element concentrations, determined by IBA, and the CD4 count. Blood obtained from 100 HIV sero-positive males and females attending clinics at the National Health Training College in Maseru metropolis, Lesotho. The CD4 cells of the samples were determined by flow cytometry (Cytoflow SL - S using CD4/CD45 monoclonal antibody and SSC/F12 getting strategy). Afterwards the plasma specimens were freeze dried and then pulverized into palettes. The palettes were coated with carbon and then irradiated with a proton beam of 3 MeV energy. X-ray emission and backscattering data were obtained and then quantified with various computational software. (author)

  5. The association between detected drug resistance mutations and CD4(+) T-cell decline in HIV-positive individuals maintained on a failing treatment regimen

    DEFF Research Database (Denmark)

    Schultze, Anna; Paredes, Roger; Sabin, Caroline

    2018-01-01

    BACKGROUND: To analyse the effect of drug resistance mutations (DRM) on CD4 cell trends in HIV-positive people maintained on virologically failing antiretroviral therapy (ART). METHODS: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with >1 CD4 co...

  6. Association between oral candidiasis and low CD4+ count among HIV positive patients in Hoima Regional Referral Hospital.

    Science.gov (United States)

    Nanteza, Martina; Tusiime, Jayne B; Kalyango, Joan; Kasangaki, Arabat

    2014-11-28

    The aim of this study was to determine the prevalence of Human Immune Virus (HIV) related oral lesions and their association with Cluster of Differentiation 4 (CD4+) count among treatment naïve HIV positive patients. This was a descriptive and analytical cross sectional study. Participants were 346 treatment naïve HIV positive adult patients. These were consecutively recruited from Hoima Regional Referral hospital between March and April 2012. Data collection involved interviews, oral examinations and laboratory analysis. A total of 168(48.6%) participants had oral lesions. The four commonest lesions were oral candidiasis (24.9%, CI = 20.6-29.7%), melanotic hyperpigmentation (17.3%, CI = 13.7-21.7%), kaposi sarcoma (9.3%, CI = 6.6-12.8%) and Oral Hairy Leukoplakia (OHL) (5.5%, CI = 3.5-8.4%). There was significant association between oral candidiasis and immunosuppression measured as CD4+ less than 350 cells/mm3 (OR = 2.69, CI = 1.608-4.502, p Oral candidiasis was the only oral lesion significantly predictive of immunosuppression (OR = 2.56, CI = 1.52-4.30, p Oral candidiasis can be considered as a marker for immunesuppression, making routine oral examinations essential in the management of HIV positive patients.

  7. Regulation and gene expression profiling of NKG2D positive human cytomegalovirus-primed CD4+ T-cells

    DEFF Research Database (Denmark)

    Jensen, Helle; Folkersen, Lasse; Skov, Søren

    2012-01-01

    we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA) to investigate the gene expression profile of NKG2D(+) CD4(+) T-cells, generated from HCMV-primed CD4(+) T-cells. We show that the HCMV-primed NKG2D(+) CD4(+) T-cells possess a higher differentiated phenotype...... than the NKG2D(-) CD4(+) T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4(+) T-cells and not by the antigen presenting cells. We observed a correlation...... CD4(+) T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D(+) CD4(+) T-cells, as well as the mechanisms regulating NKG2D cell surface expression....

  8. Second site escape of a T20-dependent HIV-1 variant by a single amino acid change in the CD4 binding region of the envelope glycoprotein

    Directory of Open Access Journals (Sweden)

    Berkhout Ben

    2006-11-01

    Full Text Available Abstract Background We previously described the selection of a T20-dependent human immunodeficiency virus type-1 (HIV-1 variant in a patient on T20 therapy. The fusion inhibitor T20 targets the viral envelope (Env protein by blocking a conformational switch that is critical for viral entry into the host cell. T20-dependent viral entry is the result of 2 mutations in Env (GIA-SKY, creating a protein that undergoes a premature conformational switch, and the presence of T20 prevents this premature switch and rescues viral entry. In the present study, we performed 6 independent evolution experiments with the T20-dependent HIV-1 variant in the absence of T20, with the aim to identify second site compensatory changes, which may provide new mechanistic insights into Env function and the T20-dependence mechanism. Results Escape variants with improved replication capacity appeared within 42 days in 5 evolution cultures. Strikingly, 3 cultures revealed the same single amino acid change in the CD4 binding region of Env (glycine at position 431 substituted for arginine: G431R. This mutation was sufficient to abolish the T20-dependence phenotype and restore viral replication in the absence of T20. The GIA-SKY-G431R escape variant produces an Env protein that exhibits reduced syncytia formation and reduced cell-cell fusion activity. The escape variant was more sensitive to an antibody acting on an early gp41 intermediate, suggesting that the G431R mutation helps preserve a pre-fusion Env conformation, similar to T20 action. The escape variant was also less sensitive to soluble CD4, suggesting a reduced CD4 receptor affinity. Conclusion The forced evolution experiments indicate that the premature conformational switch of the T20-dependent HIV-1 Env variant (GIA-SKY can be corrected by a second site mutation in Env (GIA-SKY-G431R that affects the interaction with the CD4 receptor.

  9. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer

    International Nuclear Information System (INIS)

    Hoffman, Rex; Welton, Mark L.; Klencke, Barbara; Weinberg, Vivian; Krieg, Richard

    1999-01-01

    Purpose: To assess the outcome and tolerance of HIV-positive patients with anal cancer to standard therapy based on their pretreatment CD4 count. Methods and Materials: Between 1991 and 1997, 17 HIV-positive patients with anal cancer and documented pretreatment CD4 counts were treated at the University of California, San Francisco or its affiliated hospitals with either concurrent chemotherapy and radiation or radiation alone. The outcome and complications of treatment were correlated with the patients' pretreatment CD4 count. Results: Disease for all 9 patients with pretreatment CD4 counts ≥ 200 was controlled with chemoradiation. Although four required a treatment break of 2 weeks because of toxicity, none required hospitalization. Of the 8 patients with pretreatment CD4 counts < 200, 4 experienced decreased counts, intractable diarrhea, or moist desquamation requiring hospitalization. Additionally, 4 of these 8 ultimately required a colostomy either for a therapy-related complication or for salvage. Nevertheless, 6/7 in this group who received concurrent chemotherapy and radiation had their disease controlled, whereas the patient treated with radiation alone failed and required a colostomy for salvage. Conclusion: Patients with CD4 ≥ 200 had excellent disease control with acceptable morbidity. Patients with CD4 < 200 had markedly increased morbidity; however, disease was ultimately controlled in 7/8 patients

  10. Performance evaluation of the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration in absolute number and in percentage using blood samples from children and adult patients living in the Central African Republic

    Directory of Open Access Journals (Sweden)

    Christian Diamant Mossoro-Kpinde

    2016-11-01

    Full Text Available Abstract Background The new microcapillary and fluorescence-based EC IVD-qualified Muse™ Auto CD4/CD4% single-platform assay (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany for CD4 T cell numeration in absolute number and in percentage was evaluated using Central African patients’ samples compared against the reference EC IVD-qualified BD FACSCount (Becton–Dickinson, USA flow cytometer. Methods EDTA-blood samples from 124 adults, 10 adolescents, 13 children and 3 infants were tested in parallel at 2 reference laboratories in Bangui. Results The Muse™ technique was highly reproducible, with low intra- and inter-run variabilities less than 15%. CD4 T cell counts of Muse™ and BD FACSCount in absolute number and percentage were highly correlated (r2 = 0.99 and 0.98, respectively. The mean absolute bias between Muse™ and BD FACSCount cells in absolute number and percentage were −5.91 cells/µl (95% CI −20.90 to 9.08 with limits of agreement from −77.50 to 202.40 cells/µl, and +1.69 %CD4 (95% CI ±1.29 to +2.09, respectively. The percentages of outliers outside the limits of agreement were nearly similar in absolute number (8% and percentage (10%. CD4 T cell counting by Muse™ allowed identifying the majority of individuals with CD4 T cell <200, <350 or <750 cells/µl corresponding to the relevant thresholds of therapeutic care, with sensitivities of 95.5–100% and specificities of 83.9–100%. Conclusions The Muse™ Auto CD4/CD4% Assay analyzer is a reliable alternative flow cytometer for CD4 T lymphocyte enumeration to be used in routine immunological monitoring according to World Health Organization recommendations in HIV-infected adults as well as children living in resource-constrained settings.

  11. Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

    DEFF Research Database (Denmark)

    Engsig, Frederik N; Zangerle, Robert; Katsarou, Olga

    2014-01-01

    of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. RESULTS: Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of suppression. Increasing...

  12. Regulation and gene expression profiling of NKG2D positive human cytomegalovirus-primed CD4+ T-cells.

    Directory of Open Access Journals (Sweden)

    Helle Jensen

    Full Text Available NKG2D is a stimulatory receptor expressed by natural killer (NK cells, CD8(+ T-cells, and γδ T-cells. NKG2D expression is normally absent from CD4(+ T-cells, however recently a subset of NKG2D(+ CD4(+ T-cells has been found, which is specific for human cytomegalovirus (HCMV. This particular subset of HCMV-specific NKG2D(+ CD4(+ T-cells possesses effector-like functions, thus resembling the subsets of NKG2D(+ CD4(+ T-cells found in other chronic inflammations. However, the precise mechanism leading to NKG2D expression on HCMV-specific CD4(+ T-cells is currently not known. In this study we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA to investigate the gene expression profile of NKG2D(+ CD4(+ T-cells, generated from HCMV-primed CD4(+ T-cells. We show that the HCMV-primed NKG2D(+ CD4(+ T-cells possess a higher differentiated phenotype than the NKG2D(- CD4(+ T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4(+ T-cells and not by the antigen presenting cells. We observed a correlation between CD94 and NKG2D expression in the CD4(+ T-cells following HCMV stimulation. However, knock-down of CD94 did not affect NKG2D cell surface expression or signaling. In addition, we show that NKG2D is recycled at the cell surface of activated CD4(+ T-cells, whereas it is produced de novo in resting CD4(+ T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D(+ CD4(+ T-cells, as well as the mechanisms regulating NKG2D cell surface expression.

  13. Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy.

    Science.gov (United States)

    Smith, Colette J; Sabin, Caroline A; Youle, Mike S; Kinloch-de Loes, Sabine; Lampe, Fiona C; Madge, Sara; Cropley, Ian; Johnson, Margaret A; Phillips, Andrew N

    2004-11-15

    Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm3, respectively; 84%, 84%, and 80% of subjects had a virus load of counts were associated with greater increases in CD4 cell counts during the first 3 months of HAART. From 3 months onward, a greater cumulative proportion of time spent with virus load count (an average increase of 5.2 cells/mm3/year [95% confidence interval [CI], 3.8-6.7 cells/mm3/year] for each extra 10% cumulative time spent with a virus load count, the increase was 6 cells/mm3/year less (95% CI, 2-11 cells/mm3/year) (P=.02). Sex, risk group, age, and HAART regimen were not associated with increases in CD4 cell counts. These findings emphasize the importance of maintaining virological suppression and suggest other factors that influence long-term CD4 cell response.

  14. Cd4As2Br3

    Directory of Open Access Journals (Sweden)

    Mohammed Kars

    2014-03-01

    Full Text Available Single crystals of Cd4As2Br3 (tetracadmium biarsenide tribromide were grown by a chemical transport reaction. The structure is isotypic with the members of the cadmium and mercury pnictidohalides family with general formula M4A2X3 (M = Cd, Hg; A = P, As, Sb; X = Cl, Br, I and contains two independent As atoms on special positions with site symmetry -3 and two independent Cd atoms, of which one is on a special position with site symmetry -3. The Cd4As2Br3 structure consists of AsCd4 tetrahedra sharing vertices with isolated As2Cd6 octahedra that contain As–As dumbbells in the centre of the octahedron. The Br atoms are located in the voids of this three-dimensional arrangement and bridge the different polyhedra through Cd...Br contacts.

  15. A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection.

    Directory of Open Access Journals (Sweden)

    Charline Bacchus

    Full Text Available Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI. We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM] and short-lived (transitional-memory [TTM] and effector-memory cells [TEM] resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells, although 10-fold less (p = 0.0005 than in equally infected TCM (4.5, TTM (4.7 and TEM (4.6 cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells, unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells. The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility

  16. A Single HIV-1 Cluster and a Skewed Immune Homeostasis Drive the Early Spread of HIV among Resting CD4+ Cell Subsets within One Month Post-Infection

    Science.gov (United States)

    Avettand-Fenoël, Véronique; Nembot, Georges; Mélard, Adeline; Blanc, Catherine; Lascoux-Combe, Caroline; Slama, Laurence; Allegre, Thierry; Allavena, Clotilde; Yazdanpanah, Yazdan; Duvivier, Claudine; Katlama, Christine; Goujard, Cécile; Seksik, Bao Chau Phung; Leplatois, Anne; Molina, Jean-Michel; Meyer, Laurence; Autran, Brigitte; Rouzioux, Christine

    2013-01-01

    Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3−CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that

  17. Impact on ART initiation of point-of-care CD4 testing at HIV diagnosis among HIV-positive youth in Khayelitsha, South Africa.

    Science.gov (United States)

    Patten, Gabriela E M; Wilkinson, Lynne; Conradie, Karien; Isaakidis, Petros; Harries, Anthony D; Edginton, Mary E; De Azevedo, Virginia; van Cutsem, Gilles

    2013-07-04

    Despite the rapid expansion of antiretroviral therapy (ART) programmes in developing countries, pre-treatment losses from care remain a challenge to improving access to treatment. Youth and adolescents have been identified as a particularly vulnerable group, at greater risk of loss from both pre-ART and ART care. Point-of-care (POC) CD4 testing has shown promising results in improving linkage to ART care. In Khayelitsha township, South Africa, POC CD4 testing was implemented at a clinic designated for youth aged 12-25 years. We assessed whether there was an associated reduction in attrition between HIV testing, assessment for eligibility and ART initiation. A before-and-after observational study was conducted using routinely collected data. These were collected on patients from May 2010 to April 2011 (Group A) when baseline CD4 count testing was performed in a laboratory and results were returned to the clinic within two weeks. Same-day POC CD4 testing was implemented in June 2011, and data were collected on patients from August 2011 to July 2012 (Group B). A total of 272 and 304 youth tested HIV-positive in Group A and Group B, respectively. Group B patients were twice as likely to have their ART eligibility assessed compared to Group A patients: 275 (90%) vs. 183 (67%) [relative risk (RR)=2.4, 95% CI: 1.8-3.4, ptesting and ART initiation was reduced from 36 to 28 days (p=0.6). POC CD4 testing significantly improved assessment for ART eligibility. The improvement in the proportion initiating ART and the reduction in time to initiation was not significant due to sample size limitations. POC CD4 testing reduced attrition between HIV-testing and assessment of ART eligibility. Strategies to improve uptake of ART are needed, possibly by improving patient support for HIV-positive youth immediately after diagnosis.

  18. Corrected Lymphocyte Percentages Reduce the Differences in Absolute CD4+ T Lymphocyte Counts between Dual-Platform and Single-Platform Flow Cytometric Approaches.

    Science.gov (United States)

    Noulsri, Egarit; Abudaya, Dinar; Lerdwana, Surada; Pattanapanyasat, Kovit

    2018-03-13

    To determine whether a corrected lymphocyte percentage could reduce bias in the absolute cluster of differentiation (CD)4+ T lymphocyte counts obtained via dual-platform (DP) vs standard single-platform (SP) flow cytometry. The correction factor (CF) for the lymphocyte percentages was calculated at 6 laboratories. The absolute CD4+ T lymphocyte counts in 300 blood specimens infected with human immunodeficiency virus (HIV) were determined using the DP and SP methods. Applying the CFs revealed that 4 sites showed a decrease in the mean bias of absolute CD4+ T lymphocyte counts determined via DP vs standard SP (-109 vs -84 cells/μL, -80 vs -58 cells/μL, -52 vs -45 cells/μL, and -32 vs 1 cells/μL). However, 2 participating laboratories revealed an increase in the difference of the mean bias (-42 vs -49 cells/μL and -20 vs -69 cells/μL). Use of the corrected lymphocyte percentage shows potential for decreasing the difference in CD4 counts between DP and the standard SP method.

  19. Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry

    Energy Technology Data Exchange (ETDEWEB)

    Pham, Son [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Tabarin, Thibault [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Garvey, Megan; Pade, Corinna [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Rossy, Jérémie [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Monaghan, Paul; Hyatt, Alex [CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Böcking, Till [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Leis, Andrew [CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia); Gaus, Katharina, E-mail: k.gaus@unsw.edu.au [ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, New South Wales 3220 (Australia); Mak, Johnson, E-mail: j.mak@deakin.edu.au [Deakin University, Victoria 3216 (Australia); CSIRO Australian Animal Health Laboratory, Victoria 3220 (Australia)

    2015-12-15

    Viruses are often thought to have static structure, and they only remodel after the viruses have entered target cells. Here, we detected a size expansion of virus particles prior to viral entry using cryo-electron microscopy (cryo-EM) and single molecule fluorescence imaging. HIV expanded both under cell-free conditions with soluble receptor CD4 (sCD4) targeting the CD4 binding site on the HIV-1 envelope protein (Env) and when HIV binds to receptor on cellular membrane. We have shown that the HIV Env is needed to facilitate receptor induced virus size expansions, showing that the ‘lynchpin’ for size expansion is highly specific. We demonstrate that the size expansion required maturation of HIV and an internal capsid core with wild type stability, suggesting that different HIV compartments are linked and are involved in remodelling. Our work reveals a previously unknown event in HIV entry, and we propose that this pre-entry priming process enables HIV particles to facilitate the subsequent steps in infection. - Highlights: • Cell free viruses are able to receive external trigger that leads to apparent size expansion. • Virus envelope and CD4 receptor engagement is the lynchpin of virus size expansion. • Internal capsid organisation can influence receptor mediated virus size expansion. • Pre-existing virus-associated lipid membrane in cell free virus can accommodate the receptor mediated virus size expansion.

  20. Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry

    International Nuclear Information System (INIS)

    Pham, Son; Tabarin, Thibault; Garvey, Megan; Pade, Corinna; Rossy, Jérémie; Monaghan, Paul; Hyatt, Alex; Böcking, Till; Leis, Andrew; Gaus, Katharina; Mak, Johnson

    2015-01-01

    Viruses are often thought to have static structure, and they only remodel after the viruses have entered target cells. Here, we detected a size expansion of virus particles prior to viral entry using cryo-electron microscopy (cryo-EM) and single molecule fluorescence imaging. HIV expanded both under cell-free conditions with soluble receptor CD4 (sCD4) targeting the CD4 binding site on the HIV-1 envelope protein (Env) and when HIV binds to receptor on cellular membrane. We have shown that the HIV Env is needed to facilitate receptor induced virus size expansions, showing that the ‘lynchpin’ for size expansion is highly specific. We demonstrate that the size expansion required maturation of HIV and an internal capsid core with wild type stability, suggesting that different HIV compartments are linked and are involved in remodelling. Our work reveals a previously unknown event in HIV entry, and we propose that this pre-entry priming process enables HIV particles to facilitate the subsequent steps in infection. - Highlights: • Cell free viruses are able to receive external trigger that leads to apparent size expansion. • Virus envelope and CD4 receptor engagement is the lynchpin of virus size expansion. • Internal capsid organisation can influence receptor mediated virus size expansion. • Pre-existing virus-associated lipid membrane in cell free virus can accommodate the receptor mediated virus size expansion.

  1. Some hematological parameters and the prognostic values of CD4, CD8 and total lymphocyte counts and CD4/CD8 cell count ratio in healthy HIV sero-negative, healthy HIV sero-positive and AIDS subjects in Port Harcourt, Nigeria

    Directory of Open Access Journals (Sweden)

    Blessing Didia

    2008-12-01

    Full Text Available OBJECTIVE: The present study attempts to determine normal values of CD4, CD8, CD4/CD8 ratio, total WBC and differential counts, hematocrit and total lymphocyte count (TLC in healthy HIV sero-negative and sero-positive subjects, and to assess the prognostic significance of these parameters in these subjects as compared to AIDS subjects.METHODS: A total of 300 subjects (147 M, 153 F aged between 17 and 71 years were recruited into the study. Subjects were separated according to sex and divided into three groups: Group A: healthy HIV sero-negative subjects; Group B: healthy HIV sero-positive newly diagnosed ART-naïve subjects; and Group C: AIDS subjects. CD4 and CD8 counts were determined by flow cytometry; hematocrit was determined using Hawksley micro-capillary tubes; total WBC and differential counts were determined manually with the improved Neubauer counting chamber; and TLC was obtained by multiplying the percentage of lymphocytes by the total WBC count.RESULTS: For male subjects, significant differences were found in CD4 count, CD4/CD8 count ratio, hematocrit, total WBC and TLC, whereas for female subjects, significant differences were found only in CD4 and CD4/CD8 count ratio in the three groups of subjects. In both sexes, however, these parameters were found to be highest in healthy HIV sero-negative subjects and lowest in AIDS subjects, with HIV sero-positive subjects having intermediate values. CONCLUSION: The results confirm previous reports that the CD4 count and CD4/CD8 count ratio are fairly reliable indicators of the progression of HIV infection. In addition, the results also apparently suggest that the prognostic value of CD8 count is limited and that of TLC possibly sex-dependent. The results could be of importance in our environment since previous reports have been relatively scarce.

  2. Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

    DEFF Research Database (Denmark)

    Nielsen, S. D.; Jeppesen, D. L.; Kolte, L.

    2001-01-01

    Hematologic and immunologic functions were examined in 19 HIV-negative infants of HIV-positive mothers and 19 control infants of HIV-negative mothers. Control infants were selected to match for gestational age, weight, and mode of delivery. Cord blood was obtained from all infants and used for flow...... and fetal thymic organ cultures (FTOCs). Lower naive CD4 counts (459.3 +/- 68.9 vs 1128.9 +/- 146.8 cells/microL, P HIV-positive mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P ...). In combination with lower red blood cell counts in infants of HIV-positive mothers, this finding suggested impairment of progenitor cell function. Indeed, progenitors from infants of HIV-positive mothers had decreased cloning efficiency (15.7% +/- 2.6% vs 55.8% +/- 15.9%, P =.009) and seemed to generate fewer T...

  3. Study of the ν3 band of 12CD4: Line position analysis and unambiguous fit of q2J4 terms

    Science.gov (United States)

    Ouardi, Okkacha; Kaarour, Abedlkrim

    2015-06-01

    We report the analysis of 12CD4 line positions from high-resolution rovibrational spectra, including accurate lines in the region 2160-2360 cm-1. In this analysis, 181 data points are fitted using an effective Hamiltonian expanded up to the sixth order for the ν3 fundamental band. For the assignments and analysis, we use the SPVIEW and XTDS software programs that implement the tensorial formalism developed in the Dijon group for tetrahedral molecules. Experimental transitions are assigned up to J ⩽ 15 for the ν3 cold band. Among the 37 parameters of the effective Hamiltonian for the ν3 fundamental band (of which 10 are relative to the Ground State (GS or P0), and 27 are relative to ν3), 22 relative to ν3 were fitted. The 32 parameters for ν3 allow very good simulations to be made. For this study, a total of 181 line positions were used in the least squares adjustment characterized by the root mean square deviation dRMS for line positions: 1.196 × 10-3 cm-1. On the basis of our set of 181 fits of experimental data for ν3 of 12CD4, the ambiguity of effective Hamiltonians for triply degenerate F2 states of tetrahedral molecules is verified. It is shown that, in agreement with theory, any of q2J4-type parameters cannot be determined from experimental data in a unique way, and these parameters cannot be considered as spectroscopic constants.

  4. CD4dullCD8bright double-positive T-lymphocytes have a phenotype of granzyme Bpos CD8pos memory T-lymphocytes

    NARCIS (Netherlands)

    Rentenaar, R. J.; Wever, P. C.; van Diepen, F. N.; Schellekens, P. T.; Wertheim, P. M.; ten Berge, I. J.

    1999-01-01

    BACKGROUND: T-lymphocytes that co-express CD4 and CD8 antigens may be found in small percentages in the peripheral blood of healthy individuals, and have a CD4brightCD8dull phenotype. CD4dullCD8bright T-lymphocytes have been found only in temporal association with some viral infections. METHODS:

  5. Identification and characterization of two CD4 alleles in Microminipigs

    OpenAIRE

    Matsubara, Tatsuya; Nishii, Naohito; Takashima, Satoshi; Takasu, Masaki; Imaeda, Noriaki; Aiki-Oshimo, Kayo; Yamazoe, Kazuaki; Kakisaka, Michinori; Takeshima, Shin-nosuke; Aida, Yoko; Kametani, Yoshie; Kulski, Jerzy K.; Ando, Asako; Kitagawa, Hitoshi

    2016-01-01

    Background We previously identified two phenotypes of CD4+ cells with and without reactions to anti-pig CD4 monoclonal antibodies by flow cytometry in a herd of Microminipigs. In this study, we analyzed the coding sequences of CD4 and certified the expression of CD4 molecules in order to identify the genetic sequence variants responsible for the positive and negative PBMCs reactivity to anti-pig CD4 monoclonal antibodies. Results We identified two CD4 alleles, CD4.A and CD4.B, corresponding t...

  6. Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion

    NARCIS (Netherlands)

    Stirrup, O. T.; Copas, A. J.; Phillips, A. N.; Gill, M. J.; Geskus, R. B.; Touloumi, G.; Young, J.; Bucher, H. C.; Babiker, A. G.; Kelleher, Tony; Cooper, David; Grey, Pat; Finlayson, Robert; Bloch, Mark; Ramacciotti, Tim; Gelgor, Linda; Smith, Don; Zangerle, Robert; Gill, John; Lutsar, Irja; Chêne, Geneviève; Dabis, Francois; Thiebaut, Rodolphe; Costagliola, Dominique; Guiguet, Marguerite; Vanhems, Philippe; Chaix, Marie-Laure; Ghosn, Jade; Meyer, Laurence; Boufassa, Faroudy; Hamouda, Osamah; Meixenberger, Karolin; Bannert, Norbert; Bartmeyer, Barbara; Antoniadou, Anastasia; Chrysos, Georgios; Daikos, Georgios L.; Pantazis, Nikos; Katsarou, Olga; Rezza, Giovanni; Dorrucci, Maria; Monforte, Antonella; Luca, Andrea; Prins, Maria; Helm, Jannie; Schuitemaker, Hanneke; Sannes, Mette; Brubakk, Oddbjorn; Kran, Anne-Marte; Rosinska, Magdalena; Muga, Roberto; Tor, Jordi; Olalla, Patricia; Cayla, Joan; Amo, Julia; Moreno, Santiago; Monge, Susana; Romero, Jorge; Pérez-Hoyos, Santiago; Sönnerborg, Anders; Bucher, C.; Günthard, Huldrych; Scherrer, Alexandra; Malyuta, Ruslan; Murphy, Gary; Porter, Kholoud; Johnson, Anne; Babiker, Abdel; Pillay, Deenan; Morrison, Charles; Salata, Robert; Mugerwa, Roy; Chipato, Tsungai; Price, Matt A.; Gilmour, Jill; Kamali, Anatoli; Karita, Etienne

    2018-01-01

    To investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. We make use of all pre-treatment CD4 counts, because analyses using only

  7. Fractional Brownian motion and multivariate-t models for longitudinal biomedical data, with application to CD4 counts in HIV-positive patients.

    Science.gov (United States)

    Stirrup, Oliver T; Babiker, Abdel G; Carpenter, James R; Copas, Andrew J

    2016-04-30

    Longitudinal data are widely analysed using linear mixed models, with 'random slopes' models particularly common. However, when modelling, for example, longitudinal pre-treatment CD4 cell counts in HIV-positive patients, the incorporation of non-stationary stochastic processes such as Brownian motion has been shown to lead to a more biologically plausible model and a substantial improvement in model fit. In this article, we propose two further extensions. Firstly, we propose the addition of a fractional Brownian motion component, and secondly, we generalise the model to follow a multivariate-t distribution. These extensions are biologically plausible, and each demonstrated substantially improved fit on application to example data from the Concerted Action on SeroConversion to AIDS and Death in Europe study. We also propose novel procedures for residual diagnostic plots that allow such models to be assessed. Cohorts of patients were simulated from the previously reported and newly developed models in order to evaluate differences in predictions made for the timing of treatment initiation under different clinical management strategies. A further simulation study was performed to demonstrate the substantial biases in parameter estimates of the mean slope of CD4 decline with time that can occur when random slopes models are applied in the presence of censoring because of treatment initiation, with the degree of bias found to depend strongly on the treatment initiation rule applied. Our findings indicate that researchers should consider more complex and flexible models for the analysis of longitudinal biomarker data, particularly when there are substantial missing data, and that the parameter estimates from random slopes models must be interpreted with caution. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  8. Trends in CD4 cell count response to first-line antiretroviral treatment in HIV-positive patients from Asia, 2003-2013: TREAT Asia HIV Observational Database Low Intensity Transfer.

    Science.gov (United States)

    De La Mata, Nicole L; Ly, Penh S; Ng, Oon T; Nguyen, Kinh V; Merati, Tuti P; Pham, Thuy T; Lee, Man P; Choi, Jun Y; Sohn, Annette H; Law, Matthew G; Kumarasamy, Nagalingeswaran

    2017-11-01

    Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed-effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/µl, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/µl in 2003-5 to 173 cells/µl in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers.

  9. Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer.

    Science.gov (United States)

    Matsumoto, Hirofumi; Thike, Aye Aye; Li, Huihua; Yeong, Joe; Koo, Si-Lin; Dent, Rebecca Alexandra; Tan, Puay Hoon; Iqbal, Jabed

    2016-04-01

    Tumour-infiltrating lymphocytes (TILs) signify immune response to tumour in a variety of cancers including breast cancer. However, earlier studies examining the clinical significance of TILs in breast cancers have generated mixed results. There are only a few that address the relationship between TILs and clinical outcomes in triple-negative breast cancers (TNBC). The aim of this study is to evaluate the clinical significance of TILs that express CD4 + and CD8 + , in TNBC. Immunohistochemical staining of CD4 and CD8 was performed on tissue microarrays of 164 cases of TNBC. TILs were counted separately as intratumoral when within the cancer cell nests (iTILs) and as stromal when within cancer stroma (sTILs). High CD8 + iTILs and sTILs, and CD4 + iTILs correlated with histologic grade. On Kaplan-Meier analysis, a significantly better survival rate was observed in high CD8 + iTIL (disease-free survival, DFS: P = 0.004, overall survival, OS: P = 0.02) and both high CD4 + iTILs (DFS: P = 0.025, OS: P = 0.023) and sTILs (DFS: P = 0.01, OS: P = 0.002). In multivariate analysis, CD8 + iTILs (DFS: P = 0.0095), CD4 + sTILs (DFS: P = 0.0084; OS: P = 0.0118), and CD4 (high) CD8 (high) CD8 iTILs (DFS: P = 0.0121; OS: P = 0.0329) and sTILs (DFS: P = 0.0295) showed significantly better survival outcomes. These results suggest that high levels of both CD8 + iTILs and CD4 + sTILs as well as CD4 (high) CD8 (high) iTILs and sTILs are independent prognostic factors in TNBC.

  10. Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Weizao, E-mail: chenw3@mail.nih.gov [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Feng, Yang [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Wang, Yanping [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); The Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Zhu, Zhongyu; Dimitrov, Dimiter S. [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.

  11. Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

    International Nuclear Information System (INIS)

    Chen, Weizao; Feng, Yang; Wang, Yanping; Zhu, Zhongyu; Dimitrov, Dimiter S.

    2012-01-01

    Highlights: ► Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. ► We hypothesize that CD4i antibodies could induce conformational changes in gp120. ► CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. ► CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.

  12. Quasi-Poisson versus negative binomial regression models in identifying factors affecting initial CD4 cell count change due to antiretroviral therapy administered to HIV-positive adults in North-West Ethiopia (Amhara region).

    Science.gov (United States)

    Seyoum, Awoke; Ndlovu, Principal; Zewotir, Temesgen

    2016-01-01

    CD4 cells are a type of white blood cells that plays a significant role in protecting humans from infectious diseases. Lack of information on associated factors on CD4 cell count reduction is an obstacle for improvement of cells in HIV positive adults. Therefore, the main objective of this study was to investigate baseline factors that could affect initial CD4 cell count change after highly active antiretroviral therapy had been given to adult patients in North West Ethiopia. A retrospective cross-sectional study was conducted among 792 HIV positive adult patients who already started antiretroviral therapy for 1 month of therapy. A Chi square test of association was used to assess of predictor covariates on the variable of interest. Data was secondary source and modeled using generalized linear models, especially Quasi-Poisson regression. The patients' CD4 cell count changed within a month ranged from 0 to 109 cells/mm 3 with a mean of 15.9 cells/mm 3 and standard deviation 18.44 cells/mm 3 . The first month CD4 cell count change was significantly affected by poor adherence to highly active antiretroviral therapy (aRR = 0.506, P value = 2e -16 ), fair adherence (aRR = 0.592, P value = 0.0120), initial CD4 cell count (aRR = 1.0212, P value = 1.54e -15 ), low household income (aRR = 0.63, P value = 0.671e -14 ), middle income (aRR = 0.74, P value = 0.629e -12 ), patients without cell phone (aRR = 0.67, P value = 0.615e -16 ), WHO stage 2 (aRR = 0.91, P value = 0.0078), WHO stage 3 (aRR = 0.91, P value = 0.0058), WHO stage 4 (0876, P value = 0.0214), age (aRR = 0.987, P value = 0.000) and weight (aRR = 1.0216, P value = 3.98e -14 ). Adherence to antiretroviral therapy, initial CD4 cell count, household income, WHO stages, age, weight and owner of cell phone played a major role for the variation of CD4 cell count in our data. Hence, we recommend a close follow-up of patients to adhere the prescribed medication for

  13. Efectos de la vacunación antigripal sobre el porcentaje de linfocitos T CD4 positivos en pacientes VIH 1/2 positivos: estudio de una cohorte Effects of influenza vaccination on the percentage of CD4+ T lymphocytes in HIV 1/2 positive patients: a cohort study

    Directory of Open Access Journals (Sweden)

    Leslie Barrionuevo Rosas

    2009-08-01

    Full Text Available Objetivo: Determinar la incidencia del cambio inmunitario del porcentaje de linfocitos T CD4+ en pacientes VIH 1/2 positivos en el primer trimestre posvacunación antigripal (P-CIR y secundariamente comparar las características demográficas y clínicas relacionadas con dicho cambio. Métodos: Se estudiaron 105 pacientes con VIH-sida de una cohorte retrospectiva hospitalaria entre 2001 y 2006. Se consideró P-CIR una disminución >3% del porcentaje de CD4+ prevacunal, y su asociación cruda y ajustada (sexo, edad, terapia antirretroviral, estabilidad clínica, carga viral prevacunal, CD4 total prevacunal fue evaluada por regresión logística (odds ratio [OR] con intervalo de confianza del 95% [IC95%]. Resultados: La incidencia del P-CIR fue del 33,3%, y fue persistente en un 31,4% durante los siete meses posvacunación independientemente de una viremia alta prevacunal. Asimismo, las variables demográficas y clínicas estudiadas no se relacionaron con la presencia de P-CIR, con una OR cruda de 0,90 (0,17-4,8 y una OR ajustada de 1,09 (0,17-6,8. Conclusiones: Los datos encontrados reflejan que el cambio relevante del estado inmunitario no fue despreciable en la posvacunación, aunque mayoritariamente resultó transitorio.Objective: To determine the incidence of immunologic change in the percentage of CD4+ T lymphocytes in HIV 1/2 positive patients in the first quarter after influenza vaccination (P-CIR and to compare the demographic and clinical characteristics associated with this change. Methods: We studied 105 patients with HIV/AIDS in a retrospective hospital cohort between 2001-2006. P-CIR was considered as a decrease of >3% in the prevaccination CD4+ percentage. Crude and adjusted OR (sex, age, antiretroviral therapy, clinical stability, prevaccination viremia and prevaccination total CD4 were evaluated by logistic regression (95%CI. Results: The incidence of P-CIR was 33.3%. P-CIR was persistent in 31.4% for 7 months after vaccination

  14. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes

    NARCIS (Netherlands)

    Ledergerber, B; Lundgren, JD; Walker, AS; Sabin, C; Justice, A; Reiss, P; Mussini, C; Wit, F; Monforte, AD; Weber, R; Fusco, G; Staszewski, S; Law, M; Hogg, R; Lampe, F; Gill, MJ; Castelli, F; Phillips, AN; Castelli, F; Fusco, GP; Gill, MJ; Hogg, R; Lampe, F; Law, M; Ledergerber, B; Lundgren, JD; Monforte, AD; Mussini, C; Phillips, AN; Reiss, P; Staszewski, S; Walker, AS; Rooney, P; Taylor, S; Couldwell, D; Austin, D; Block, M; Clemons, J; Finlayson, R; Law, M; Petoumenos, K; Quan, D; Smith, D; O'Connor, C; Gorton, C; Allen, D; Mulhall, B; Mutimer, K; Smith, D; Keeffe, N; Cooper, D; Carr, A; Miller, J; Pell, C; Ellis, D; Baker, D; Kidd, J; McFarlane, R; Liang, MT; Brown, K; Huffam, S; Savage, J; Morgan, S; Knibbs, P; Sowden, D; Walker, A; Orth, D; Lister, G; Chuah, J; Fankhauser, W; Dickson, B; Bradford, D; Wilson, C; Ree, H; Magon, H; Moore, R; Russell, D; McGovern, G; McNair, R; Bal, J; Fairley, K; Roth, N; Eu, B; Strecker, S; Russell, D; Wood, H; Mijch, A; Hoy, J; Pierce, A; McCormack, C; Watson, K; Medland, N; Daye, J; Mallal, S; French, M; Skett, J; Maxwel, D; Cain, A; Montroni, M; Scalise, G; Costantini, A; Giacometti, A; Tirelli, U; Nasti, G; Pastore, G; Ladisa, N; Perulli, ML; Suter, F; Arici, C; Chiodo, F; Gritti, FM; Colangeli, [No Value; Fiorini, C; Guerra, L; Carosi, G; Cadeo, GP; Castelli, F; Minardi, C; Vangi, D; Rizzardini, G; Migliorino, G; Manconi, PE; Piano, P; Ferraro, T; Scerbo, A; Pizzigallo, E; Ricci, F; Santoro, D; Pusterla, L; Carnevale, G; Galloni, D; Vigano, P; Mena, M; Ghinelli, F; Sighinolfi, L; Leoncini, F; Mazzotta, F; Pozzi, M; Lo Caputo, S; Angarano, G; Grisorio, B; Ferrara, S; Grima, P; Tundo, P; Pagano, G; Piersantelli, N; Alessandrini, A; Piscopo, R; Toti, M; Chigiotti, S; Soscia, F; Taccooni, L; Orani, A; Perini, P; Scasso, A; Vincenti, A; Scalzini, A; Fibbia, G; Moroni, M; Lazzarin, A; Cargnel, A; Vigevani, GM; Caggese, L; Monforte, AD; Tordato, F; Novati, R; Galli, A; Merli, S; Pastecchia, C; Moioli, C; Esposito, R; Mussini, C; Abrescia, N; Chirianni, A; Izzo, C; Piazza, M; De Marco, M; Montesarchio, [No Value; Manzillo, E; Nappa, S; Colomba, A; Abbadessa, [No Value; Prestileo, T; Mancuso, S; Ferrari, C; Pzzaferri, P; Filice, G; Minoli, L; Bruno, R; Maserati, R; Pauluzzi, S; Baldelli, F; Petrelli, E; Cioppi, A; Alberici, F; Ruggieri, A; Menichetti, F; Martinelli, C; De Stefano, C; La Gala, A; Zauli, T; Ballardini, G; Magnani, G; Ursitti, MA; Arlotti, M; Ortolani, P; Ortona, L; Dianzani, F; Ippolito, G; Antinori, A; Antonucci, G; D'Elia, S; Narciso, P; Petrosillo, N; Vullo, [No Value; De Luca, A; Del Forno, L; Zaccarelli, M; De Longis, P; Ciardi, M; D'Offizi, G; Noto, P; Lichtner, M; Capobianchi, MR; Girardi, E; Pezzotti, P; Rezza, G; Mura, MS; Mannazzu, M; Caramello, P; Sinicco, A; Soranzo, ML; Gennero, L; Sciandra, M; Salassa, B; Grossi, PA; Basilico, C; Poggio, A; Bottari, G; Raise, E; Pasquinucci, S; De Lalla, F; Tositti, G; Resta, F; Chimienti, A; Lepri, AC; Bachmann, S; Battegay, M; Bernasconi, E; Bucher, H; Burgisser, P; Cattacin, S; Egger, M; Erb, P; Fierz, W; Fischer, M; Flepp, M; Fontana, A; Francioli, P; Furrer, HJ; Gorgievski, M; Hirschel, B; Kaiser, L; Kind, C; Klimkait, T; Ledergerber, B; Lauper, U; Opravil, M; Paccaud, F; Pantaleo, G; Perrin, L; Piffaretti, JC; Rickenbach, M; Rudin, C; Schupbach, J; Speck, R; Tarr, P; Telenti, A; Trkola, A; Vernazza, P; Weber, R; Yerly, S; de Wolf, F; van Sighem, AI; van Valkengoed, [No Value; Gras, L; Bronsveld, W; Prins, JM; Bos, JC; Schattenkerk, JKME; Godfried, MH; Lange, JMA; Lowe, SH; van der Meer, JTM; Nellen, FJB; Pogany, K; van der Poll, T; Reiss, P; Ruys, TA; Sankatsing, S; van der Valk, M; van Vonderen, MGA; Wit, FWMN; ten Veen, JH; van Dam, PS; Hillebrand-Haverkort, ME; Brinkman, K; Frissen, PHJ; Weigel, HM; Mulder, JW; van Gorp, ECM; Meenhorst, PL; Mairuhu, ATA; Veenstra, J; Danner, SA; Van Agtmael, MA; Claessen, FAP; Geerlings, SE; Perenboom, RM; Richter, C; van der Berg, J; van Leusen, R; Vriesendorp, R; Jeurissen, FJF; Kauffmann, RH; Koger, ELW; Bravenboer, B; Mudrikova, T; Sprenger, HG; Miesen, WMAJ; ten Kate, RW; van Houte, DPF; Leemhuis, MP; Pole, M; Schippers, EF; Schreij, G; van de Geest, S; Verbon, A; Koopmans, PP; Telgt, M; van der Ven, AJAM; van der Ende, Marchina E.; Gyssens, IC; de Marie, S; Nouwen, JL; Juttmann, [No Value; Schneider, MME; Bonten, MJM; Borleffs, JCC; Hoepelman, IM; Jaspers, CAJJ; Schouten, [No Value; Schurink, CAM; Blok, WL; Groenveld, PHP; Jurriaans, S; Back, NKT; Cuijpers, T; Rietra, PJGM; Roozendaal, KJ; Pauw, W; van Zanten, AP; Smits, PHM; von Blomberg, BME; Savelkoul, P; Zaaijer, H; Swanink, C; Franck, PFH; Lampe, AS; Jansen, CL; Hendriks, R; Schirm, J; Benne, D; Veenendaal, D; Storm, H; van Zeijl, JH; Claas, HCJ; Bruggeman, CAMVA; Goossens, VJ; Galama, JMD; Poort, YAGM; Niesters, MG; Osterhaus, ADME; Buiting, AGM; Swaans, CAM; Boucher, CAB; Schuurman, R; Boel, E; Jansz, AF; Veldkamp, A; Beijnen, JH; Crommentuyn, KML; Huitema, ADR; Kappelhoff, B; de Maat, MMR; Burger, DM; Hugen, PWH; Dabis, F; Thiebaut, R; Chene, G; Lawson-Ayayi, S; Meyer, L; Boufassa, F; Hamouda, O; Pezzotti, P; Rezza, G; Touloumi, G; Hatzakis, A; Karafoulidou, A; Katsarou, O; Brettle, R; Del Amo, J; del Romero, J; van Asten, L; van Benthem, B; Prins, M; Coutinho, R; Kirk, O; Pedersen, C; Aguado, IH; Perez-Hoyos, S; Eskild, A; Bruun, JN; Sannes, M; Sabin, C; Lee, C; Johnson, AM; Phillips, AN; Babiker, A; Darbyshire, J; Gill, N; Porter, K; Francioli, P; Vanhems, P; Egger, M; Rickenbach, M; Cooper, D; Kaldor, J; Ashton, L; Cooper, D; Kaldor, J; Ashton, L; Cooper, D; Vizzard, J; Muga, R; Vanhems, P; Gill, J; Cayla, J; de Olalla, PG; Day, NE; De Angelis, D; Porter, K; Babiker, A; Walker, S; Darbyshire, J; Tyrer, F; Beral, [No Value; Coutinho, R; Darbyshire, J; Del Amo, J; Gill, N; Lee, C; Meyer, L; Rezza, G; Raffanti, S; Becker, S; Scarsella, A; Braun, J; Justice, A; Fusco, G; Most, B; Balu, R; Gilbert, L; Fleenor, R; Ising, T; Dieterich, D; Fusco, J; Losso, M; Duran, A; Vetter, N; Clumeck, N; De Wit, S; Kabeya, K; Poll, B; Colebunders, R; Machala, L; Rozsypal, H; Nielsen, J; Lundgren, J; Kirk, O; Olsen, CH; Gerstoft, J; Katzenstein, T; Hansen, ABE; Skinhoj, P; Pedersen, C; Zilmer, K; Rauka, M; Katlama, C; De Sa, M; Viard, JP; Saint-Marc, T; Vanhems, P; Pradier, C; Dietrich, M; Manegold, C; van Lunzen, J; Stellbrink, HJ; Miller, [No Value; Staszewski, S; Goebel, FD; Salzberger, B; Rockstroh, J; Kosmidis, J; Gargalianos, P; Sambatakou, H; Perdios, J; Panos, G; Filandras, A; Banhegyi, D; Mulcahy, F; Yust, [No Value; Burke, M; Pollack, S; Hassoun, J; Sthoeger, Z; Maayan, S; Vella, S; Chiesi, A; Arici, C; Pristera, R; Mazzotta, F; Gabbuti, A; Esposito, R; Bedini, A; Chirianni, A; Montesarchio, E; Vullo, [No Value; Santopadre, P; Narciso, P; Antinori, A; Franci, P; Zaccarelli, M; Lazzarin, A; Castagna, A; Monforte, AD; Viksna, L; Rozentale, B; Chaplinskas, S; Hemmer, R; Staub, T; Reiss, P; Bruun, J; Maeland, A; Ormaasen, [No Value; Knysz, B; Gasiorowski, J; Horban, A; Prokopowicz, D; Wiercinska-Drapalo, A; Boron-Kaczmarska, A; Pynka, M; Beniowski, M; Trocha, H; Smiatacz, T; Antunes, F; Mansinho, K; Maltez, F; Duiculescu, D; Streinu-Cercel, A; Mokras, M; Stanekova, D; Gonzalez-Lahoz, J; Diaz, B; Garcia-Benayas, T; Martin-Carbonero, L; Soriano, [No Value; Clotet, B; Jou, A; Conejero, J; Tural, C; Gatell, JM; Miro, JM; Zamora, L; Blaxhult, A; Karlsson, A; Pehrson, P; Ledergerber, B; Weber, R; Francioli, P; Hirschel, B; Schiffer, [No Value; Furrer, H; Chentsova, N; Barton, S; Johnson, AM; Mercey, D; Phillips, A; Youle, M; Johnson, MA; Mocroft, A; Murphy, M; Weber, J; Scullard, G; Fisher, M; Brettle, R; Loveday, C; Clotet, B; Ruiz, L; Staszewski, S; Helm, EB; Carlebach, A; Mosch, M; Muller, A; Haberl, A; Korn, S; Stephan, C; Bickel, M; Gute, P; Locher, L; Lutz, T; Klauke, S; Doerr, HW; Sturmer, M; Sabin, C; Dauer, B; Jennings, B; Alexander, C; Braitstein, P; Chan, K; Cote, H; Gataric, N; Harrigan, PR; Harris, M; Bonner, S; Hogg, R; Montaner, J; O'Shaughnessy, M; Wood, E; Yip, B; Lampe, F; Chaloner, C; Gumley, H; Ransom, D; Sabin, CA; Mocroft, A; Lipman, M; Phillips, AN; Youle, M; Johnson, M; Gill, J; Read, R; Carosi, G; Castelli, F; Paraninfo, G; Casari, S; Pan, A; Patroni, A; Torti, C; Quiros-Roldan, E; Tomasoni, L; Moretti, F; Nasta, P; Uccelli, MC; Cadeo, GP; Bertelli, D; Orani, A; Perini, P; Nigro, M; Rizzardini, G; Migliorino, M; Abeli, C; Mazzotta, F; Suter, F; Maggiolo, F; Arici, C; Ghinelli, F; Sighinolfi, L; Minoli, L; Maserati, R; Novati, S; Tinelli, C; Pastore, G; Ladisa, N; Carnevale, G; Poggio, A; Riccio, G; Mussini, C; Borghi, [No Value; Bedini, A; Esposito, R; ten Napel, C.H.

    2004-01-01

    Background Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological

  15. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes

    DEFF Research Database (Denmark)

    Ledergerber, Bruno; Lundgren, Jens D; Walker, A Sarah

    2014-01-01

    Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure....

  16. Responsiveness of T cells to interleukin-7 is associated with higher CD4+ T cell counts in HIV-1-positive individuals with highly active antiretroviral therapy-induced viral load suppression.

    Science.gov (United States)

    Camargo, Jose F; Kulkarni, Hemant; Agan, Brian K; Gaitan, Alvaro A; Beachy, Lisa A; Srinivas, Sowmya; He, Weijing; Anderson, Stephanie; Marconi, Vincent C; Dolan, Matthew J; Ahuja, Sunil K

    2009-06-15

    Despite suppression of the human immunodeficiency virus type 1 (HIV-1) load by highly active antiretroviral therapy (HAART), recovery of CD4+ T cell counts can be impaired. We investigated whether this impairment may be associated with hyporesponsiveness of T cells to gamma-chain (gammac) cytokines known to influence T cell homeostasis. The responsiveness of T cells to interleukin (IL)-2, IL-7, and IL-15 was determined by assessing cytokine-induced phosphorylation of the signal transducer and activator of transcription 5 (STAT5) in peripheral T cells obtained from 118 HIV-positive subjects and 13 HIV-negative subjects. The responsiveness of T cells to interleukin (IL)-7 but not to IL-2 or IL-15 was lower among HIV-positive subjects than among HIV-negative subjects. Among subjects with viral load suppression, the degree of IL-7 responsiveness (1) correlated with naive CD4+ T cell counts and was a better immune correlate of the prevailing CD4+ T cell count than were levels of human leukocyte antigen-DR1 or programmed death-1, which are predictors of T cell homeostasis during HIV infection; and (2) was greater in subjects with complete (i.e., attainment of >or=500 CD4+ T cells/mm3>or=5 years after initiation of HAART) versus incomplete immunologic responses. The correlation between plasma levels of IL-7 and CD4+ T cell counts during HAART was maximal in subjects with increased IL-7 responsiveness. Responsiveness of T cells to IL-7 is associated with higher CD4+ T cell counts during HAART and thus may be a determinant of the extent of immune reconstitution.

  17. World Health Organization guidelines should not change the CD4 ...

    African Journals Online (AJOL)

    The World Health Organization (WHO) currently recommends that HIV-positive adults start antiretroviral therapy (ART) at CD4 counts <350 cells/μl. Several countries have changed their guidelines to recommend ART irrespective of CD4 count or at a threshold of 500 CD4 cells/μl. Consequently, WHO is currently revising its ...

  18. World Health Organization guidelines should not change the CD4 ...

    African Journals Online (AJOL)

    2013-03-02

    Mar 2, 2013 ... The World Health Organization (WHO) currently recommends that HIV-positive adults start antiretroviral therapy (ART) at. CD4 counts <350 cells/µl. Several countries have changed their guidelines to recommend ART irrespective of CD4 count or at a threshold of 500 CD4 cells/µl. Consequently, WHO is ...

  19. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL

    DEFF Research Database (Denmark)

    O'Connor, Jemma L; Vjecha, Michael J; Phillips, Andrew N

    2017-01-01

    =0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART...

  20. Prognostic value of single measurements of beta-2-microglobulin, immunoglobulin A in HIV disease after controlling for CD4 lymphocyte counts and plasma HIV RNA levels

    DEFF Research Database (Denmark)

    Ullum, H; Lepri, A Cozzi; Katzenstein, T L

    2000-01-01

    The interrelationships between the CD4 lymphocyte count, plasma viral load [human immunodeficiency virus (HIV) RNA], beta-2-microglobulin (beta2-M) and immunoglobulin A (IgA) and the mortality risk was explored in 234 HIV-infected individuals (median CD4 count 230 cells/mm3, range 1-1,247). Product......-moment correlation analysis was used to study the association between beta2-M, IgA and HIV RNA. A proportional hazards Cox model was used to estimate the relative hazard (RH) of death. Both beta2-M (r = 0.49, p HIV RNA. High beta2-M levels were...... associated with an increased risk of death in both univariate Cox analysis and after adjustment for HIV RNA, CD4 lymphocyte count and age [RH = 1.16 per 100 nmol/l higher beta2-M, 95% confidence interval (CI) 1.05-1.27]. Raised IgA levels were associated with shorter survival in individuals with a CD4 count...

  1. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

    Science.gov (United States)

    Goel, Gautam; King, Tim; Daveson, A James; Andrews, Jane M; Krishnarajah, Janakan; Krause, Richard; Brown, Gregor J E; Fogel, Ronald; Barish, Charles F; Epstein, Roger; Kinney, Timothy P; Miner, Philip B; Tye-Din, Jason A; Girardin, Adam; Taavela, Juha; Popp, Alina; Sidney, John; Mäki, Markku; Goldstein, Kaela E; Griffin, Patrick H; Wang, Suyue; Dzuris, John L; Williams, Leslie J; Sette, Alessandro; Xavier, Ramnik J; Sollid, Ludvig M; Jabri, Bana; Anderson, Robert P

    2017-07-01

    A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet. We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post

  2. Phenotypical and functional characterization of double-negative (CD4-CD8-) alpha beta T-cell receptor positive cells from an immunodeficient patient

    DEFF Research Database (Denmark)

    Illum, N; Ralfkiaer, E; Pallesen, G

    1991-01-01

    We have characterized CD4-CD8- double-negative (DN) alpha beta TCR+ T cells from a patient with immunodeficiency, lymphocytosis, lymphadenopathy, and hepatosplenomegaly. The majority of peripheral blood lymphocytes were DN alpha beta TCR+ T cells as evaluated by FACS and biochemical analysis...... (MoAbs) indicated a polyclonal T-cell expansion. Thymic biopsy showed normal histology, whereas lymph node biopsy samples showed altered histological and immunohistological patterns with markedly expanded paracortical areas containing the DN T cells of the same phenotype as found in peripheral blood T...

  3. Trends of CD4 cell count levels at the initiation of antiretroviral therapy over time and factors associated with late initiation of antiretroviral therapy among Asian HIV-positive patients

    Science.gov (United States)

    Kiertiburanakul, Sasisopin; Boettiger, David; Lee, Man Po; Omar, Sharifah Fs; Tanuma, Junko; Ng, Oon Tek; Durier, Nicolas; Phanuphak, Praphan; Ditangco, Rossana; Chaiwarith, Romanee; Kantipong, Pacharee; Lee, Christopher Kc; Mustafa, Mahiran; Saphonn, Vonthanak; Ratanasuwan, Winai; Merati, Tuti Parwati; Kumarasamy, Nagalingeswaran; Wong, Wing Wai; Zhang, Fujie; Pham, Thanh Thuy; Pujari, Sanjay; Choi, Jun Yong; Yunihastuti, Evy; Sungkanuparph, Somnuek

    2014-01-01

    Introduction Although antiretroviral therapy (ART) has been rapidly scaled up in Asia, most HIV-positive patients in the region still present with late-stage HIV disease. We aimed to determine trends of pre-ART CD4 levels over time in Asian HIV-positive patients and to determine factors associated with late ART initiation. Methods Data from two regional cohort observational databases were analyzed for trends in median CD4 cell counts at ART initiation and the proportion of late ART initiation (CD4 cell counts ART initiation and mortality were determined. Results A total of 2737 HIV-positive ART-naïve patients from 22 sites in 13 Asian countries and territories were eligible. The overall median (IQR) CD4 cell count at ART initiation was 150 (46–241) cells/mm3. Median CD4 cell counts at ART initiation increased over time, from a low point of 115 cells/mm3 in 2008 to a peak of 302 cells/mm3 after 2011 (p for trend 0.002). The proportion of patients with late ART initiation significantly decreased over time from 79.1% before 2007 to 36.3% after 2011 (p for trend ART initiation were year of ART initiation (e.g. 2010 vs. before 2007; OR 0.40, 95% CI 0.27–0.59; pART initiation were late ART initiation (HR 2.13, 95% CI 1.19–3.79; p=0.010), sex (male vs. female; HR 2.12, 95% CI 1.31–3.43; p=0.002), age (≥51 vs. ≤30 years; HR 3.91, 95% CI 2.18–7.04; pART initiation among Asian patients significantly increases over time but the proportion of patients with late ART initiation is still significant. ART initiation at higher CD4 cell counts remains a challenge. Strategic interventions to increase earlier diagnosis of HIV infection and prompt more rapid linkage to ART must be implemented. PMID:24598459

  4. In vitro differentiation from a pluripotent human CD4+CD8+ thymic cloned cell into four phenotypically distinct subsets.

    Science.gov (United States)

    Boumsell, L; Schmid, M; Dastot, H; Gouttefangeas, C; Mathieu-Mahul, D; Bensussan, A

    1990-11-01

    Human thymic cell differentiation is almost totally unknown. In the present study we developed an in vitro system using human thymic cloned cells to analyze precursor-progeny relationship. We obtained several CD4+CD8+ double positive thymic clones that could give rise after several weeks in culture only to either CD4 or CD8 single positive clones. By contrast we isolated a unique pluripotent thymic double positive clone, termed B12, which differentiated into four phenotypically distinct T cell clones, namely double-positive CD4+CD8+, double-negative CD4-CD8- or either single-positive phenotype. We derived stable subclones representative of each phenotype and we showed by molecular analysis that they expressed the same TCR. Utilization of either CD3 or anticlonotypic mAb revealed that this TCR expressed by the four subclones was functional.

  5. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice

    International Nuclear Information System (INIS)

    Hanna, Zaher; Priceputu, Elena; Hu, Chunyan; Vincent, Patrick; Jolicoeur, Paul

    2006-01-01

    HIV-1 Nef has the ability to downmodulate CD4 cell surface expression. Several studies have shown that CD4 downregulation is required for efficient virus replication and high infectivity. However, the pathophysiological relevance of this phenomenon in vivo, independently of its role in sustaining high virus loads, remains unclear. We studied the impact of the CD4 downregulation function of Nef on its pathogenesis in vivo, in the absence of viral replication, in the CD4C/HIV transgenic (Tg) mouse model. Two independent Nef mutants (RD35/36AA and D174K), known to abrogate CD4 downregulation, were tested in Tg mice. Flow cytometry analysis showed that downregulation of murine CD4 was severely decreased or abrogated on Tg T cells expressing respectively Nef RD35/36AA and Nef D174K . Similarly, the severe depletion of double-positive CD4 + CD8 + and of single-positive CD4 + CD8 - thymocytes, usually observed with Nef Wt , was not detected in Nef RD35/36AA and Nef D174K Tg mice. However, both mutant Tg mice showed a partial depletion of peripheral CD4 + T cells. This was accompanied, as previously reported for Net Wt Tg mice, by the presence of an activated/memory-like phenotype (CD69 + , CD25 + , CD44 + , CD45RB Low , CD62 Low ) of CD4 + T cells expressing Nef RD35/36AA and to a lesser extent Nef D174K . In addition, both mutants retained the ability to block CD4 + T cell proliferation in vitro after anti-CD3 stimulation, but not to enhance apoptosis/death of CD4 + T cells. Therefore, it appears that Nef-mediated CD4 downregulation is associated with thymic defects, but segregates independently of the activated/memory-like phenotype, of the partial depletion and of the impaired in vitro proliferation of peripheral CD4 + T cells. Histopathological assessment revealed the total absence of or decrease severity and frequency of organ AIDS-like diseases (lung, heart and kidney pathologies) in respectively Nef RD35/36AA and Nef D174K Tg mice, relative to those developing in

  6. Relationships between CD4+ Counts and the Presence of Oral ...

    African Journals Online (AJOL)

    Relationships between CD4+ Counts and the Presence of Oral Lesions in Human Immunodeficiency Virus Positive Women in Nigeria. ... Annals of Medical and Health Sciences Research ... Keywords: CD4+ counts, Human immunodeficiency virus/Acquired immune deficiency syndrome positive women, Oral lesions ...

  7. Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study

    NARCIS (Netherlands)

    Lodi, Sara; Phillips, Andrew; Logan, Roger; Olson, Ashley; Costagliola, Dominique; Abgrall, Sophie; van Sighem, Ard; Reiss, Peter; Miró, José M.; Ferrer, Elena; Justice, Amy; Gandhi, Neel; Bucher, Heiner C.; Furrer, Hansjakob; Moreno, Santiago; Monge, Susana; Touloumi, Giota; Pantazis, Nikos; Sterne, Jonathan; Young, Jessica G.; Meyer, Laurence; Seng, Rémonie; Dabis, Francois; Vandehende, Marie-Anne; Pérez-Hoyos, Santiago; Jarrín, Inma; Jose, Sophie; Sabin, Caroline; Hernán, Miguel A.; Ainsworth, J.; Anderson, J.; Babiker, A.; Delpech, V.; Dunn, D.; Easterbrook, P.; Fisher, M.; Gazzard, B.; Gilson, R.; Gompels, M.; Hill, T.; Johnson, M.; Leen, C.; Orkin, C.; Phillips, A.; Pillay, D.; Porter, K.; Sabin, C.; Walsh, J.; Glabay, A.; Thomas, R.; Jones, K.; Perry, N.; Pullin, A.; Churchill, D.; Bulbeck, S.; Mandalia, S.; Clarke, J.; Munshi, S.; Post, F.; Khan, Y.; Patel, P.; Karim, F.; Duffell, S.; Williams, I.; Dooley, D.; Schwenk, A.; Youle, M.; Lampe, F.; Chaloner, C.; Puradiredja, D. Ismajani; Bansi, L.; Weber, J.; Kemble, C.; Mackie, N.; Winston, A.; Wilson, A.; Bezemer, D. O.; Kesselring, A. M.; van Sighem, A. I.; Smit, C.; Zaheri, S.; Kortmann, W.; Prins, J. M.; Kuijpers, T. W.; Godfried, M. H.; Pajkrt, D.; Bos, J. C.; van der Valk, M.; Grijsen, M. L.; Wiersinga, W. J.; Vrouwe, Lieve; Brinkman, K.; Blok, W. L.; Ziekenhuis, Andreas; Veenstra, J.; Lettinga, K. D.; Mulder, J. W.; Lauw, F. N.; van Agtmael, M. A.; Perenboom, R. M.; Bomers, M.; Richter, C.; van der Berg, J. P.; Gisolf, E. H.; Schippers, E. F.; van Elzakker, E. P.; Bravenboer, B.; Kootstra, G. J.; Sprenger, H. G.; Doedens, R.; van Assen, S.; Gasthuis, Kennemer; Soetekouw, R.; Kroon, F. P.; van Dissel, J. T.; Arend, S. M.; Jolink, H.; Bauer, M. P.; Weijer, S.; Lowe, S.; Lashof, A. Oude; Posthouwer, D.; Koopmans, P. P.; Warris, A.; van Crevel, R.; Nouwen, J. L.; Nispen, M. H.; Verbon, A.; Hassing, R. J.; Hartwig, N. G.; Ziekenhuis, Maasstad; Pogany, K.; Ziekenhuis, Sint Elisabeth; Juttmann, J. R.; van Kasteren, M. E. E.; Mudrikova, T.; Ellerbroek, P. M.; Oosterheert, J. J.; Barth, R. E.; Kinderziekenhuis, Wilhelmina; Bont, L. J.; de Ruyter Ziekenhuis, Admiraal; Stegeman, A.; Alleman, M. A.; Bouwhuis, J. W.; Abgrall, S.; Barin, F.; Bentata, M.; Billaud, E.; Boué, F.; Burty, C.; Cabié, A.; de Truchis, P.; Duval, X.; Duvivier, C.; Enel, P.; Fredouille-Heripret, L.; Gasnault, J.; Gaud, C.; Katlama, C.; Khuong, M. A.; Lang, J. M.; Lascaux, A. S.; Launay, O.; Mahamat, A.; Mary-Krause, M.; Meynard, J. L.; Pavie, J.; Pialoux, G.; Pilorgé, F.; Poizot-Martin, I.; Pradier, C.; Reynes, J.; Rouveix, E.; Simon, A.; Tissot-Dupont, H.; Viard, J. P.; Viget, N.; Jacquemet, N.; Costagliola, D.; Grabar, S.; Guiguet, M.; Lanoy, E.; Lièvre, L.; Lacombe, J. M.; Potard, V.; Pitié, G. H.; Bricaire, F.; Herson, S.; Desplanque, N.; Meyohas, M. C.; Picard, O.; Cadranel, J.; Mayaud, C.; Clauvel, J. P.; Decazes, J. M.; Gerard, L.; Molina, J. M.; Lariboisière-Fernand, G. H.; Honoré, P.; Jeantils, V.; Tassi, S.; Mechali, D.; Taverne, B.; Bouvet, E.; Ecobichon, J. L.; Matheron, S.; Picard-Dahan, C.; Yeni, P.; Dupont, C.; Chandemerle, C.; Mortier, E.; Tisne-Dessus, D.; Weiss, L.; Tarnier-Cochin, G. H.; Auperin, I.; Gilquin, J.; Roudière, L.; Fior, R.; Delfraissy, J. F.; Goujard, C.; Jung, C.; Vittecoq, D.; Fraisse, P.; Beck-Wirth, G.; Stahl, J. P.; Lecercq, P.; Gourdon, F.; Laurichesse, H.; Fresard, A.; Basse-Normandie, Corevih; Bazin, C.; Verdon, R.; Bourgogne, Corevih; Bretagne, Corevih; Arvieux, C.; Michelet, C.; Goudeau, A.; Maître, M. F.; Hoen, B.; Faller, J. P.; Haute-Normandie, Corevih; Borsa-Lebas, F.; Caron, F.; Daures, J. P.; Lorraine, Corevih; May, T.; Rabaud, C.; Berger, J. L.; Rémy, G.; Arlet-Suau, E.; Cuzin, L.; Massip, P.; Legrand, M. F. Thiercelin; Pontonnier, G.; de Calais, Corevih Nord-Pas; Yasdanpanah, Y.; Dellamonica, P.; Pugliese, P.; Quinsat, D.; Ravaux, I.; Tissot, H.; Delmont, J. P.; Moreau, J.; Gastaut, J. A.; Retornaz, F.; Soubeyrand, J.; Galinier, A.; Ruiz, J. M.; Allegre, T.; Blanc, P. A.; Bonnet, D.; Lepeu, G.; Granet-Brunello, P.; Esterni, J. P.; Cohen-Valensi, R.; Nezri, M.; Chadapaud, S.; Laffeuillade, A.; Raffi, F.; Boibieux, A.; Peyramond, D.; Livrozet, J. M.; Touraine, J. L.; Strobel, M.; Saint-Martin, C. H.; Bissuel, F.; Pradinaud, R.; Sobesky, M.; Martinique, Corevih; Guyon, Félix; Contant, M.; HC, Bucher; CA, Fux; HH, Hirsch; de Tejada B, Martinez; Casabona, J.; Miró, Jose M.; de Barcelona-Idibaps, Clínic; Gallois, A.; Esteve, A.; Podzamczer, D.; Murillas, J.; Gatell, J. M.; Manzardo, C.; Tural, C.; Clotet, B.; Ferrer, E.; Riera, M.; Segura, F.; Navarro, G.; Vilaró, J.; Masabeu, A.; García, I.; Guadarrama, M.; Cifuentes, C.; Dalmau, D.; Agustí, C.; Montoliu, A.; Pérez, I.; Gargoulas, Freyra; Blanco, J. L.; Garcia-Alcaide, F.; Martínez, E.; García-Goez, J. F.; Sirera, G.; Negredo, E.; Miranda, C.; Capitan, M. C.; Saumoy, M.; Imaz, A.; Tiraboschi, J. M.; Murillo, O.; Bolao, F.; Peña, C.; Cabellos, C.; Vila, A.; Sala, M.; Cervantes, M.; Amengual, Jose; Navarro, M.; Barrufet, P.; Molina, J.; Alvaro, M.; Mercadal, J.; Fernández, Juanse; Ospina, Jesús E.; Berenguer, J.; García, F.; Gutiérrez, F.; Labarga, P.; Moreno, S.; Caro-Murillo, A. M.; Sobrino, P.; Jarrín, I.; Sirvent, J. L. Gómez; Rodríguez, P.; Alemán, M. R.; Alonso, M. M.; López, A. M.; Hernández, M. I.; Soriano, V.; Barreiro, P.; Medrano, J.; Rivas, P.; Herrero, D.; Blanco, F.; Vispo, M. E.; Martín, L.; Ramírez, G.; Rubio, R.; Pulido, F.; Moreno, V.; Cepeda, C.; Iribarren, J. A.; Camino, X.; Rodríguez-Arrondo, F.; von Wichmann, M. A.; Pascual, L.; Goenaga, M. A.; Masiá, M.; Ramos, J. M.; Padilla, S.; Sánchez-Hellín, V.; Bernal, E.; Montolio, F.; Peral, Y.; Marañón, Gregorio; López, J. C.; Miralles, P.; Cosín, J.; Sánchez, M.; Gutiérrez, I.; Ramírez, M.; Padilla, B.; Vidal, F.; Veloso, S.; Viladés, C.; López-Dupla, M.; Olona, M.; Vargas, M.; Lacruz, J.; Salavert, M.; Montero, M.; Cuéllar, S.; Sanz, J.; Oteo, J. A.; Blanco, J. R.; Ibarra, V.; Metola, L.; Sanz, M.; Pérez-Martínez, L.; Sola, J.; Uriz, J.; Castiello, J.; Reparaz, J.; Arriaza, M. J.; Irigoyen, C.; Antela, A.; Casado, J. L.; Dronda, F.; Moreno, A.; Pérez, M. J.; López, D.; Gutiérrez, C.; Martí, P.; García, L.; Page, C.; Hernández, J.; Peña, A.; Muñoz, L.; Parra, J.; Viciana, P.; Leal, M.; López-Cortés, L. F.; Mata, R.; Justice, A. C.; Rimland, D.; Jones-Taylor, C.; Oursler, K. A.; Brown, S.; Garrison, S.; Rodriguez-Barradas, M.; Masozera, N.; Goetz, M.; Leaf, D.; Simberkoff, M.; Blumenthal, D.; Leung, J.; Peck, R.; Mattocks, K.; Braithwaite, S.; Cook, R.; Conigliaro, J.; Crothers, K.; Chang, J.; Crystal, S.; Day, N.; Erdos, J.; Freiberg, M.; Kozal, M.; Gerschenson, M.; Good, B.; Gordon, A.; Goulet, J. L.; Hernán, M. A.; Kraemer, K.; Lim, J.; Maisto, S.; O'Connor, P.; Papas, R.; Robins, J. M.; Rinaldo, C.; Roberts, M.; Samet, J.; Tierney, B.; Whittle, J.; Brettle, R.; Fidler, S.; Goldberg, D.; Hawkins, D.; Jaffe, H.; Johnson, A.; McLean, K.; Porter, Kholoud; Ewings, Fiona; Fairbrother, Keith; Gnatiuc, Louisa; Murphy, Brendan; Douglas, G.; Kennedy, N.; Pritchard, J.; Andrady, U.; Gwynedd, Ysbyty; Rajda, N.; Maw, R.; McKernan, S.; Drake, S.; Gilleran, G.; White, D.; Ross, J.; Toomer, S.; Hewart, R.; Wilding, H.; Woodward, R.; Dean, G.; Heald, L.; Horner, P.; Glover, S.; Bansaal, D.; Carne, C.; Browing, M.; Stanley, B.; O'Mahony, C.; Fraser, P.; Hayman, B.; Joshi, U.; Ralph, S.; Wade, A.; Mette, R.; Lalik, J.; Summerfield, H.; El-Dalil, A.; France, A. J.; White, C.; Robertson, R.; Gordon, S.; Lean, C.; Morris, S.; Vithayathil, K.; McLean, L.; Winter, A.; Gale, D.; Jacobs, S.; Tayal, S.; Short, L.; Williams, G.; Minton, J.; Dhar, J.; Nye, F.; DeSouza, C. B.; Isaksen, A.; McDonald, L.; Franca, A.; William, L.; Peters, B.; El, S.; Easterbrook, P. J.; Mazhude, C.; Johnstone, R.; Fakoya, A.; Mchale, J.; Waters, A.; Kegg, S.; Mitchell, S.; Byrne, P.; Rice, P.; Mullaney, S. A.; McCormack, S.; David, D.; Melville, R.; Phillip, K.; Balachandran, T.; Mabey, S.; Sukthankar, A.; Murphy, C.; Wilkins, E.; Ahmad, S.; Cook, James; Haynes, J.; Keynes, Milton; Evans, E.; Ong, E.; Das, R.; Grey, R.; Meaden, J.; Bignell, C.; Loay, D.; Peacock, K.; Eliot, George; Girgis, M. R.; Morgan, B.; Palfreeman, A.; Wilcox, J.; Tobin, J.; Tucker, L.; Saeed, A. M.; Williams, O.; Clwyd, Glan; Lacey, H.; Herman, S.; Kinghorn, D.; Devendra, S. V.; Wither, J.; Dawson, S.; Rowen, D.; Harvey, J.; Chauhan, M.; Kellock, D.; Young, S.; Dannino, S.; Kathir, Y.; Rooney, G.; Currie, J.; Fitzgerald, M.; Devendra, S.; Keane, F.; Booth, G.; Arumainayyagam, J.; Chandramani, S.; Robinson, T.; Curless, E.; Gokhale, R.; Tariq, A.; Luzzi, G.; Fairley, I.; Wallis, F.; Smit, E.; Ward, F.; Loze, B.; Morlat, P.; Bonarek, M.; Bonnet, F.; Nouts, C.; Louis, I.; Reliquet, V.; Sauser, F.; Biron, C.; Mounoury, O.; Hue, H.; Brosseau, D.; Ghosn, J.; Rannou, M. T.; Bergmann, J. F.; Badsi, E.; Rami, A.; Girard, P. M.; Samanon-Bollens, D.; Campa, P.; Tourneur, M.; Desplanques, N.; Jeanblanc, F.; Chiarello, P.; Makhloufi, D.; Herriot, E.; Blanc, A. P.; Allègre, T.; Baillat, V.; Lemoing, V.; de Boever, C. Merle; Tramoni, C.; Sobesky, G.; Abel, S.; Beaujolais, V.; Slama, L.; Fournier, I.; Gerbe, J.; Trepo, C.; Koffi, K.; Miailhes, P.; Thoirain, V.; Brochier, C.; Souala, F.; Ratajczak, M.; Beytoux, J.; Jacomet, C.; Montpied, G.; Olivier, C.; Paré, A.; Lortholary, O.; Dupont, B.; Maignan, A.; Raymond, I.; Leport, C.; Jadand, C.; Jestin, C.; Longuet, P.; Boucherit, S.; Sereni, D.; Lascoux, C.; Prevoteau, F.; Sobel, A.; Levy, Y.; Lelièvre, J. D.; Mondor, H.; Aumaître, H.; Delmas, B.; Saada, M.; Medus, M.; Salmon, D.; Tahi, T.; Yazdanpanah, Y.; Pavel, S.; Marien, M. C.; Dron, C. H.; Beck, C.; Benomar, M.; Muller, E.; Tubiana, R.; Mohand, H. Ait; Touam, F.; Folzer, A.; Obadia, M.; Prudhomme, L.; Bonnet, E.; Balzarin, F.; Pichard, E.; Chennebault, J. M.; Fialaire, P.; Loison, J.; Galanaud, P.; Bornarel, D.; Six, M.; Ferret, P.; Batisse, D.; Devidas, A.; Chevojon, P.; Turpault, I.; Philip, G.; Morel, P.; Timsit, J.; Amirat, N.; Cabane, J.; Tredup, J.; Chavanet, C.; Buisson, M.; Treuvetot, S.; Choutet, P.; Bastides, F.; Boyer, L.; Wassoumbou, S.; Oksenhendeler, E.; Gérard, L.; Bernard, L.; Berthé, H.; Poincaré, R.; Domart, Y.; Merrien, D.; Belan, A. Greder; Mignot, A.; Gayraud, M.; Bodard, L.; Meudec, A.; Pape, E.; Vinceneux, P.; Simonpoli, A. M.; Zeng, A.; Mourier, L.; Fournier, L.; Jacquet, M.; Fuzibet, J. G.; Sohn, C.; Rosenthal, E.; Quaranta, M.; Sabah, M.; Audhuy, B.; Schieber, A.; Pasteur, L.; Moreau, P.; Vaillant, O.; Huchon, G.; Compagnucci, A.; de Lacroix Szmania, I.; Lamaury, I.; Saint-Dizier, F.; Garipuy, D.; Drogoul, M. P.; Martin, I. Poizot; Fabre, G.; Lambert, G.; Lagarde, P.; David, F.; Roche-Sicot, J.; Saraux, J. L.; Leprêtre, A.; Veil, S.; Fampin, B.; Uludag, A.; Morin, A. S.; Bletry, O.; Zucman, D.; Regnier, A.; Girard, J. J.; Quinsat, D. T.; Heripret, L.; Grihon, F.; Houlbert, D.; Ruel, M.; Chemlal, K.; Debab, Y.; Nicolle, C.; Perronne, V.; Quesnay, F.; Slama, B.; Duffaut, H.; Perré, P.; Miodovski, C.; Guermonprez, G.; Dulioust, A.; Ballanger, R.; Patey, O.; Semaille, C.; Deville, J.; Beclere, Antoine; Boue, F.; Chambrin, V.; Pignon, C.; Estocq, G. A.; Levy, A.; Bicetre, Le Kremlin; Duracinsky, M.; Bras, P. Le; Ngussan, M. S.; Lambert, T.; Segeral, O.; Lezeau, P.; Laurian, Y.; Piketty, C.; Karmochkine, M.; Eliaszewitch, M.; Jayle, D.; Tisne, D.; Colasante, U.; Vilde, J. L.; Bollens, D.; Binet, D.; Diallo, B.; Lagneau, J. L.; Pietrie, M. P.; Sicard, D.; Stieltjes, N.; Michot, J.; Bourdillon, F.; Obenga, G.; Escaut, L.; Bolliot, C.; Schneider, L.; Iguertsira, M.; Stein, A.; Tomei, C.; Dhiver, C.; Gallais, J.; Gallais, H.; Durant, J.; Mondain, V.; Perbost, I.; Cassuto, J. P.; Karsenti, J. M.; Ceppi, C.; Krivitsky, J. A.; Honore, P.; Delgado, J.; Rouzioux, C.; Burgard, M.; Boufassa, L.; Peynet, J.; Pérez-Hoyos, S.; Schiaffino, A.; Monge, D. Alvarez S.; Pujol, I.; Muga, R.; Sanvisens, A.; Tor, J.; Rivas, I.; Vallecillo, G.; del Romero, J.; Raposo, P.; Rodríguez, C.; Vera, M.; Alastrue, E. Fernandez I.; Tasa, C. Santos T.; Juan, A.; Trullen, J.; de Olalla, P. Garcia; Cayla, J.; Sambeat, M. A.; Guerrero, R.; Rivera, E.; Marco, A.; Quintana, M.; Gonzalez, C.; Castilla, J.; Guevara, M.; de Mendoza, C.; Zahonero, N.; Ortíz, M.; G, Daikos; T, Kordossis; G, Panos; H, Sambatakou; M, Chini; Nelson, M.; Asboe, D.; Man, S.-L.; Smith, C.; Grabowska, H.; Gras, L. A. J.; Branger, J.; Scherpbier, H. J.; van der Meer, J. T. M.; Wit, F. W. M. N.; van der Poll, T.; Nellen, F. J. B.; Lange, J. M. A.; Geerlings, S. E.; van Vugt, M.; Frissen, P. H. J.; Schouten, W. E. M.; van den Berk, G. E. L.; Vrouenraets, S. M. E.; van Eeden, A.; Verhagen, D. W. M.; Claessen, F. A. P.; Peters, E. J. G.; van Nieuwkoop, C.; Leyten, E. M. S.; Gelinck, L. B. S.; Ziekenhuis, Catharina; Pronk, M. J. H.; Delsing, C. E.; Scholvinck, E. H.; Bierman, W. F. W.; ten Kate, R. W.; de Boer, M. G. J.; ter Vollaard, H. J. M.; Zuiderzee, M. C.; Schreij, G.; Keuter, M.; van der Ven, A. J. A. M.; ter Hofstede, H. J. M.; Dofferhoff, A. S. M.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; Schurink, C. A. M.; Rijnders, B. J. A.; van Gorp, E. C. M.; Smeulders, A. W. M.; den Hollander, J. G.; Hoepelman, A. I. M.; Schneider, M. M. E.; Jaspers, C. A. J. J.; Arends, J. E.; Wassenberg, M. W. M.; Geelen, S. P. M.; Wolfs, T. F. W.; Cotte, L.; Tattevin, P.; Selinger-Leneman, H.; Diemer, M.; Sellier, P.; Crickx, B.; Lesprit, Ph; Rey, D.; Lucht, F.; Chavanet, P.; Eglinger, P.; Aleksandrowicz, K.; Pelissier, L.; Aubert, V.; Barth, J.; Battegay, M.; Bernasconi, E.; Böni, J.; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Egger, M.; Elzi, L.; Fehr, J.; Fellay, J.; Furrer, H.; Gorgievski, M.; Günthard, H.; Hasse, B.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kovari, H.; Ledergerber, B.; Martinetti, G.; Metzner, K.; Müller, N.; Nadal, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Yerly, S.; Force, L.; Mallolas, J.; López-Dieguez, M.; Romeu, J.; Jou, A.; Masó, M.; Bejarano, G.; del Amo, J.; Muñoz, M. A.; Arrizabalaga, A. J.; Aramburu, M. J.; Escolano, C.; Sanjuan, M.; Peraire, J.; Aldeguer, J. L.; Blanes, M.; de los Santos, I.; Hernández, B.; Pumares, M.; Trastoy, M.; Fiellin, D. A.; Titanji, R.; Butt, A.; Brandt, C.; Bryant, K.; Gandhi, N.; Gaziano, M.; Miller, P.; Mole, L.; Darbyshire, J.; Cursley, Adam; Eduards, S.; Estreich, S.; Magdy, A.; Jebakumar, S. P. R.; McMillan, S.; Green, S.; Sivakumar, K.; Monteiro, E.; Jendrulek, I.; Deheragada, A.; Rajamanoharan, S.; Parrinello, M.; Chakvetadze, C.; Berrebi, V.; Augustin-Normand, C.; Morelon, S.; Ragnaud, J. M.; Dominguez, S.; Dumont, C.; Drenou, B.; Drobacheff, C.; Gonzales-Canali, A.; Cheret, A.; Brancion, C.; Ravault, I.; Nau, P.; Beuscart, C.; Daniel, C.; Chaillou, S.; Niault, M.; Richier, L.; Abraham, B.; Perino, C.; Tremollieres, F.; Boudon, P.; Malbec, D.; Remy, G.; Béguinot, I.; Peretti, D.; Medintzeff, N.; Kazatchkine, M.; Fonquernie, L.; Lelievre, J. D.; Tissot Dupont, H.; Vallon, A.; Venti, H.; Bouchaud, O.; Hurtado, I.; Belda, J.; Gargalianos-Kakolyris, P.; Katsarou, O.; Lazanas, M.; Paparizos, V.; Paraskevis, D.; Skoutelis, A.; Touloumi, G.; Pantazis, N.; Bakoyannis, G.; Gioukari, V.; Antoniadou, A.; Papadopoulos, A.; Petrikkos, G.; Daikos, G.; Psichogiou, M.; Xylomenos, G.; Kouramba, A.; Ioannidou, P.; Kordossis, T.; Kontos, A.; Tsogas, N.; Leuow, K.; Kourkounti, S.; Sambatakou, H.; Mariolis, I.; Papastamopoulos, V.; Baraboutis, I.

    2015-01-01

    Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation,

  8. Prolactin increases CD4/CD8 cell ratio in thymus-grafted congenitally athymic nude mice.

    OpenAIRE

    Gaufo, G O; Diamond, M C

    1996-01-01

    One distinctive effect on T-cell development was analyzed by selectively increasing serum prolactin (PRL) concentration in thymus-grafted congenitally athymic nude mice and by neutralizing PRL in suspension cultures of thymus from 1-day-old neonatal mice. Flow cytometric analysis of single-positive CD4+ and CD8+ cells derived from inguinal lymph nodes revealed a CD4/CD8 cell ratio of 2.2 +/- 0.18 (mean +/- SEM) in thymus-grafted nude mice that is similar to the ratio for immune-competent BALB...

  9. Survival of the fittest: positive selection of CD4+ T cells expressing a membrane-bound fusion inhibitor following HIV-1 infection.

    Science.gov (United States)

    Kimpel, Janine; Braun, Stephen E; Qiu, Gang; Wong, Fay Eng; Conolle, Michelle; Schmitz, Jörn E; Brendel, Christian; Humeau, Laurent M; Dropulic, Boro; Rossi, John J; Berger, Annemarie; von Laer, Dorothee; Johnson, R Paul

    2010-08-23

    Although a variety of genetic strategies have been developed to inhibit HIV replication, few direct comparisons of the efficacy of these inhibitors have been carried out. Moreover, most studies have not examined whether genetic inhibitors are able to induce a survival advantage that results in an expansion of genetically-modified cells following HIV infection. We evaluated the efficacy of three leading genetic strategies to inhibit HIV replication: 1) an HIV-1 tat/rev-specific small hairpin (sh) RNA; 2) an RNA antisense gene specific for the HIV-1 envelope; and 3) a viral entry inhibitor, maC46. In stably transduced cell lines selected such that >95% of cells expressed the genetic inhibitor, the RNA antisense envelope and viral entry inhibitor maC46 provided the strongest inhibition of HIV-1 replication. However, when mixed populations of transduced and untransduced cells were challenged with HIV-1, the maC46 fusion inhibitor resulted in highly efficient positive selection of transduced cells, an effect that was evident even in mixed populations containing as few as 1% maC46-expressing cells. The selective advantage of the maC46 fusion inhibitor was also observed in HIV-1-infected cultures of primary T lymphocytes as well as in HIV-1-infected humanized mice. These results demonstrate robust inhibition of HIV replication with the fusion inhibitor maC46 and the antisense Env inhibitor, and importantly, a survival advantage of cells expressing the maC46 fusion inhibitor both in vitro and in vivo. Evaluation of the ability of genetic inhibitors of HIV-1 replication to confer a survival advantage on genetically-modified cells provides unique information not provided by standard techniques that may be important in the in vivo efficacy of these genes.

  10. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

    Directory of Open Access Journals (Sweden)

    Jie Dong

    Full Text Available After a tightly regulated developmental program in the thymus, "mature" single positive (SP thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+ pre-RTEs, a population of CD4(+ SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+ pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+ pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+ pre-RTEs is independent of MHC class II and Aire molecules.

  11. Distinct and overlapping effector functions of expanded human CD4+, CD8α+ and CD4-CD8α- invariant natural killer T cells.

    Directory of Open Access Journals (Sweden)

    Vincent O'Reilly

    Full Text Available CD1d-restricted invariant natural killer T (iNKT cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4(+, CD8α(+ and CD4(-CD8α(- double-negative (DN subsets. CD4(+ iNKT cells expanded more readily than CD8α(+ and DN iNKT cells upon mitogen stimulation. CD8α(+ and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d(+ cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α and Th2 (IL-4, IL-5 and IL-13 cytokines. Relative amounts followed a CD8α>DN>CD4 pattern for Th1 and CD4>DN>CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4(+ and CD8α(+ fractions, respectively. Only CD4(+ iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α(+, DN or CD4(+ iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

  12. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    Science.gov (United States)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  13. HIV controllers exhibit enhanced frequencies of major histocompatibility complex class II tetramer+ Gag-specific CD4+ T cells in chronic clade C HIV-1 infection

    DEFF Research Database (Denmark)

    Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos

    2017-01-01

    = 0.02). These data identify an association between HIV-specific CD4+ T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight...... complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4+ T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+ T cell epitopes in clade C virus infection, constructed MHC class II tetramers......, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4+ T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4+ T cells in HIV controllers than progressors (P...

  14. Further Characterization of the Bifunctional HIV Entry Inhibitor sCD4-FIT45

    Directory of Open Access Journals (Sweden)

    Alexander Falkenhagen

    2017-06-01

    Full Text Available HIV entry into target cells is a highly sequential and time-sensitive process. In recent years, potent HIV Env-targeting antibodies, such as VRC01, have been identified. However, antibodies bind only to a single epitope, and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast, HIV cannot escape from binding to soluble CD4 (sCD4 without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FIT45 (sCD4-FIT45 and examined delivery of the bifunctional entry inhibitor via gene therapy. Here, we extend our studies and analyze the ability of sCD4-FIT45 to inhibit HIV Env-mediated cell fusion and HIV entry of several primary isolates. sCD4-FIT45 inhibited both cell fusion and HIV entry with remarkable antiviral activity. The mean 50% inhibitory concentrations (IC50 for sCD4-FIT45 were <0.2 μg/mL in both assays. Importantly, inhibition by sCD4-FIT45 was more potent than by VRC01, sCD4, or the previously described bifunctional protein sCD4-scFv17b. In contrast to sCD4, sCD4-FIT45 as well as VRC01 and sCD4-scFv17b did not mediate cell fusion between HIV Env+ and CD4−CCR5+ cells. The results presented here provide further evidence for the testing of sCD4-FIT45 and development of bifunctional proteins based on the sCD4-fusion inhibitor architecture.

  15. Further Characterization of the Bifunctional HIV Entry Inhibitor sCD4-FIT45.

    Science.gov (United States)

    Falkenhagen, Alexander; Joshi, Sadhna

    2017-06-16

    HIV entry into target cells is a highly sequential and time-sensitive process. In recent years, potent HIV Env-targeting antibodies, such as VRC01, have been identified. However, antibodies bind only to a single epitope, and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast, HIV cannot escape from binding to soluble CD4 (sCD4) without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env) that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FI T45 (sCD4-FI T45 ) and examined delivery of the bifunctional entry inhibitor via gene therapy. Here, we extend our studies and analyze the ability of sCD4-FI T45 to inhibit HIV Env-mediated cell fusion and HIV entry of several primary isolates. sCD4-FI T45 inhibited both cell fusion and HIV entry with remarkable antiviral activity. The mean 50% inhibitory concentrations (IC 50 ) for sCD4-FI T45 were <0.2 μg/mL in both assays. Importantly, inhibition by sCD4-FI T45 was more potent than by VRC01, sCD4, or the previously described bifunctional protein sCD4-scFv 17b . In contrast to sCD4, sCD4-FI T45 as well as VRC01 and sCD4-scFv 17b did not mediate cell fusion between HIV Env + and CD4 - CCR5 + cells. The results presented here provide further evidence for the testing of sCD4-FI T45 and development of bifunctional proteins based on the sCD4-fusion inhibitor architecture. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. The ADAMTS131239-1253peptide is a dominant HLA-DR1-restricted CD4+T-cell epitope.

    Science.gov (United States)

    Gilardin, Laurent; Delignat, Sandrine; Peyron, Ivan; Ing, Mathieu; Lone, Yu-Chun; Gangadharan, Bagirath; Michard, Baptiste; Kherabi, Yousra; Sharma, Meenu; Pashov, Anastas; Latouche, Jean-Baptiste; Hamieh, Mohamad; Toutirais, Olivier; Loiseau, Pascale; Galicier, Lionel; Veyradier, Agnès; Kaveri, Srini; Maillère, Bernard; Coppo, Paul; Lacroix-Desmazes, Sébastien

    2017-11-01

    Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against "A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13 th member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4 + T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4 + T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4 + T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted in silico and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4 + T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS13 1239-1253 peptide as the single immunodominant HLA-DR1-restricted CD4 + T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4 + T cells from Sure-L1 mice and was recognized by CD4 + T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS13 1239-1253 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4 + T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS13 1239-1253 -loaded HLA-DR tetramers. Copyright© Ferrata Storti Foundation.

  17. The ADAMTS131239–1253 peptide is a dominant HLA-DR1-restricted CD4+ T-cell epitope

    Science.gov (United States)

    Gilardin, Laurent; Delignat, Sandrine; Peyron, Ivan; Ing, Mathieu; Lone, Yu-Chun; Gangadharan, Bagirath; Michard, Baptiste; Kherabi, Yousra; Sharma, Meenu; Pashov, Anastas; Latouche, Jean-Baptiste; Hamieh, Mohamad; Toutirais, Olivier; Loiseau, Pascale; Galicier, Lionel; Veyradier, Agnès; Kaveri, Srini; Maillère, Bernard; Coppo, Paul; Lacroix-Desmazes, Sébastien

    2017-01-01

    Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against “A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13th member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4+ T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4+ T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4+ T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted in silico and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4+ T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS131239–1253 peptide as the single immunodominant HLA-DR1-restricted CD4+ T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4+ T cells from Sure-L1 mice and was recognized by CD4+ T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS131239–1253 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4+ T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS131239–1253-loaded HLA-DR tetramers. PMID:28751567

  18. Lymphocytes T CD4 et immunité anti-tumorale naturelle : impact de la chimiothérapie, émergence de lymphocytes T CD4 cytotoxiques

    OpenAIRE

    Peguillet , Isabelle

    2014-01-01

    Historically, CD8 positive Cytotoxic T Lymphocytes (CTL) have been associated with an effector immune response, while T cells with a CD4 phenotype where considered helper T cells. More recent data suggest that CD4 positive T cells are also capable of a direct cytotoxic activity. Through a systematic analysis of the IL-2 (CD25) as well as IL-7 (CD127) receptors α on the surface of CD4+ CTL in peripheral blood of patients before during and after treatment we were able to identify a specific CD4...

  19. Enteric parasitic infections in HIV-infected patients with low CD4 counts in Toto, Nigeria

    International Nuclear Information System (INIS)

    Abaver, D.T.; Nwobegahay, J.M.; Goon, D.T.; Khoza, L.B

    2012-01-01

    Objectives: Enteric parasites are a major cause of diarrhoea in HIV/AIDS patients with low CD4 counts. Parasitic infections in HIV-infected individuals can reduce their quality of life and life span, especially those who are severely immunosuppressed with a CD4 T-lymphocyte count 0.05). Conclusions: Low CD4 counts in HIV-infected patients can lead to enteric infections. This information strengthens the importance of monitoring CD4 counts and intestinal parasites. Routine CD4 testing will greatly improve the prognosis of HIV positive patients. (author)

  20. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

    Smyth, Lucy J C; Starkey, Cerys; Vestbo, Jørgen

    2007-01-01

    BACKGROUND: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD. OBJECTIVE: To compare T-regulatory cell numbers in the BAL from COPD patients......, smokers with normal lung function, and healthy nonsmokers (HNS). METHODS: BAL and peripheral blood mononuclear cell (PBMC) samples were obtained from 26 COPD patients, 19 smokers, and 8 HNS. Flow cytometry was performed for regulatory phenotypic markers. RESULTS: COPD patients had increased BAL CD8...... numbers compared to smokers and HNS. CD4 numbers were similar between groups. There was increased BAL CD4CD25(bright) expression in smokers (median 28.8%) and COPD patients (median 23.1%) compared to HNS (median 0%). Increased FoxP3 expression was confirmed in BAL CD4CD25(bright) cells. BAL CD4CD25 cells...

  1. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study

    DEFF Research Database (Denmark)

    Lodwick, Rebecca K; Sabin, Caroline A; Porter, Kholoud

    2010-01-01

    Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries....

  2. Shortened telomere length is demonstrated in T-cell subsets together with a pronounced increased telomerase activity in CD4 positive T cells from blood of patients with mycosis fungoides and parapsoriasis.

    Science.gov (United States)

    Wu, K D; Hansen, E R

    2001-10-01

    We have recently demonstrated that telomerase activity is increased and telomere length shortened in lymphocytes from peripheral blood of patients with cutaneous T-cell lymphoma. In order to determine which cell type has increased telomerase activity and shortened telomere length, CD4+, CD8+, CLA+ CD3+ and CLA- CD3+ T cells were isolated from peripheral blood of 25 patients, including 15 patients with mycosis fungoides and 10 patients with parapsoriasis. Eleven healthy individuals were used as controls; CD19+ B cells were separated from each individual as an internal control. The results showed that the increased telomerase activity was significantly predominating in the CD4+ T-cell subset. Significantly shortened telomere length was found in CD4+ and CD8+ T-cell subsets from the patients compared with the same cell subsets obtained from healthy individuals. However, no difference was observed between the subsets; CD19+ B cells collected from patients and healthy control individuals had similar telomerase activity and telomere length which was significantly different from the values found in T cells. The telomere length was significantly shorter in CLA+ CD3+ subset than in CLA- CD3+ subset. Interestingly, increased telomerase activity and shortened telomere length was also detected in CD4+ T cells from patients with parapsoriasis indicating that alteration of telomerase activity and telomere length in CD4+ T cells is an early event in the pathogenesis of cutaneous T-cell lymphoma. Thus, the results indicate that a significant high level of telomerase activity and shortened telomere length frequently occur in T cells of patients with CTCL and may reflect tumorigenesis.

  3. A general approach for controlling transcription and probing epigenetic mechanisms: application to the CD4 locus.

    Science.gov (United States)

    Wan, Mimi; Kaundal, Ravinder; Huang, Haichang; Zhao, Jiugang; Yang, Xiaojun; Chaiyachati, Barbara H; Li, Sicong; Chi, Tian

    2013-01-15

    Synthetic regulatory proteins such as tetracycline (tet)-controlled transcription factors are potentially useful for repression as well as ectopic activation of endogenous genes and also for probing their regulatory mechanisms, which would offer a versatile genetic tool advantageous over conventional gene targeting methods. In this study, we provide evidence supporting this concept using Cd4 as a model. CD4 is expressed in double-positive and CD4 cells but irreversibly silenced in CD8 cells. The silencing is mediated by heterochromatin established during CD8 lineage development via transient action of the Cd4 silencer; once established, the heterochromatin becomes self-perpetuating independently of the Cd4 silencer. Using a tet-sensitive Cd4 allele harboring a removable Cd4 silencer, we found that a tet-controlled repressor recapitulated the phenotype of Cd4-deficient mice, inhibited Cd4 expression in a reversible and dose-dependent manner, and could surprisingly replace the Cd4 silencer to induce irreversible Cd4 silencing in CD8 cells, thus suggesting the Cd4 silencer is not the (only) determinant of heterochromatin formation. In contrast, a tet-controlled activator reversibly disrupted Cd4 silencing in CD8 cells. The Cd4 silencer impeded this disruption but was not essential for its reversal, which revealed a continuous role of the silencer in mature CD8 cells while exposing a remarkable intrinsic self-regenerative ability of heterochromatin after forced disruption. These data demonstrate an effective approach for gene manipulation and provide insights into the epigenetic Cd4 regulatory mechanisms that are otherwise difficult to obtain.

  4. Idiopathic CD4 lymphocytopenia presenting as refractory cryptococcal meningitis

    Directory of Open Access Journals (Sweden)

    Sharma A

    2010-01-01

    Full Text Available Idiopathic CD4 T-lymphocytopenia (ICL is a syndrome characterized by depletion of CD4 T-cells without evidence of human immunodeficiency virus (HIV infection. There are a few reported cases of ICL associated with different diseases and clinical conditions, most commonly the opportunistic infections like Tuberculosis, fungal and parasitic diseases which are also seen in HIV-positive patients. We report a case without risk factors or laboratory evidence of HIV infection who presented with refractory cryptococcal meningitis and was found to have ICL.

  5. Idiopathic CD4 lymphocytopenia presenting as refractory cryptococcal meningitis

    Science.gov (United States)

    Sharma, A.; Lal, V.; Modi, M.; Khurana, D.; Bal, S.; Prabhakar, S.

    2010-01-01

    Idiopathic CD4 T-lymphocytopenia (ICL) is a syndrome characterized by depletion of CD4 T-cells without evidence of human immunodeficiency virus (HIV) infection. There are a few reported cases of ICL associated with different diseases and clinical conditions, most commonly the opportunistic infections like Tuberculosis, fungal and parasitic diseases which are also seen in HIV-positive patients. We report a case without risk factors or laboratory evidence of HIV infection who presented with refractory cryptococcal meningitis and was found to have ICL. PMID:20814499

  6. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs ...

    African Journals Online (AJOL)

    East African Medical Journal Vol. 90 No. 12 (Supplement) December 2013. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs) IN ROUTINE CLINICAL CARE OVER ONE YEAR. PERIOD IN A COHORT OF HAART NAIVE, HIV POSITIVE KENYAN PATIENTS. C. F. Otieno, MBChB, MMed (Int. Med), ...

  7. Comparison of local cytokine gene expression and the distribution of eosinophils and CD4-positive cell subsets in the paranasal sinus mucosa between atopic and non-atopic subjects

    Directory of Open Access Journals (Sweden)

    Sachio Takeno

    2004-01-01

    Conclusions: These results indicate that high expression of Th2-type cytokines concomitant with the infiltration of a predominant number of CD4+ cells and their Th2 subsets play a role in the pathogenesis of eosinophil inflammation in sinus mucosa. In addition, the finding that some of the non-atopic patients also shared Th-2 type immune responses provides support for the concept of chronic sinusitis as a Th2-mediated disease process.

  8. Memory CD4 T cells in influenza.

    Science.gov (United States)

    Zens, Kyra D; Farber, Donna L

    2015-01-01

    Influenza A virus is a significant cause of morbidity and mortality worldwide, particularly among young children and the elderly. Current vaccines induce neutralizing antibody responses directed toward highly variable viral surface proteins, resulting in limited heterosubtypic protection to new viral serotypes. By contrast, memory CD4 T cells recognize conserved viral proteins and are cross-reactive to multiple influenza strains. In humans, virus-specific memory CD4 T cells were found to be the protective correlate in human influenza challenge studies, suggesting their key role in protective immunity. In mouse models, memory CD4 T cells can mediate protective responses to secondary influenza infection independent of B cells or CD8 T cells, and can influence innate immune responses. Importantly, a newly defined, tissue-resident CD4 memory population has been demonstrated to be retained in lung tissue and promote optimal protective responses to an influenza infection. Here, we review the current state of results regarding the generation of memory CD4 T cells following primary influenza infection, mechanisms for their enhanced efficacy in protection from secondary challenge including their phenotype, localization, and function in the context of both mouse models and human infection. We also discuss the generation of memory CD4 T cells in response to influenza vaccines and its future implications for vaccinology.

  9. CD4 T cells mediate both positive and negative regulation of the immune response to HIV infection: complex role of T follicular helper cells and Regulatory T cells in pathogenesis

    Directory of Open Access Journals (Sweden)

    Chansavath ePhetsouphanh

    2015-01-01

    Full Text Available HIV-1 infection results in chronic activation of cells in lymphoid tissue, including T cells, B cells and myeloid lineage cells. The resulting characteristic hyperplasia is an amalgam of proliferating host immune cells in the adaptive response, increased concentrations of innate response mediators due to viral and bacterial products, and homeostatic responses to inflammation. While it is generally thought that CD4 T cells are greatly depleted, in fact, two types of CD4 T cells appear to be increased, namely regulatory T cells (Tregs and T follicular helper cells (Tfh. These cells have opposing roles, but may both be important in the pathogenic process. Whether Tregs are failing in their role to limit lymphocyte activation is unclear, but there is no doubt now that Tfh are associated with B cell hyperplasia and increased germinal centre activity. Antiretroviral therapy (ART may reduce the lymphocyte activation, but not completely, and therefore there is a need for interventions that selectively enhance normal CD4 function without exacerbating Tfh, B cell or Treg dysfunction.

  10. CD4 T lymphocyte counts in patients undergoing splenectomy during living donor liver transplantation.

    Science.gov (United States)

    Natsuda, Koji; Eguchi, Susumu; Takatsuki, Mistuhisa; Soyama, Akihiko; Hidaka, Masaaki; Hara, Takanobu; Kugiyama, Tota; Baimakhanov, Zhassulan; Ono, Shinichiro; Kitasato, Amane; Fujita, Fumihiko; Kanetaka, Kengo; Kuroki, Tamotsu

    2016-02-01

    The role of splenectomy in increasing the CD4-positive T lymphocyte counts (hereafter: CD4 counts) and the CD4 to CD8 ratio have not yet been fully investigated, especially in the case of HIV-positive patients undergoing liver transplantation (LT). The change in the total lymphocyte counts of 32 patients who underwent one-stage splenectomy with living donor (LD) LT with (n=13) or without rituximab (RTX, n=19) therapy were examined to validate our cohort of ABO-incompatible LDLT with RTX. Subsequently, perioperative changes in CD4 counts and the CD 4 to CD8 ratio were measured in 13 patients who underwent ABO-incompatible LDLT/RTX with splenectomy. (1) The administration of RTX did not significantly affect the total lymphocyte counts of patients after LDLT/splenectomy in any of the observation periods. (2) The CD4 counts were significantly higher at 2years after LDLT in comparison to the perioperative CD4 counts but not within the 3-month period (p=0.039). The CD4/CD8 ratio gradually decreased after LDLT/splenectomy under RTX treatment. An immediate increase in the CD4 counts therefore cannot be expected after LDLT with splenectomy. The total lymphocyte and CD4 counts were rather stable in the peritransplant period even in ABO incompatible LDLT with RTX. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Long-term treatment of pigs with low doses of monoclonal antibodies against porcine CD4 and CD8 antigens

    DEFF Research Database (Denmark)

    Lohse, Louise; Nielsen, Jens; Eriksen, Lis

    2006-01-01

    In vivo depletion of lymphocyte subsets allows investigation of the role of specific subsets in protective immunity. In the present study we evaluated the effects of long-term, low-dose treatment with murine monoclonal antibodies (mAbs) against porcine CD4 and CD8 surface antigens on lymphocyte....... Treatment with the anti-CD4 mAb almost completely eliminated the CD4(+) T-cell subset from the circulation after 2 weeks of therapy. This depletion persisted until the end of the experimental period 5 weeks after initiated therapy. Treatment with the anti-CD8 mAb was less effective, reducing the CD8(+) T......-cell subset in peripheral blood by approximately 50% of the initial level after 3 weeks of therapy. Further, the anti-CD8 mAb-treated pigs showed a parallel increase in the CD4(+) T-cell subset from day 7. Two-colour FCM analysis indicated that a shift in phenotype from single-positive CD4(+)/CD8(-) to double...

  12. Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents.

    Science.gov (United States)

    Milagres, Lucimar G; Costa, Priscilla R; Silva, Giselle P; Carvalho, Karina I; Pereira-Manfro, Wânia F; Ferreira, Bianca; Barreto, Daniella M; Frota, Ana Cristina C; Hofer, Cristina B; Kallas, Esper G

    2014-01-01

    Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules) of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44%) of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%). Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM) subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies.

  13. Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents.

    Directory of Open Access Journals (Sweden)

    Lucimar G Milagres

    Full Text Available Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44% of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%. Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies.

  14. Multidimensional Clusters of CD4+T Cell Dysfunction Are Primarily Associated with the CD4/CD8 Ratio in Chronic HIV Infection

    DEFF Research Database (Denmark)

    Frederiksen, Juliet Wairimu; Buggert, Marcus; Noyan, Kajsa

    2015-01-01

    each of the HIV-infected individuals. Principle component analyses demonstrated that using an artificial reference lead to a better separation of the HIV-infected individuals from the healthy controls as compared to using a single HIV-infected subject as a reference or analyzing data manually. Multiple...... correlation analyses between laboratory parameters and pathological CD4+ clusters revealed that the CD4/CD8 ratio was the preeminent surrogate marker of CD4+ T cells dysfunction using all three methods. Increased frequencies of an early-differentiated CD4+ T cell cluster with high CD38, HLA-DR and PD-1...... expression were best correlated (Rho = -0.80, P value = 1.96x10-11) with HIV disease progression as measured by the CD4/CD8 ratio. The novel approach described here can be used to identify cell clusters that distinguish healthy from HIV infected subjects and is biologically relevant for HIV disease...

  15. Combining CD4 recovery and CD4: CD8 ratio restoration as an indicator for evaluating the outcome of continued antiretroviral therapy: an observational cohort study.

    Science.gov (United States)

    Lee, Shui Shan; Wong, Ngai Sze; Wong, Bonnie Chun Kwan; Wong, Ka Hing; Chan, Kenny Chi Wai

    2017-09-15

    Immune recovery following highly active antiretroviral therapy (HAART) is commonly assessed by the degree of CD4 reconstitution alone. In this study, we aimed to assess immune recovery by incorporating both CD4 count and CD4:CD8 ratio. Observational cohort study SETTING AND PARTICIPANTS: Clinical data from Chinese HIV-positive patients attending the largest HIV service in Hong Kong and who had been on HAART for ≥4 years were accessed. Optimal immune outcome was defined as a combination of a CD4 count ≥500/μL and a CD4:CD8 ratio ≥0.8. A total of 718 patients were included for analysis (6353 person-years). At the end of year 4, 318 out of 715 patients achieved CD4 ≥500/μL, of which only 33% (105 out of 318) concurrently achieved CD4:CD8 ratio ≥0.8. Patients with a pre-HAART CD8 ≤800/μL (428 out of 704) were more likely to be optimal immune outcome achievers with CD4 ≥500/μL and CD4:CD8 ratio ≥0.8, the association of which was stronger after adjusting for pre-HAART CD4 counts. In a multivariable logistic model, optimal immune outcome was positively associated with male gender, younger pre-HAART age and higher pre-HAART CD4 count, longer duration of HAART and pre-HAART CD8 ≤800/μL. Treatment regimen and cumulative viral loads played no significant role in the pattern of immune recovery. A combination of CD4 count and CD4:CD8 ratio could be a useful approach for the characterisation of treatment outcome over time, on top of monitoring CD4 count alone. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  16. Chromosomal localisation of the CD4cre transgene in B6·Cg-Tg(Cd4-cre)1Cwi mice.

    Science.gov (United States)

    Westendorf, Kerstin; Durek, Pawel; Ayew, Samia; Mashreghi, Mir-Farzin; Radbruch, Andreas

    2016-09-01

    The B6·Cg-Tg(Cd4-cre)1Cwi line expresses CRE recombinase under the control of the promoter and regulatory elements of the Cd4 gene. Here we show that CRE recombinase expression reduces the number and frequencies of CD4 positive subsets in a dose-dependent manner and localize the integration site of the transgenic construct to position 60335693-60341285 (qD) of chromosome 3. The insert contains at least 15 complete sequential copies of the transgenic construct. Based on this information we describe a novel PCR assay for genetic typing of transgenic mice. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Correlation analysis on total lymphocyte count and CD4 count of HIV-infected patients.

    Science.gov (United States)

    Liu, F R; Guo, F; Ye, J J; Xiong, C F; Zhou, P L; Yin, J G; Ye, L X

    2008-06-01

    To determine the relationship between CD4 count and other blood indices and to explore the prediction of total lymphocyte count (TLC) for CD4 count in HIV-infected patients. Cross-sectional study was performed for the prediction of TLC and other indices for CD4 count, and historical cohort study was performed for the TLC changes as a surrogate for CD4 changes of patients on antiretroviral therapy (ART) to further understanding the utility of TLC changes for AIDS patients' management. In our cross-sectional study, both TLC and white blood corpuscle count positively correlated to CD4 count, but differed in these patients. For patients on ART, the prediction of TLC for CD4 count is better than that of patient without ART. Further investigation of historical cohort study indicated that, among AIDS patients on highly active antiretroviral therapy, their TLC and haemoglobin changes also positively correlated to CD4 change, with a total correlation coefficient of 0.31 (p TLC change for CD4 change differed each time point when patients underwent ART. Total lymphocyte count and its change can be used as alternative in conjunction with other indices to CD4 count and its change in the management of HIV-infected individuals in China.

  18. Increased Hepatitis E Virus Seroprevalence Correlates with Lower CD4+ Cell Counts in HIV-Infected Persons in Argentina.

    Directory of Open Access Journals (Sweden)

    José D Debes

    Full Text Available Hepatitis E virus (HEV is a single-stranded RNA virus that can cause hepatitis in an epidemic fashion. HEV usually causes asymptomatic or limited acute infections in immunocompetent individuals, whereas in immunosuppressed individuals such as transplant recipients, HEV can cause chronic infections. The risks and outcomes of HEV co-infection in patients infected with human immunodeficiency virus (HIV are poorly characterized. We used a third generation immunoassay to measure serum IgG antibodies specific for HEV in 204 HIV-infected individuals from Argentina and a control group of 433 HIV-negative individuals. We found 15 of 204 (7.3%, 95%CI 3.74-10.96% individuals in the HIV-positive group to have positive HEV IgG levels suggestive of previous infection, compared to 19 of 433 (4.4%, 95% CI 2.5-6.3% individuals in the HIV-negative control group (p = 0.12. Among HIV-positive individuals, those with HEV seropositivity had lower CD4 counts compared to those that were HEV seronegative (average CD4 count of 234 vs 422 mm3, p = 0.01, indicating that patients with lower CD4 counts were more likely to be HEV IgG positive. Moreover, HEV seropositivity in patients with CD4 counts 200 mm3 (p = 0.012. We found a positive PCR result for HEV in one individual. Our study found that increased seroprevalence of HEV IgG correlated with lower CD4 counts in HIV-infected patients in Argentina.

  19. CD4-cell counts and presence of AIDS in HIV-positive patients entering specialized care-a comparison of migrant groups in the German ClinSurv HIV Cohort Study, 1999-2013.

    Science.gov (United States)

    Zeitlmann, Nadine; Gunsenheimer-Bartmeyer, Barbara; Santos-Hövener, Claudia; Kollan, Christian; An der Heiden, Matthias

    2016-12-07

    Although early presentation to HIV-care is essential to ensure timely initiation of antiretroviral therapy, recent studies have shown that especially migrants present to HIV-care at a later stage of HIV-infection. Currently, thirty percent of all newly diagnosed HIV cases in Germany originate from abroad. So far it is unknown, which specific migrant groups in Germany are particularly at risk for late presentation to HIV-care. We used data from the Clinical Surveillance of HIV Disease (ClinSurv) cohort, a multi-centre observational cohort (01/01/1999 and 31/07/2013) and included treatment-naïve patients with valid information on country of origin and date of enrolment. Migrants were patients with country of origin outside Germany. We compared time trends for percentage of AIDS (CDC Stage C) and mean CD4-count at enrolment between migrants from Western Europe (WE), Central Europe (CE), Eastern Europe (EE), Sub-Saharan Africa (SSA), South East Asia (SEA) and non-migrants using multivariable regressions. Male non-migrants with mean age of 38-years constituted the reference group. In total, 10,211 patients fulfilled the inclusion criteria, of which 2784 were migrants (SSA: 42%, CE: 17%, WE: 11%, EE: 10%, SEA: 9%). The percentage of patients with AIDS at enrolment was higher in SSA (Odds Ratio (OR) SSA : 1.44, 95%-confidence interval (95%-CI):1.12-1.84) and SEA-migrants (OR SEA :2.16, 95%-CI:1.43-3.27). In addition, female SEA-migrants, were more likely to present with AIDS than their male counterparts (OR:2.22, 95%-CI:1.18-4.17). Mean CD4-count at enrolment was lower for SSA- (Mean CD4-count ratio (IRR):0.72; 95%-CI:0.64-0.82) and SEA-migrants (IRR:0.62, 95%-CI:0.49-0.78). Over time, it increased in non-migrants and CE-migrants (by 1 and 3%/year, respectively), whereas no increase was seen for SEA and SSA. SSA and SEA-migrants in Germany present to HIV-care at a later stage of HIV infection than non-migrants. Additionally, previous research found a higher risk for late

  20. Time scales of CD4+ T cell depletion in HIV infection

    NARCIS (Netherlands)

    Boer, R.J. de

    2007-01-01

    The hallmark of HIV infection is the depletion of CD4⁺ T cells in peripheral blood, lymphoid organs, and mucosal tissues. Since CD4⁺ T cells play an essential role in immune defenses against almost all pathogens, HIV-positive patients are subject to a variety of opportunistic infections.

  1. Interleukin-4 mediates CD8 induction on human CD4+ T-cell clones

    NARCIS (Netherlands)

    Paliard, X.; Malefijt, R. W.; de Vries, J. E.; Spits, H.

    1988-01-01

    CD4 and CD8 antigens are simultaneously expressed on most of the cortical thymocytes, that weakly express the T-cell antigen receptor(TCR)/CD3 complex. Mature peripheral T cells, however, strongly express the TCR complex and are positive for either CD4 or CD8. Nevertheless, a small percentage of

  2. Clinical Evaluation of the BD FACSPresto™ Near-Patient CD4 Counter in Kenya.

    Directory of Open Access Journals (Sweden)

    Francis Angira

    Full Text Available The BD FACSPresto™ Near-Patient CD4 Counter was developed to expand HIV/AIDS management in resource-limited settings. It measures absolute CD4 counts (AbsCD4, percent CD4 (%CD4, and hemoglobin (Hb from a single drop of capillary or venous blood in approximately 23 minutes, with throughput of 10 samples per hour. We assessed the performance of the BD FACSPresto system, evaluating accuracy, stability, linearity, precision, and reference intervals using capillary and venous blood at KEMRI/CDC HIV-research laboratory, Kisumu, Kenya, and precision and linearity at BD Biosciences, California, USA.For accuracy, venous samples were tested using the BD FACSCalibur™ instrument with BD Tritest™ CD3/CD4/CD45 reagent, BD Trucount™ tubes, and BD Multiset™ software for AbsCD4 and %CD4, and the Sysmex™ KX-21N for Hb. Stability studies evaluated duration of staining (18-120-minute incubation, and effects of venous blood storage <6-24 hours post-draw. A normal cohort was tested for reference intervals. Precision covered multiple days, operators, and instruments. Linearity required mixing two pools of samples, to obtain evenly spaced concentrations for AbsCD4, total lymphocytes, and Hb.AbsCD4 and %CD4 venous/capillary (N = 189/ N = 162 accuracy results gave Deming regression slopes within 0.97-1.03 and R2 ≥0.96. For Hb, Deming regression results were R2 ≥0.94 and slope ≥0.94 for both venous and capillary samples. Stability varied within 10% 2 hours after staining and for venous blood stored less than 24 hours. Reference intervals results showed that gender-but not age-differences were statistically significant (p<0.05. Precision results had <3.5% coefficient of variation for AbsCD4, %CD4, and Hb, except for low AbsCD4 samples (<6.8%. Linearity was 42-4,897 cells/μL for AbsCD4, 182-11,704 cells/μL for total lymphocytes, and 2-24 g/dL for Hb.The BD FACSPresto system provides accurate, precise clinical results for capillary or venous blood samples

  3. Characterization of circulating CD4+ CD8+ lymphocytes in healthy individuals prompted by identification of a blood donor with a markedly elevated level of CD4+ CD8+ lymphocytes.

    OpenAIRE

    Prince, H E; Golding, J; York, J

    1994-01-01

    During flow cytometric analysis of lymphocytes from healthy donors, we identified a donor (donor A) with 22% CD4+ CD8+ cells (versus values of < 4% for 65 other controls). To determine if CD4+ CD8+ cells from donor A and other controls were similar, we first defined the phenotypic profile of control CD4+ CD8+ cells. Enriched CD4+ CD8+ cell populations for 10 controls were prepared by a two-step positive selection scheme with anti-CD4-coated magnetic beads and anti-CD8-coated culture flasks; t...

  4. Unbalanced expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Lin Cheng

    Full Text Available ABSTRACT Objective: The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of patients with rheumatoid arthritis. Methods: Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6+CD4+T, CD4+CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. Results: The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23 ± 10.71% vs. (18.83 ± 7.32%, p < 0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71 ± 1.63 vs. (2.00 ± 1.27, p = 0.002; (2.62 ± 2.08 vs. (0.62 ± 0.29, p < 0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90 (6.10 ± 80.10% vs. (52.49 ± 19.18%, p < 0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49 ± 19.18% vs. (23.18 ± 5.62% vs. (18.06 ± 7.80%, X 2 = 24.03, p < 0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs [(46.02 ± 14.68% vs. 17.90 (6.10 ± 80.10% vs. (34.22 ± 10.33%, X 2 = 38.29, p < 0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+CD25+T cells. Conclusion: AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood.

  5. Unbalanced expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+and CD4+CD25+T cells of rheumatoid arthritis.

    Science.gov (United States)

    Cheng, Lin; Qian, Long; Tan, Yue; Wang, Guo-Sheng; Li, Xiao-Mei; Li, Xiang-Pei; Luo, Chao-Yin

    The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6 + CD4 + and CD4 + CD25 + T cells of patients with rheumatoid arthritis. Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6 + CD4 + T, CD4 + CD25 + T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23±10.71)% vs. (18.83±7.32)%, p<0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71±1.63) vs. (2.00±1.27), p=0.002; (2.62±2.08) vs. (0.62±0.29), p<0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4 + CD25 + T cells was significantly lower than that from controls [17.90 (6.10±80.10)% vs. (52.49±19.18)%, p<0.01]; In healthy controls, the percentage of AhR positive cells in CD4 + CD25 + T cells was significantly higher than that in CCR6 + CD4 + T cells, and was also significantly higher than that in PBMCs [(52.49±19.18)% vs. (23.18±5.62)% vs. (18.06±7.80)%, X 2 =24.03, p<0.01]; in RA patients, the percentage of AhR positive cells in CCR6 + CD4 + T cells was significantly increased than that in CD4 + CD25 + T cells and PBMCs [(46.02±14.68)% vs. 17.90 (6.10±80.10)% vs. (34.22±10.33)%, X 2 =38.29, p<0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6 + CD4 + T and CD4 + CD25 + T cells. AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

  6. Pathogenic CD4+ T cells in patients with asthma.

    Science.gov (United States)

    Muehling, Lyndsey M; Lawrence, Monica G; Woodfolk, Judith A

    2017-12-01

    Asthma encompasses a variety of clinical phenotypes that involve distinct T cell-driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4 + T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, T H 2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of T H 2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell "hubs" are discussed. We also describe advances in understanding the origins of atypical T H 2 cells in asthmatic patients, the role of T H 1 cells and other non-T H 2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell-based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  7. Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

    Science.gov (United States)

    Madani, Navid; Princiotto, Amy M.; Zhao, Connie; Jahanbakhshsefidi, Fatemeh; Mertens, Max; Herschhorn, Alon; Melillo, Bruno; Smith, Amos B.

    2016-01-01

    ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility. IMPORTANCE The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important

  8. eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients.

    Directory of Open Access Journals (Sweden)

    Meredith E Davis-Gardner

    2017-12-01

    Full Text Available Antibody-dependent cell-mediated cytotoxity (ADCC can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8. Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1 can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2 exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.

  9. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

    DEFF Research Database (Denmark)

    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...... from a total of 14 patients were enriched from a mean percentage of CD4 cells in PBMC of 18% to 91% CD4 cells in the enriched cell fraction. Furthermore, we found that this separation did not lead to an increase in viral load. The MACS performed equally well on cells from HIV-positive patients and HIV......-negative donors. CD4 cells from HIV-positive patients were readily expanded with PHA; 19-fold by day 10, 50-fold by day 20, and 156-fold by day 25. However, CD4 cells from HIV-positive patients grew at a slower rate than CD4 cells from HIV-negative donors. The expanded CD4 cells showed a high degree of CD4...

  10. CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) Regulatory T Cell Subsets in Mediating Autoimmune Reactivity in Systemic Lupus Erythematosus Patients.

    Science.gov (United States)

    Żabińska, Marcelina; Krajewska, Magdalena; Kościelska-Kasprzak, Katarzyna; Jakuszko, Katarzyna; Bartoszek, Dorota; Myszka, Marta; Klinger, Marian

    2016-10-01

    The available clinical as well as experimental studies implicate participation of T regulatory (Treg) subsets in the pathogenesis and course of systemic lupus erythematosus (SLE). Introduction of the CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) regulatory subpopulations analysis into immunological processes assessment and disease activation prognosis in patients with lupus nephritis (LN) may improve monitoring of disease activity and enable an early, and thus more effective, therapeutic treatment. The main goal of the study was to investigate whether the quantitative changes of Treg subpopulations are related to the clinical status of patients with LN. Fifty-four adult SLE patients divided into two groups according to their SLEDAI and renal SLEDAI scores were enrolled into the study. Subpopulations of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) phenotypes were determined by flow cytometry. The control group had higher absolute number of CD4(+)CD25(+)Foxp3(+) cells compared with the study group (p < 0.001). Also, significant inverse correlation in the absolute number of CD4(+)CD25(+)Foxp3(+) cells and SLEDAI score was observed. There were significant differences in the percentage and absolute number of CD4(+)CD25(+)Foxp3(+) lymphocytes between active and non-active LN groups. The study group had statistically lower values of CD4(+)CD25(+)CD127(-) cells, both in the percentage (p < 0.001) as well as their absolute number (p = 0.014) compared to the control group. There were also statistically significant positive correlations between the absolute number of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) Tregs. (1) reduction in the number of regulatory CD4(+)CD25(+)Foxp3(+) cells is a promising indicator of the activity of SLE, particularly of renal involvement; (2) determination of the number of regulatory cells using the CD4(+)CD25(+)CD127(-) phenotype is unreliable in patients with SLE.

  11. A species-specific amino acid difference in the macaque CD4 receptor restricts replication by global circulating HIV-1 variants representing viruses from recent infection.

    Science.gov (United States)

    Humes, Daryl; Emery, Sandra; Laws, Elizabeth; Overbaugh, Julie

    2012-12-01

    HIV-1 replicates poorly in macaque cells, and this had hindered the advancement of relevant nonhuman primate model systems for HIV-1 infection and pathogenesis. Several host restriction factors have been identified that contribute to this species-specific restriction to HIV-1 replication, but these do not fully explain the poor replication of most strains of HIV-1 in macaque cells. Only select HIV-1 envelope variants, typically those derived from viruses that have been adapted in cell culture, result in infectious chimeric SIVs encoding HIV-1 envelope (SHIVs). Here we demonstrate that most circulating HIV-1 variants obtained directly from infected individuals soon after virus acquisition do not efficiently mediate entry using the macaque CD4 receptor. The infectivity of these viruses is ca. 20- to 50-fold lower with the rhesus and pig-tailed macaque versus the human CD4 receptor. In contrast, culture-derived HIV-1 envelope variants that facilitate efficient replication in macaques showed similar infectivity with macaque and human CD4 receptors (within ∼2-fold). The ability of an envelope to mediate entry using macaque CD4 correlated with its ability to mediate entry of cells expressing low levels of the human CD4 receptor and with soluble CD4 sensitivity. Species-specific differences in the functional capacity of the CD4 receptor to mediate entry mapped to a single amino acid difference at position 39 that is under strong positive selection, suggesting that the evolution of CD4 may have been influenced by its function as a viral receptor. These results also suggest that N39 in human CD4 may be a critical residue for interaction of transmitted HIV-1 variants. These studies provide important insights into virus-host cell interactions that have hindered the development of relevant nonhuman primate models for HIV-1 infection and provide possible markers, such as sCD4 sensitivity, to identify potential HIV-1 variants that could be exploited for development of better

  12. eCD4-Ig variants that more potently neutralize HIV-1.

    Science.gov (United States)

    Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E; Prasad, Neha R; Alfant, Barnett; Weber, Jesse A; Farzan, Michael

    2018-03-28

    The HIV-1 entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralizes all HIV-1, HIV-2 and SIV isolates that it has been tested against, suggesting that it may be useful in clinical settings where antibody escape is a concern. Here we characterize three new eCD4-Ig variants, each with different architectures and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig, and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications. IMPORTANCE HIV-1 bNAbs have properties different from antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral lifecycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the

  13. Hierarchical Cd4SiS6/SiO2 Heterostructure Nanowire Arrays

    OpenAIRE

    Liu, Jian; Wang, Chunrui; Xie, Qingqing; Cai, Junsheng; Zhang, Jing

    2009-01-01

    Abstract Novel hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays were fabricated on silicon substrates by a one-step thermal evaporation of CdS powder. The as-grown products were characterized using scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. Studies reveal that a typical hierarchical Cd4SiS6/SiO2 heterostructure nanowire is composed of a single crystalline Cd4SiS6 nanowire core sheathed with amorphous SiO2 sheath. Furthermore, secondar...

  14. Sulfasalazine: arthritis drug increases CD4 count?

    Science.gov (United States)

    Smith, D

    1995-03-03

    Sulfasalazine, a drug commonly used to treat arthritis, has been shown to increase CD4 counts in people with HIV, substantially in some patients. Researchers published their findings in April's Journal of Rheumatology (vol. 21, no. 4). Sulfasalazine has been known to suppress certain inflammatory responses of the immune system, including the production of cytokines such as tumor necrosis factor and interleukins 1 and 2; and to be a scavenger of superoxide radicals thought to provoke HIV by affecting the long terminal repeat of the virus. If sulfasalazine lowers oxidative stress, or pacifies certain overactive components of the immune response, it would be consistent with some current directions in HIV research. Side effects of the drug have been a sulfa-like reaction in some patients, bone marrow suppression with long-term use, and immunosuppression affecting cytokine production. CD4 counts are considered poor markers for HIV activity. There are tests, however, that bypass these markers to identify the impact of treatments like sulfasalazine on viral load. A sulfasalazine control trial headed by Dr. Eddys Disla began recruiting March 1st in the New York area (212) 955-6996. Those with anecdotal experience using sulfasalazine are asked to call Denny Smith or John James at (415) 255-0588.

  15. CD4+Foxp3+CD25+/- Tregs characterize liver tissue specimens of patients suffering from drug-induced autoimmune hepatitis: A clinical-pathological study.

    Science.gov (United States)

    Qu, Li-Mei; Wang, Shu-Hua; Yang, Kun; Brigstock, David R; Sun, Li; Gao, Run-Ping

    2018-02-19

    The diagnosis of drug-induced autoimmune hepatitis (DIAIH) and its differentiation from idiopathic autoimmune hepatitis (AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4 + Foxp3 + CD25 +/- regulatory T cells (Tregs) in liver tissues or peripheral blood lymphocytes. A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4 + Foxp3 + CD25 +/- Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4 + Foxp3 + CD25 +/- Tregs in peripheral blood were analyzed by flow cytometry. The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and 309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation, higher frequencies of zone 3 necrosis and higher number of lobular CD4 + Foxp3 + CD25 - Tregs compared with AIH (P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4 + Foxp3 + CD25 - Tregs (P < 0.05). However, the frequency of peripheral blood CD4 + Foxp3 + CD25 +/- Tregs were not significantly different between DIAIH and AIH. The differences of ALT, AST and the number of lobular CD4 + Foxp3 + CD25 - Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage. Copyright © 2018. Published by Elsevier B.V.

  16. Interleukin 1-induced down-regulation of antibody binding to CD4 molecules on human lymphocytes

    DEFF Research Database (Denmark)

    Tvede, N; Christensen, L D; Ødum, Niels

    1988-01-01

    Interleukin 1 (IL-1) is involved in the early activation of T lymphocytes. The CD4 antigen, described as a phenotypic marker of helper T cells, is also important in early T-cell activation by its ability to bind to MHC class II molecules on antigen-presenting cells, and to transmit positive (and ...... with actinomycin D or cytochalasin B, indicating that protein synthesis and intact microfilament function were essential for re-expression of CD4 binding. The mechanism by which CD4 molecules are physically and/or functionally modulated by IL-1 is unclear....

  17. HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+Gag-Specific CD4+T Cells in Chronic Clade C HIV-1 Infection.

    Science.gov (United States)

    Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos; Mewalal, Nikoshia; Pretorius, Karyn; Ismail, Nasreen; Buus, Søren; Stryhn, Anette; Carrington, Mary; Walker, Bruce D; Ndung'u, Thumbi; Ndhlovu, Zaza M

    2017-04-01

    Immune control of viral infections is heavily dependent on helper CD4 + T cell function. However, the understanding of the contribution of HIV-specific CD4 + T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4 + T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4 + T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4 + T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4 + T cells in HIV controllers than progressors ( P = 0.0001), and these expanded Gag-specific CD4 + T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control ( r = -0.5, P = 0.02). These data identify an association between HIV-specific CD4 + T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4 + T cell responses in natural infections. IMPORTANCE Increasing evidence suggests that virus-specific CD4 + T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4 + T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV

  18. Hierarchical Cd4SiS6/SiO2 Heterostructure Nanowire Arrays.

    Science.gov (United States)

    Liu, Jian; Wang, Chunrui; Xie, Qingqing; Cai, Junsheng; Zhang, Jing

    2009-10-29

    Novel hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays were fabricated on silicon substrates by a one-step thermal evaporation of CdS powder. The as-grown products were characterized using scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. Studies reveal that a typical hierarchical Cd4SiS6/SiO2 heterostructure nanowire is composed of a single crystalline Cd4SiS6 nanowire core sheathed with amorphous SiO2 sheath. Furthermore, secondary nanostructures of SiO2 nanowires are highly dense grown on the primary Cd4SiS6 core-SiO2 sheath nanowires and formed hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays which stand vertically on silicon substrates. The possible growth mechanism of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays is proposed. The optical properties of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays are investigated using Raman and Photoluminescence spectroscopy.

  19. Hierarchical Cd4SiS6/SiO2 Heterostructure Nanowire Arrays

    Directory of Open Access Journals (Sweden)

    Liu Jian

    2009-01-01

    Full Text Available Abstract Novel hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays were fabricated on silicon substrates by a one-step thermal evaporation of CdS powder. The as-grown products were characterized using scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. Studies reveal that a typical hierarchical Cd4SiS6/SiO2 heterostructure nanowire is composed of a single crystalline Cd4SiS6 nanowire core sheathed with amorphous SiO2 sheath. Furthermore, secondary nanostructures of SiO2 nanowires are highly dense grown on the primary Cd4SiS6 core-SiO2 sheath nanowires and formed hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays which stand vertically on silicon substrates. The possible growth mechanism of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays is proposed. The optical properties of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays are investigated using Raman and Photoluminescence spectroscopy.

  20. Profound reduction of CD4+ lymphocytes without HIV infection: two ...

    African Journals Online (AJOL)

    Idiopathic CD4+ lymphocytopenia is a disorder associated with low CD4+ T cell count and opportunistic infections resembling AIDS. Most cases are described in developed countries. We report two HIV-negative patients with idiopathic CD4+ lymphocytopenia and AIDS-defining events diagnosed in Djibouti. The first patient ...

  1. Baseline CD4 lymphocyte count among HIV patients in Kano ...

    African Journals Online (AJOL)

    kemrilib

    macrophages), the devastating effect of HIV on the immune system is not surprising. Given that HIV induced immunodeficiency is largely due to infection and gradual depletion of. CD4+ T-helper cells, CD4 count has become a useful indicator of immune function in infected patients. Hence CD4 count along with viral load ...

  2. Choosing a new CD4 technology: Can statistical method comparison tools influence the decision?

    Science.gov (United States)

    Scott, Lesley E; Kestens, Luc; Pattanapanyasat, Kovit; Sukapirom, Kasma; Stevens, Wendy S

    2017-11-01

    Method comparison tools are used to determine the accuracy, precision, agreement, and clinical relevance of a new or improved technology versus a reference technology. Guidelines for the most appropriate method comparison tools as well as their acceptable limits are lacking and not standardized for CD4 counting technologies. Different method comparison tools were applied to a previously published CD4 dataset (n = 150 data pairs) evaluating five different CD4 counting technologies (TruCOUNT, Dual Platform, FACSCount, Easy CD4, CyFlow) on a single specimen. Bland-Altman, percentage similarity, percent difference, concordance correlation, sensitivity, specificity and misclassification method comparison tools were applied as well as visualization of agreement with Passing Bablock and Bland-Altman scatter plots. The FACSCount (median CD4 = 245 cells/µl) was considered the reference for method comparison. An algorithm was developed using best practices of the most applicable method comparison tools, and together with a modified heat map was found useful for method comparison of CD4 qualitative and quantitative results. The algorithm applied the concordance correlation for overall accuracy and precision, then standard deviation of the absolute bias and percentage similarity coefficient of variation to identify agreement, and lastly sensitivity and misclassification rates for clinical relevance. Combining method comparison tools is more useful in evaluating CD4 technologies compared to a reference CD4. This algorithm should be further validated using CD4 external quality assessment data and studies with larger sample sizes. © 2017 International Clinical Cytometry Society. © 2017 International Clinical Cytometry Society.

  3. Varicella Zoster Virus Necrotizing Retinitis in Two Patients with Idiopathic CD4 Lymphocytopenia.

    Science.gov (United States)

    Gupta, Meenakashi; Jardeleza, Maria Stephanie R; Kim, Ivana; Durand, Marlene L; Kim, Leo; Lobo, Ann-Marie

    2016-10-01

    Progressive outer retinal necrosis (PORN) associated with varicella zoster virus (VZV) is usually diagnosed in HIV positive or immunosuppressed patients. We report two cases of immunocompetent patients with necrotizing viral retinitis found to have idiopathic CD4 lymphocytopenia. Clinical presentation, examination, imaging, and laboratory testing of two patients with VZV retinitis are presented. An HIV negative patient with history of herpes zoster presented with rapid loss of vision and examination consistent with PORN. PCR testing confirmed VZV. Lymphocytopenia was noted with a CD4 count of 25/mm(3). A second HIV negative patient presented with blurred vision and lid swelling and was found to have peripheral VZV retinitis confirmed by PCR. Laboratory workup revealed lymphocytopenia with a CD4 count of 133/mm(3). VZV necrotizing retinitis classic for PORN can occur in HIV negative patients. Idiopathic CD4 lymphocytopenia should be considered healthy patients who develop ocular infections seen in the immunocompromised.

  4. Binding of the mannose-specific lectin, Griffithsin, to HIV-1 gp120 exposes the CD4-binding site

    CSIR Research Space (South Africa)

    Alexandre, Kabamba B

    2011-09-01

    Full Text Available and Reagent Program. The subtype C-specific anti-V3 MAb 3468L was isolated from an HIV-positive patient (22). The anti-CCR5 inhibitor PRO140, the CD4 receptor surrogate CD4-IgG2, and soluble CD4 (sCD4) were generously provided by Progenics Pharmaceuticals..., except that the 50% infective dose (ID50) and ID80 were calculated. Since PRO140 is a CCR5 inhibitor, TZM-bl cells were first incubated with a dilution series of the compound prior to the addition of the virus with or without GRFT (in a dilution series...

  5. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Kara G Lassen

    2006-07-01

    Full Text Available HIV-1 latency in resting CD4+ T cells represents a major barrier to virus eradication in patients on highly active antiretroviral therapy (HAART. We describe here a novel post-transcriptional block in HIV-1 gene expression in resting CD4+ T cells from patients on HAART. This block involves the aberrant localization of multiply spliced (MS HIV-1 RNAs encoding the critical positive regulators Tat and Rev. Although these RNAs had no previously described export defect, we show that they exhibit strict nuclear localization in resting CD4+ T cells from patients on HAART. Overexpression of the transcriptional activator Tat from non-HIV vectors allowed virus production in these cells. Thus, the nuclear retention of MS HIV-1 RNA interrupts a positive feedback loop and contributes to the non-productive nature of infection of resting CD4+ T cells. To define the mechanism of nuclear retention, proteomic analysis was used to identify proteins that bind MS HIV-1 RNA. Polypyrimidine tract binding protein (PTB was identified as an HIV-1 RNA-binding protein differentially expressed in resting and activated CD4+ T cells. Overexpression of PTB in resting CD4+ T cells from patients on HAART allowed cytoplasmic accumulation of HIV-1 RNAs. PTB overexpression also induced virus production by resting CD4+ T cells. Virus culture experiments showed that overexpression of PTB in resting CD4+ T cells from patients on HAART allowed release of replication-competent virus, while preserving a resting cellular phenotype. Whether through effects on RNA export or another mechanism, the ability of PTB to reverse latency without inducing cellular activation is a result with therapeutic implications.

  6. Multiple dendritic cell populations activate CD4+ T cells after viral stimulation.

    Directory of Open Access Journals (Sweden)

    Adele M Mount

    2008-02-01

    Full Text Available Dendritic cells (DC are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8alpha DC play a prominent, and sometimes exclusive, role in driving amplification of CD8(+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4(+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4(+ and CD8(+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8alpha DC populations in the amplification of CD8(+ and CD4(+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8(+ T cells are dominated by presentation of antigen by CD8alpha DC but can involve non-CD8alpha DC. In contrast, CD4(+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4(+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity.

  7. Nanostructure and force spectroscopy analysis of human peripheral blood CD4+ T cells using atomic force microscopy.

    Science.gov (United States)

    Hu, Mingqian; Wang, Jiongkun; Cai, Jiye; Wu, Yangzhe; Wang, Xiaoping

    2008-09-12

    To date, nanoscale imaging of the morphological changes and adhesion force of CD4(+) T cells during in vitro activation remains largely unreported. In this study, we used atomic force microscopy (AFM) to study the morphological changes and specific binding forces in resting and activated human peripheral blood CD4(+) T cells. The AFM images revealed that the volume of activated CD4(+) T cells increased and the ultrastructure of these cells also became complex. Using a functionalized AFM tip, the strength of the specific binding force of the CD4 antigen-antibody interaction was found to be approximately three times that of the unspecific force. The adhesion forces were not randomly distributed over the surface of a single activated CD4(+) T cell, indicated that the CD4 molecules concentrated into nanodomains. The magnitude of the adhesion force of the CD4 antigen-antibody interaction did not change markedly with the activation time. Multiple bonds involved in the CD4 antigen-antibody interaction were measured at different activation times. These results suggest that the adhesion force involved in the CD4 antigen-antibody interaction is highly selective and of high affinity.

  8. Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells.

    Science.gov (United States)

    Lee, Guinevere Q; Orlova-Fink, Nina; Einkauf, Kevin; Chowdhury, Fatema Z; Sun, Xiaoming; Harrington, Sean; Kuo, Hsiao-Hsuan; Hua, Stephane; Chen, Hsiao-Rong; Ouyang, Zhengyu; Reddy, Kavidha; Dong, Krista; Ndung'u, Thumbi; Walker, Bruce D; Rosenberg, Eric S; Yu, Xu G; Lichterfeld, Mathias

    2017-06-30

    HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.

  9. Anti-HER2 CD4+T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer.

    Science.gov (United States)

    De La Cruz, Lucy M; McDonald, Elizabeth S; Mick, R; Datta, Jashodeep; Nocera, Nadia F; Xu, Shuwen; Fisher, Carla S; Czerniecki, Brian J

    2017-04-01

    In human epidermal growth factor 2-positive breast cancer (HER2 + BC), neoadjuvant chemotherapy and anti-HER2-targeted therapy (nCT) achieves a complete pathologic response (pCR) in 40-67% of patients. Posttreatment magnetic resonance imaging (pMRI) is considered the gold standard, with high specificity but lower sensitivity for assessing response. The authors previously determined that anti-HER2Th1 immune response is associated with pathologic response after nCT in HER2 + BC patients. This study contrasted pMRI with anti-HER2Th1 response for assessing pCR in HER2 + BC. A retrospective review of HER2 + BC patients at the authors' institution was performed. Original pMRI reports were collected, and images were reviewed by a breast radiologist blinded to pCR and immune response. The post-nCT imaging-based tumor response was assessed by Response Evaluation Criteria in Solid Tumors. The anti-HER2Th1 response was determined by ex vivo stimulation of peripheral blood mononuclear cells with six major histocompatibility complex (MHC) class 2-derived HER2 peptides via enzyme-linked immunospot (ELISPOT). Posttreatment MRI and anti-HER2Th1 responses were cross-tabulated with pCR. Standard diagnostic metrics were computed. For 30 patients, pMRI and anti-HER2Th1 immune response were measured, with 13 patients (43.3%) achieving pCR. The mean anti-HER2Th1 response in pCR was 167 (range 53-418), and response was superior to the original pMRI and had higher accuracy than the blinded pMRI review (area under the curve 0.97 vs 0.55; sensitivity 100 vs 46.2%; specificity 94.1 vs 64.7%; overall accuracy 96.7 vs 56.7%). The presence of a high anti-HER2Th1 response is superior to pMRI for the assessment of pCR in HER2 + BC. This assay has considerable promise, and validation in a large-scale study is warranted.

  10. Correlation between total lymphocyte count, hemoglobin, hematocrit and CD4 count in HIV patients in Nigeria.

    Science.gov (United States)

    Emuchay, Charles Iheanyichi; Okeniyi, Shemaiah Olufemi; Okeniyi, Joshua Olusegun

    2014-04-01

    The expensive and technology limited setting of CD4 count testing is a major setback to the initiation of HAART in a resource limited country like Nigeria. Simple and inexpensive tools such as Hemoglobin (Hb) measurement and Total Lymphocyte Count (TLC) are recommended as substitute marker. In order to assess the correlations of these parameters with CD4 count, 100 "apparently healthy" male volunteers tested HIV positive aged ≥ 20 years but ≤ 40 years were recruited and from whom Hb, Hct, TLC and CD4 count were obtained. The correlation coefficients, R, the Nash-Sutcliffe Coefficient of Efficiency (CoE) and the p-values of the ANOVA model of Hb, Hct and TLC with CD4 count were assessed. The assessments show that there is no significant relationship of any of these parameters with CD4 count and the correlation coefficients are very weak. This study shows that Hb, Hct and TLC cannot be substitute for CD4 count as this might lead to certain individuals' deprivation of required treatment.

  11. Antrum- and Corpus Mucosa-Infiltrating CD4+ Lymphocytes in Helicobacter pylori Gastritis Display a Th1 Phenotype

    Science.gov (United States)

    Sommer, Frank; Faller, Gerhard; Konturek, Peter; Kirchner, Thomas; Hahn, Eckhart G.; Zeus, Jürgen; Röllinghoff, Martin; Lohoff, Michael

    1998-01-01

    In this study, cytokine patterns produced by CD4+ T cells isolated from antrum or corpus gastral biopsy specimens of 10 patients with Helicobacter pylori-positive gastritis were compared. To this end, expression of intracellular cytokines (interleukin-4 [IL-4] and gamma interferon) and of CD4 was assessed by flow cytometry. Ten to 60% of the isolated CD4+ T cells produced gamma interferon upon stimulation. With the exception of one patient, IL-4-positive CD4+ cells were not detected. Therefore, CD4+ cells infiltrating antrum and corpus stomach mucosa during H. pylori infection show a Th1 phenotype. This polarized Th1-type response may contribute to the inability of the immune system to eradicate H. pylori infection. PMID:9784570

  12. Reactivation of HIV-1 proviruses in immune-compromised mice engrafted with human VOA-negative CD4+ T cells.

    Science.gov (United States)

    Yuan, Zhe; Kang, Guobin; Lu, Wuxun; Li, Qingsheng

    2017-01-01

    HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses. To explore the utility of NOD scid gamma (NSG) mice as an in vivo model to reactivate HIV-1 proviruses from VOA-negative CD4+ T cells, resting CD4+ T cells from an HIV-1 latently infected individual were isolated and the human CD4+ T cells corresponding to VOA-positive and VOA-negative CD4+ T cells were engrafted into NSG mice. Plasma viral load (pVL) and human CD4+ T cells were quantified every other week using qRT-PCR and flow cytometry. We found that NSG mice reactivated latently infected HIV-1 from VOA-positive CD4+ T cells as well as VOA-negative CD4+ T cells. Engrafted CD4+ T cells proliferated considerably in vivo , peaked prior to provirus reactivation, and lasted for up to 14 weeks. Sequence analyses revealed that reactivated proviruses in VOA-positive and VOA-negative CD4+ T cells are different. Taken together, NSG mice can support long-term engraftment of human CD4+ T cells and reactivate VOA-positive and VOA-negative proviruses. Therefore, this in vivo model has the potential to be used to study the underlying mechanisms of HIV-1 latency and reactivation.

  13. Do gender differences in CD4 cell counts matter?

    NARCIS (Netherlands)

    Prins, M. [= Maria; Robertson, J. R.; Brettle, R. P.; Aguado, I. H.; Broers, B.; Boufassa, F.; Goldberg, D. J.; Zangerle, R.; Coutinho, R. A.; van den Hoek, A.

    1999-01-01

    To examine the effect of gender on disease progression and whether gender differences in CD4 lymphocyte counts persisted for the entire course from HIV seroconversion until (death from) AIDS. CD4 lymphocyte counts were modelled in 221 female and 443 male seroconverters following seroconversion,

  14. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs ...

    African Journals Online (AJOL)

    enhances immunity by sustained HIV- viral suppression, increase in CD4+ cell count and immune restoration. ... Seventy three (70.9%) of patients still had immune depletion with low CD4+ cell counts at one year of receiving HAART. ..... homeostasis and function in advanced HIV disease. Science 1997; 277: 112- 116. 7.

  15. Immunophenotypic enumeration of CD4 T-lymphocyte values in ...

    African Journals Online (AJOL)

    McRoy

    absolute CD4+ LCs of 838 cells/μl was observed by chng et al. among healthy Asian population comprising of individuals from China, India and. Malaysia.[27] .... smoking. Cytometry B Clin Cytom 2003;52:32-36. 16. Nag VL, Agarwal P, Venkatesh V, Rastogi P,. Tandon R, Agrawal SK. A pilot study on observations on CD4 ...

  16. Immunophenotypic enumeration of CD4 T-lymphocyte values in ...

    African Journals Online (AJOL)

    McRoy

    lymphocytes play a central role in regulation of immune response.[2] These ..... influence of sex hormones on lymphocyte subpopulations. ... Friedland GH. Early treatment for HIV-The Time. Has Come. N Engl J Med 1990;322:1000-1002. 7. Gebo KA, Gallant JE, Keruly JC, Moore RD. Absolute CD4 vs. CD4 percentage for ...

  17. Single-position Hall effect measurements

    DEFF Research Database (Denmark)

    2014-01-01

    A method for determining a distance (Y) between a first position on and an electrical boundary (34) of a test sample by a multi-point probe comprising four contact elements, comprising: contacting the test sample with the four contact elements (20,22,24,26) at the first position, applying a magne...

  18. Single-position Hall effect measurements

    DEFF Research Database (Denmark)

    2014-01-01

    A method for determining a distance (Y) between a first position on and an electrical boundary (34) of a test sample by a multi-point probe comprising four contact elements, comprising: contacting the test sample with the four contact elements (20,22,24,26) at the first position, applying...... a magnetic field at the first position, performing a first and a second four-point measurement and deriving a first and a second resistance value, calculating a first resistance difference from the first and second resistance values, performing a third and a fourth four-point measurement and deriving a third...

  19. Opportunistic intestinal parasites and CD4 count in HIV infected people

    Directory of Open Access Journals (Sweden)

    R Amatya

    2011-10-01

    Full Text Available Background: Opportunistic intestinal infections cause a significant morbidity and mortality among the HIV infected people. The present study was undertaken to find the prevalence of intestinal opportunistic parasitic infections among the HIV infected populace in eastern Nepal and to correlate the occurrence with the CD4 T cell counts. Materials and Methods: Stool from 122 HIV infected people were examined microscopically for the presence of parasitic ova/cyst. CD4 T cell enumeration was done using FACS Count (Becton Dickinson. Stool from 100 age matched HIV negative controls were also examined. Results: A male preponderance in the parasite positivity was seen. Twenty five of symptomatic and 2.8% of asymptomatic harboured one or more intestinal parasites.12.3% of the study population had intestinal parasitoses with 7.3% being infected with opportunistic parasites. The mean CD4 count of the subjects was 307 while those with parasitoses were 204. A statistically significant difference was seen between the CD4 counts of symptomatic and asymptomatic patients. Conclusion: Coccidian parasites are frequent opportunistic intestinal parasites infecting HIV infected patients. A lowered CD4 count predisposes to acquisition of these agents. Regular monitoring of CD4 counts and screening for these opportunistic agents in the HIV infected will help reduce the mortality and morbidity associated with infections by these agents. Keywords: HIV; Opportunistic infection; CD4 count; AIDS DOI: http://dx.doi.org/10.3126/jpn.v1i2.5405 JPN 2011; 1(2: 118-121

  20. Absolute Lymphocyte Count Is Not a Suitable Alternative to CD4 Count for Determining Initiation of Antiretroviral Therapy in Fiji

    Directory of Open Access Journals (Sweden)

    Dashika A. Balak

    2014-01-01

    Full Text Available Introduction. An absolute lymphocyte count is commonly used as an alternative to a CD4 count to determine initiation of antiretroviral therapy for HIV-infected individuals in Fiji when a CD4 count is unavailable. Methods. We conducted a retrospective analysis of laboratory results of HIV-infected individuals registered at all HIV clinics in Fiji. Results. Paired absolute lymphocyte and CD4 counts were available for 101 HIV-infected individuals, and 96% had a CD4 count of ≤500 cells/mm3. Correlation between the counts in individuals was poor (Spearman rank correlation r=0.5. No absolute lymphocyte count could be determined in this population as a suitable surrogate for a CD4 count of either 350 cells/mm3 or 500 cells/mm3. The currently used absolute lymphocyte count of ≤2300 cells/μL had a positive predictive value of 87% but a negative predictive value of only 17% for a CD4 of ≤350 cells/mm3 and if used as a surrogate for a CD4 of ≤500 cells/mm3 it would result in all HIV-infected individuals receiving ART including those not yet eligible. Weight, CD4 count, and absolute lymphocyte count increased significantly at 3 months following ART initiation. Conclusions. Our findings do not support the use of absolute lymphocyte count to determine antiretroviral therapy initiation in Fiji.

  1. Comparison of HIV-1 viral loads, CD4-Th2-lymphocytes and effects ...

    African Journals Online (AJOL)

    Methodology: A 9-month prospective longitudinal study was conducted among HIV-1 infected individuals aged 21-55 years with CD4+ cell counts ≥ 350cells/µL in fishing villages of North-Western Tanzania. Single stool samples were examined for S. mansoni eggs using Kato Katz technique at 6-month follow-up and 12 ...

  2. Characteristics of Plasmacytoid Dendritic Cell and CD4+ T Cell in HIV Elite Controllers

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Herbeuval

    2012-01-01

    Full Text Available Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load and massive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers, and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers.

  3. Correlation of CD4 counts with microalbuminuria in HIV patients

    Science.gov (United States)

    Bakri, S.; Haerani, R.; Hasyim, K.; Sudirman, K.; Tarukallo, N.

    2018-03-01

    One of the manifestations of kidney disease is Microalbuminuria (MA). CD4 T cells are cells that play a central role in immune protection, wherein HIV infections, they are the primary target of the virus. CD4 cells counts is an indirect reflection of the activity and viral load of HIV. This study aimed to determine the correlation of CD4 counts with MA in HIV patients. A cross-sectional with thedescriptive analytical study was in HIV patients >18 years old without a history of Diabetes Mellitus. The result of thestatistical test is significant if the value of p HIV patients.

  4. Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase

    OpenAIRE

    Olofsson, Peder S.; Steinberg, Benjamin E.; Sobbi, Roozbeh; Cox, Maureen A.; Ahmed, Mohamed N.; Oswald, Michaela; Szekeres, Ferenc; Hanes, William M.; Introini, Andrea; Liu, Shu Fang; Holodick, Nichol E.; Rothstein, Thomas L.; L?vdahl, Cecilia; Chavan, Sangeeta S.; Yang, Huan

    2016-01-01

    Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been defined. We previously described that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals 1 . Here we show that these CD4+ CD44high CD62Llow T helper cells by gene expression are a distinct T cell population defined by ChAT (CD4 TChAT)....

  5. Access to CD4 Testing for Rural HIV Patients: Findings from a Cohort Study in Zimbabwe.

    Directory of Open Access Journals (Sweden)

    Florian Vogt

    Full Text Available CD4 cell count measurement remains an important diagnostic tool for HIV care in developing countries. Insufficient laboratory capacity in rural Sub-Saharan Africa is frequently mentioned but data on the impact at an individual patient level are lacking. Urban-rural discrepancies in CD4 testing have not been quantified to date. Such evidence is crucial for public health planning and to justify new yet more expensive diagnostic procedures that could circumvent access constraints in rural areas.To compare CD4 testing among rural and urban HIV patients during the first year of treatment.Records from 2,145 HIV positive adult patients from a Médecins sans Frontières (Doctors without Borders HIV project in Beitbridge, Zimbabwe, during 2011 and 2012 were used for a retrospective cohort analysis. Covariate-adjusted risk ratios were calculated to estimate the effects of area of residence on CD4 testing at treatment initiation, six and 12 months among rural and urban patients.While the proportion of HIV patients returning for medical consultations at six and 12 months decreased at a similar rate in both patient groups, CD4 testing during consultations dropped to 21% and 8% for urban, and 2% and 1% for rural patients at six and 12 months, respectively. Risk ratios for missing CD4 testing were 0.8 (95% CI 0.7-0.9, 9.2 (95% CI 5.5-15.3, and 7.6 (95% 3.7-17.1 comparing rural versus urban patients at treatment initiation, six and 12 months, respectively.CD4 testing was low overall, and particularly poor in rural patients. Difficulties with specimen transportation were probably a major factor underlying this difference and requires new diagnostic approaches. Our findings point to severe health system constraints in providing CD4 testing overall that need to be addressed if effective monitoring of HIV patients is to be achieved, whether by alternative CD4 diagnostics or newly-recommended routine viral load testing.

  6. 10 Prevalence of intestinal parasites in relation to CD4 counts and ...

    African Journals Online (AJOL)

    Abstract: Parasitic infections continue to take their toll on HIV positive patients by influencing the blood qualitatively and quantitatively. The objective of this study was to determine the prevalence of intestinal parasitic infections in relation to anaemia and CD4 counts among HIV-infected patients in Benin City,. Nigeria.

  7. Reference values of CD4 T-lymphocytes in human ...

    African Journals Online (AJOL)

    exposed uninfected infants in Kano.Nigeria. ... Journal of Medicine in the Tropics ... Studies to evaluate CD4 count in vertically exposed, but human immunodeficiency virus (HIV) negative infants from this region have not been done previously.

  8. The Effect of Low CD4+ Lymphocyte Count on the Radiographic Patterns of HIV Patients with Pulmonary Tuberculosis among Nigerians

    Directory of Open Access Journals (Sweden)

    Christopher Affusim

    2013-01-01

    Full Text Available Objective. To assess the radiographic features in patients with Human Immunodeficiency Virus (HIV complicated by pulmonary tuberculosis (PTB, and the association with CD4 lymphocyte count and sputum smear. Method. A prospective study was carried out on 89 HIV positive patients with PTB. The demographics, smoking history, sputum smear result, chest radiographic findings and CD4 lymphocyte count were documented. Results. Out of the 89 patients recruited in the study, 41 were males and 48 were females. Eighteen (18 patients had typical radiographic features, 60 patients had atypical radiographic features while only 11 of them had normal radiographic films. Sixty eight (68 patients had CD4 count <200 cells/mm3, 19 patients had CD4 count between 200–499 cells/mm3, while only 2 patients had CD4 count from 500 cells/mm3 upwards. The association between low CD4 count and radiographic finding was statistically significant, ( value . Sixty (60 patients had negative sputum smear for Acid and Alcohol Fast Bacilli (AAFB, while the remaining 29 patients had positive smear. The association between low CD4 count and negative smear was statistically significant ( value . Conclusion. The radiographic pattern and the result of the sputum smear for AAFB has a significant relationship and association with the immune status of patients with Human Immunodeficiency Virus (HIV complicated by pulmonary tuberculosis.

  9. Correlation of CD4 counts with clinical and histopathological findings in disseminated histoplasmosis: a 10-year retrospective study.

    Science.gov (United States)

    Sirait, Sondang P; Bramono, Kusmarinah; Hermanto, Nathalia

    2017-09-01

    Disseminated cutaneous histoplasmosis (DCH) is one of the manifestations of systemic histoplasmosis infection in HIV-positive patients. Interaction between host immune status and histoplasmosis infection is still poorly understood. It is thought that immune status, represented by CD4 counts, may be correlated with clinical and histopathological findings. To correlate the CD4 counts with the different clinical and histopathological findings in cutaneous histoplasmosis. This was a serial case report of seven HAART-treated HIV positive patients with disseminated histoplasmosis observed within the period of January 2004 through December 2014 from the Dermatology and Venereology Department, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. The patients came with different complaints and clinical findings. CD4 counts were recorded prior to lesion biopsy. The CD4 counts were independent from clinical morphology and distribution of lesions. Lower CD4 counts were associated with the presence of intraepidermal yeast-like cells, whereas there is the ability of forming granulomas at higher CD4 counts. CD4 count correlates to histopathological findings of cutaneous histoplasmosis. © 2017 The International Society of Dermatology.

  10. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

    DEFF Research Database (Denmark)

    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...... expression and no loss of polyclonality. Only in two of six cultures were we able to detect HIV-antigen production, and using an LTR-PCR and an RT assay, we did not find activation of the HIV infection during the culture period. Thus, the method described separates and expands CD4 cells from HIV......-positive patients without activation of the HIV infection....

  11. CD4(+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.

    Directory of Open Access Journals (Sweden)

    Jamie C Zampell

    Full Text Available Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema.We used mouse-tail lymphedema and axillary lymph node dissection (ANLD models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis.Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model.Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but not CD8+ or CD25+ cell inflammation markedly

  12. Maternal CD4+ microchimerism in HIV-exposed newborns after spontaneous vaginal delivery or caesarean section.

    Science.gov (United States)

    Buxmann, H; Reitter, A; Bapistella, S; Stürmer, M; Königs, C; Ackermann, H; Louwen, F; Bader, P; Schlößer, R L; Willasch, A M

    2016-07-01

    Maternal CD4+ cell microchimerism may be greater after caesarean section compared to spontaneous vaginal delivery and could cause mother-to-child transmission (MTCT) in HIV-exposed newborns. To evaluate maternal CD4+ cell microchimerism in HIV-exposed newborns after spontaneous vaginal delivery or caesarean section. In this prospective single-centre study, neonates whose mothers were infected with HIV and had normal MTCT risk according to the German Austrian Guidelines were considered for study enrolment. Maternal CD4+ cell microchimerism in the newborns' umbilical cord blood was measured and compared by mode of delivery. Thirty-seven HIV-infected mothers and their 39 newborns were included in the study. None of the 17 (0.0%) newborns delivered vaginally had quantifiable maternal CD4+ cells (95% confidence interval (CI): 0.00-0.00) in their circulation at birth compared with four of 16 (25.0%) newborns delivered via planned caesarean section, who showed 0.01-0.66% maternal cells (95% CI: -0.06-0.16; P=0.02) in their circulation. The intention to treat analysis, which included six additional newborns delivered by unplanned caesarean section, showed quantifiable maternal CD4+ cells in one (0.05%; 95% CI: -0.02-0.04) of 23 (4.3%) newborn at birth compared to four of 16 (25.0%) born via planned caesarean section (95% CI: -0.06-0.16; P=0.04). There was no MTCT in any of the newborns. In this small cohort, spontaneous vaginal delivery in HIV-infected women with normal MTCT risk was associated with lower maternal CD4+ cell transfer to newborns compared to planned caesarean section. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Percentages of CD4+CD161+ and CD4−CD8−CD161+ T Cells in the Synovial Fluid Are Correlated with Disease Activity in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Jinlin Miao

    2015-01-01

    Full Text Available Objective. CD161 has been identified as a marker of human IL-17-producing T cells that are implicated in the pathogenesis of rheumatoid arthritis (RA. This study aimed to investigate the potential link between the percentage of CD161+ T cells and disease activity in RA patients. Methods. Peripheral blood (PB from 54 RA patients and 21 healthy controls was evaluated. Paired synovial fluid (SF (n = 17 was analyzed. CD161 expression levels on CD4+, CD8+, and CD4−CD8− T cells were assessed by flow cytometry. Results. The percentage of CD4+CD161+ T cells in RA SF was higher than RA PB, and it was positively correlated with DAS28, erythrocyte sedimentation rate (ESR, and C-reactive protein (CRP. CD4−CD8−CD161+ T cell percentage was decreased in RA PB and was further reduced in RA SF, and its level in SF was inversely correlated with DAS28, ESR, and CRP. However, CD8+CD161+ T cell percentage was neither changed in RA PB and SF nor correlated with disease activity indices. Conclusion. An increased CD4+CD161+ T cell percentage and a decreased CD4−CD8−CD161+ T cell percentage are present in RA SF and are associated with disease activity, and the accumulation of CD4+CD161+ T cells in SF may contribute to the local inflammation of RA.

  14. Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes

    International Nuclear Information System (INIS)

    Ozsahin, Mahmut; Ozsahin, Huelya; Yuquan, Shi; Larsson, Boerje; Wuergler, Friedrich E.; Crompton, Nigel E. A.

    1997-01-01

    Purpose: An assay for radiosensitivity has numerous applications in the clinic. Avoidance of acute responses, prediction of normal tissue toxicity, and individualization of patient radiotherapy are included among these. We have developed a rapid assay (about 24 h) able to predict intrinsic radiosensitivity of CD4 and CD8 T-lymphocytes based on radiation-induced apoptosis. Methods and Materials: Fresh blood samples (1-2 ml in heparinized tubes) were irradiated with 0-, 2-, and 8-Gy X rays at a dose rate of approximately 3 Gy/min. Following irradiation, the cells were collected and prepared for flow-cytometric analysis and cell sorting. In conjunction with the CellQuest software available with the FACSVantage cell sorter (Becton-Dickinson), two T-lymphocyte types were analyzed on the basis of their cell-specific antigens (CD4 and CD8), and DNA was stained with DAPI. Following the separation of these cell types, radiation-induced cell death was assessed. Cytotoxicity was characterized by gradual degradation of internucleosomal DNA which results in a sub-G1 peak on the DNA histogram, and by the associated loss of surface antigens causing an intermediate positive peak in the antibody histogram. Using the assay, we investigated the interdonor variation in a cohort of 45 healthy adult blood donors and 5 children [one had immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF), and one had ataxia telangiectasia (AT)]. Intradonor variation was assessed with 10 different experiments from a single donor. Results: CD4 and CD8 T-lymphocyte radiosensitivities were correlated (r 0.63 and 0.65 for 2 and 8 Gy, respectively) in 45 adult donors. Both for CD4 and CD8 cells, 2 and 8 Gy irradiation responses showed a good correlation (r 0.77 for both). Interdonor variation was significantly higher than intradonor variation (p < 0.0005) for all CD4 and CD8 data. We observed a decrease in the antigen fluorescence of dying cells, a phenomenon referred to as antigen

  15. Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4+ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy.

    Science.gov (United States)

    Liu, Bingfeng; Zou, Fan; Lu, Lijuan; Chen, Cancan; He, Dalian; Zhang, Xu; Tang, Xiaoping; Liu, Chao; Li, Linghua; Zhang, Hui

    2016-11-01

    Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8 + T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4 + T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure. The presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen

  16. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.

    Science.gov (United States)

    Tebas, Pablo; Stein, David; Tang, Winson W; Frank, Ian; Wang, Shelley Q; Lee, Gary; Spratt, S Kaye; Surosky, Richard T; Giedlin, Martin A; Nichol, Geoff; Holmes, Michael C; Gregory, Philip D; Ando, Dale G; Kalos, Michael; Collman, Ronald G; Binder-Scholl, Gwendolyn; Plesa, Gabriela; Hwang, Wei-Ting; Levine, Bruce L; June, Carl H

    2014-03-06

    CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe. We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (PCCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).

  17. Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

    Science.gov (United States)

    Ma, Qin-Yun; Huang, Da-Yu; Zhang, Hui-Jun; Wang, Shaohua; Chen, Xiao-Feng

    2017-11-15

    LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4 + CD25 - T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4 + T cells directly ex vivo and primarily in the CD4 + CD25 - fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4 + CD25 - cells Compared to LAG3-nonexpressing CD4 + CD25 - cells, LAG3-expressing CD4 + CD25 - cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8 + T effector cells. LAG3-expressing CD4 + CD25 - cells also presented impaired proliferation compared with LAG3-nonexpressing CD4 + CD25 - cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8 + T cells co-incubated with LAG3-expressing CD4 + CD25 - cells at equal cell numbers demonstrated significantly lower proliferation than CD8 + T cells incubated alone. Co-culture with CD8 + T cell and LAG3-expressing CD4 + CD25 - T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4 + CD25 - T cells. In addition, we found that LAG3-expressing CD4 + CD25 - T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4 + CD25 - T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Visualization of the human CD4{sup +} T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γc{sup null} (NOG) mice by retrogenic expression of the human TCR gene

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Takeshi, E-mail: takeshi-takahashi@ciea.or.jp; Katano, Ikumi; Ito, Ryoji; Ito, Mamoru

    2015-01-02

    Highlights: • β-Lactoglobulin (BLG) specific TCR genes were introduced to human HSC by retrovirus. • Human HSC with BLG-specific TCR were transplanted into NOG-HLA-DR4 I-A{sup −/−} mice. • BLG-specific TCR induced positive selection of thymocytes. • BLG-specific TCR positive CD4{sup +} T cells mediated immune responses in humanized mice. - Abstract: The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4{sup +} T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4{sup +} T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A{sup o}). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4{sup +}CD8{sup −} single-positive cells. Adoptive transfer of mature CD4{sup +} T cells expressing the TCR into recipient NOG-DR4/I-A{sup o} mice demonstrated that human CD4{sup +} T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice.

  19. Visualization of the human CD4+ T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γcnull (NOG) mice by retrogenic expression of the human TCR gene

    International Nuclear Information System (INIS)

    Takahashi, Takeshi; Katano, Ikumi; Ito, Ryoji; Ito, Mamoru

    2015-01-01

    Highlights: • β-Lactoglobulin (BLG) specific TCR genes were introduced to human HSC by retrovirus. • Human HSC with BLG-specific TCR were transplanted into NOG-HLA-DR4 I-A −/− mice. • BLG-specific TCR induced positive selection of thymocytes. • BLG-specific TCR positive CD4 + T cells mediated immune responses in humanized mice. - Abstract: The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4 + T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4 + T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A o ). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4 + CD8 − single-positive cells. Adoptive transfer of mature CD4 + T cells expressing the TCR into recipient NOG-DR4/I-A o mice demonstrated that human CD4 + T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice

  20. Alternative pathway for the development of Vα14+ NKT cells directly from CD4-CD8- thymocytes that bypasses the CD4+CD8+ stage.

    Science.gov (United States)

    Dashtsoodol, Nyambayar; Shigeura, Tomokuni; Aihara, Minako; Ozawa, Ritsuko; Kojo, Satoshi; Harada, Michishige; Endo, Takaho A; Watanabe, Takashi; Ohara, Osamu; Taniguchi, Masaru

    2017-03-01

    Although invariant V α 14 + natural killer T cells (NKT cells) are thought to be generated from CD4 + CD8 + double-positive (DP) thymocytes, the developmental origin of CD4 - CD8 - double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (T H 1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage. These findings provide new insight into understanding of the development of NKT cells and propose a role for timing of expression of the invariant T cell antigen receptor in determining the functional properties of NKT cells.

  1. Prevalence of HIV infection and median CD4 counts among health care workers in South Africa.

    Science.gov (United States)

    Connelly, Daniela; Veriava, Youssef; Roberts, Sue; Tsotetsi, Josephine; Jordan, Annie; DeSilva, Eliot; Rosen, Sydney; DeSilva, Mary Bachman

    2007-02-01

    To determine the prevalence of HIV infection and the extent of disease progression based on CD4 count in a public health system workforce in southern Africa. Cross-sectional voluntary, anonymous, unlinked survey including an oral fluid or blood sample and a brief demographic questionnaire. Two public hospitals in Gauteng, South Africa. All 2 032 professional and support staff employed by the two hospitals. HIV prevalence and CD4 cell count distribution. Overall prevalence of HIV was 11.5%. By occupation, prevalence was highest among student nurses (13.8%) and nurses (13.7%). The highest prevalence by age was in the 25 - 34-year group (15.9%). Nineteen per cent of HIV-positive participants who provided blood samples had CD4 counts less than or equal to 200 cells/ microl 28% had counts 201 - 350 cells/ microl, 18% had counts 351 - 500 cells/ microl, and 35% had counts above 500 cells/ microl. One out of 7 nurses and nursing students in this public sector workforce was HIV-positive. A high proportion of health care workers had CD4 counts below 350 cells/ microl, and many were already eligible for antiretroviral therapy under South African treatment guidelines. Given the short supply of nurses in South Africa, knowledge of prevalence in this workforce and provision of effective AIDS treatment are crucial for meeting future staffing needs.

  2. Acceptability and feasibility of point-of-care CD4 testing on HIV continuum of care in low and middle income countries: a systematic review.

    Science.gov (United States)

    Pham, Minh D; Agius, Paul A; Romero, Lorena; McGlynn, Peter; Anderson, David; Crowe, Suzanne M; Luchters, Stanley

    2016-08-02

    CD4 testing is, and will remain an important part of HIV treatment and care in low and middle income countries (LMICs). We report the findings of a systematic review assessing acceptability and feasibility of POC CD4 testing in field settings. Electronic databases were searched for studies published in English between 2005 and 2015 that describe POC CD4 platforms. Studies conducted in LMICs and under field conditions outside a laboratory environment were eligible. Qualitative and descriptive data analysis was used to present the findings. Twelve studies were included, 11 of which were conducted in sub-Saharan countries and used one POC CD4 test (The Alere Pima CD4). Patients reported positively regarding the implementation of POC CD4 testing at primary health care and community level with ≥90 % of patients accepting the test across various study settings. Health service providers expressed preference toward POC CD4 testing as it is easy-to-use, efficient and satisfied patients' needs to a greater extent as compared to conventional methods. However, operational challenges including preference toward venous blood rather than finger-prick sampling, frequent device failures and operator errors, quality of training for test operators and supervisors, and increased staff workload were also identified. POC CD4 testing seems acceptable and feasible in LIMCs under field conditions. Further studies using different POC CD4 tests available on the market are required to provide critical data to support countries in selection and implementation of appropriate POC CD4 technologies.

  3. How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

    Directory of Open Access Journals (Sweden)

    Ole Audun Werner Haabeth

    2014-04-01

    Full Text Available CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315, where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

  4. Characterization of CD4⁺ cytotoxic lymphocytes and apoptosis markers induced by Trypanossoma cruzi infection.

    Science.gov (United States)

    Keesen, T S L; Gomes, J A S; Fares, R C G; de Araújo, F F; Ferreira, K S; Chaves, A T; Rocha, M O C; Correa-Oliveira, R

    2012-09-01

    Although the pathophysiology of Chagas disease is not completely understood, it is widely accepted that involvement of the immune response is critical in determining the outcome of the disease. In this context, CD4⁺ T cells may play an important role in generating different mechanisms of protection. In addition to effector and regulatory functions, CD4⁺ T cells may be also involved with lytic activities against the parasite and may have a relevant role on control of the infection. In this study, we have evaluated CD4⁺ T cells expressing cytotoxic and apoptosis markers in response to Trypanossoma cruzi infection in indeterminate (IND) and cardiac (CARD) patients with Chagas disease and non-infected individuals (NI). Our data demonstrated that: (1) CD4⁺ T cells presented higher ex vivo granzyme B expression in patients with Chagas disease compared with healthy individuals and that antigen induced a greater granzyme B expression in IND patients; (2) CD95L expression in CD4⁺ CD95⁺ T cells from IND patients is higher than in CARD and NI; (3) IND and CARD patients had an increased frequency of caspase-3 after in vitro stimulation and also expressed a high frequency of annexinV⁺ 7ADD⁺ within CD4⁺ T cells; (4) Lastly, a positive correlation was seen between cytotoxic molecules and CD45RO memory marker in CD4⁺ T cells and between caspase-3 and CD95L within CD4⁺ CD95⁺ T cells. These results suggest new insights into the functional competence of CD4⁺ T cells among the different clinical forms of Chagas disease, which will lead to a better understanding of their influence during immune responses against T. cruzi. © 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd.

  5. Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals.

    Directory of Open Access Journals (Sweden)

    Jorge Carrillo

    Full Text Available Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies, can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine.

  6. Functional and Phenotypic Plasticity of CD4+ T Cell Subsets

    Directory of Open Access Journals (Sweden)

    Tiffany Caza

    2015-01-01

    Full Text Available The remarkable plasticity of CD4+ T cells allows individuals to respond to environmental stimuli in a context-dependent manner. A balance of CD4+ T cell subsets is critical to mount responses against pathogen challenges to prevent inappropriate activation, to maintain tolerance, and to participate in antitumor immune responses. Specification of subsets is a process beginning in intrathymic development and continuing within the circulation. It is highly flexible to adapt to differences in nutrient availability and the tissue microenvironment. CD4+ T cell subsets have significant cross talk, with the ability to “dedifferentiate” given appropriate environmental signals. This ability is dependent on the metabolic status of the cell, with mTOR acting as the rheostat. Autoimmune and antitumor immune responses are regulated by the balance between regulatory T cells and Th17 cells. When a homeostatic balance of subsets is not maintained, immunopathology can result. CD4+ T cells carry complex roles within tumor microenvironments, with context-dependent immune responses influenced by oncogenic drivers and the presence of inflammation. Here, we examine the signals involved in CD4+ T cell specification towards each subset, interconnectedness of cytokine networks, impact of mTOR signaling, and cellular metabolism in lineage specification and provide a supplement describing techniques to study these processes.

  7. Owl monkey CCR5 reveals synergism between CD4 and CCR5 in HIV-1 entry.

    Science.gov (United States)

    Nahabedian, John; Sharma, Amit; Kaczmarek, Maryska E; Wilkerson, Greg K; Sawyer, Sara L; Overbaugh, Julie

    2017-12-01

    Studying HIV-1 replication in the presence of functionally related proteins from different species has helped define host determinants of HIV-1 infection. Humans and owl monkeys, but not macaques, encode a CD4 receptor that permits entry of transmissible HIV-1 variants due to a single residue difference. However, little is known about whether divergent CCR5 receptor proteins act as determinants of host-range. Here we show that both owl monkey (Aotus vociferans) CD4 and CCR5 receptors are functional for the entry of transmitted HIV-1 when paired with human versions of the other receptor. By contrast, the owl monkey CD4/CCR5 pair is generally a suboptimal receptor combination, although there is virus-specific variation in infection with owl monkey receptors. Introduction of the human residues 15Y and 16T within a sulfation motif into owl monkey CCR5 resulted in a gain of function. These findings suggest there is cross-talk between CD4 and CCR5 involving the sulfation motif. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Antibodies to the CD4-binding site of HIV-1 gp120 suppress gp120-specific CD4 T cell response while enhancing antibody response

    Directory of Open Access Journals (Sweden)

    Hioe Catarina E

    2008-07-01

    Full Text Available Abstract Background The binding of Abs to the CD4-binding site (CD4bs of HIV-1 envelope gp120 has been shown to obstruct the processing and generation of helper epitopes from this antigen, resulting in poor presentation of various gp120 epitopes by MHC class II to CD4 T cells. However, the physiologic significance of these inhibitory anti-CD4bs Abs in vivo has remained unclear. In this study, we evaluated the immunologic effects of anti-CD4bs Abs in vivo using a murine model. Results Animals were immunized with recombinant envelope proteins with or without CD4-binding activity (designated CD4bs+ Env and CD4bs– Env, respectively. As expected, anti-CD4bs Abs were generated only after immunization with CD4bs+ Env and not with CD4bs– Env. The presence of anti-CD4bs Abs was associated with lower levels of envelope-specific lymphoproliferation in animals immunized with CD4bs+ Env. To further determine the specific role of the anti-CD4bs Abs, we immunized mice with gp120 in the presence of an inhibitory anti-CD4bs mAb or a non-inhibitory anti-gp120 mAb. The data show that the presence of anti-CD4bs mAb reduced CD4 T cell responses to gp120. However, we also detected significantly higher titers of anti-gp120 Abs following immunization with gp120 and the anti-CD4bs mAb. Conclusion Anti-CD4bs Abs can exert discordant effects on the gp120-specific CD4 T cell and Ab responses in vivo, indicating the importance of these particular Abs in influencing both the cellular and the humoral immune responses against HIV-1.

  9. Total lymphocyte count as a substitute to cd4 count in management of hiv infected individuals in resource limited society

    International Nuclear Information System (INIS)

    Daud, M.Y.; Qazi, R.A.

    2015-01-01

    Pakistan is a resource limited society and gold standard parameters to monitor HIV disease activity are very costly. The objective of the study was to evaluate total lymphocyte count (TLC) as a surrogate to CD4 count to monitor disease activity in HIV/AIDS in resource limited society. Methods: This cross sectional study was carried out at HIV/AIDS treatment centre, Pakistan Institute of Medical Sciences (PIMS), Islamabad. A total of seven hundred and seventy four (774) HIV positive patients were enrolled in this study, and their CD4 count and total lymphocyte count were checked to find any correlation between the two by using Spearman ranked correlation coefficient. Results: The mean CD4 count was (434.30 ± 269.23), with minimum CD4 count of (9.00), and maximum of (1974.00). The mean total lymphocyte count (TLC) was (6764.0052 ± 2364.02) with minimum TLC (1200.00) and maximum TLC was (20200.00). Using the Pearson's correlation (r) there was a significant and positive correlation between TLC and CD4 count. (r2=0.127 and p=0.000) at 0.01 level. Conclusion: Our study showed a significant positive correlation between CD4 count and total lymphocyte count (TLC), so TLC can be used as a marker of disease activity in HIV infected patients. (author)

  10. Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting

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    Lawn Stephen D

    2008-07-01

    Full Text Available Abstract Background Viral load monitoring is not available for the vast majority of patients receiving antiretroviral therapy in resource-limited settings. However, the practical utility of CD4 cell count measurements as an alternative monitoring strategy has not been rigorously assessed. Methods In this study, we used a novel modelling approach that accounted for all CD4 cell count and VL values measured during follow-up from the first date that VL suppression was achieved. We determined the associations between CD4 counts (absolute values and changes during ART, VL measurements and risk of virological failure (VL > 1,000 copies/ml following initial VL suppression in 330 patients in South Africa. CD4 count changes were modelled both as the difference from baseline (ΔCD4 count and the difference between consecutive values (CD4 count slope using all 3-monthly CD4 count measurements during follow-up. Results During 7093.2 patient-months of observation 3756 paired CD4 count and VL measurements were made. In patients who developed virological failure (n = 179, VL correlated significantly with absolute CD4 counts (r = - 0.08, P = 0.003, ΔCD4 counts (r = - 0.11, P P P = 0.99, P = 0.92 and P = 0.75, respectively. Moreover, in a receiver operating characteristic (ROC curve, the association between a negative CD4 count slope and virological failure was poor (area under the curve = 0.59; sensitivity = 53.0%; specificity = 63.6%; positive predictive value = 10.9%. Conclusion CD4 count changes correlated significantly with VL at group level but had very limited utility in identifying virological failure in individual patients. CD4 count is an inadequate alternative to VL measurement for early detection of virological failure.

  11. [MHC class I antigens, CD4 and CD8 expressions in polymyositis and dermatomyositis].

    Science.gov (United States)

    Graça, Carla Renata; Kouyoumdjian, João Aris

    2015-01-01

    To analyze the frequencies of the expression of major histocompatibility complex class I (MHC-I) antigens, and CD4 and CD8 cells in skeletal muscle in polymyositis (PM) and dermatomyositis (DM). This was a retrospective study of 34 PM cases, 8 DM cases, and 29 control patients with non-inflammatory myopathies. MHC-I antigens were expressed in the sarcolemma and/or sarcoplasm in 79.4% of PM cases, 62.5% of DM cases, and 27.6% of controls (CD4 expression was observed in 76.5%, 75%, and 13.8%, respectively). There was a high suspicion of PM/DM (mainly PM) in patients in whom MHC-I antigens and CD4 were co-expressed. In 14.3% of PM/DM cases, we observed MHC-I antigens expression alone, without inflammatory cells. MCH-I antigens expression and CD4 positivity might add to strong diagnostic suspicion of PM/DM. No cellular infiltration was observed in 14.3% of such cases. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

  12. HIV-1 induces DCIR expression in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Alexandra A Lambert

    2010-11-01

    Full Text Available The C-type lectin receptor DCIR, which has been shown very recently to act as an attachment factor for HIV-1 in dendritic cells, is expressed predominantly on antigen-presenting cells. However, this concept was recently challenged by the discovery that DCIR can also be detected in CD4(+ T cells found in the synovial tissue from rheumatoid arthritis (RA patients. Given that RA and HIV-1 infections share common features such as a chronic inflammatory condition and polyclonal immune hyperactivation status, we hypothesized that HIV-1 could promote DCIR expression in CD4(+ T cells. We report here that HIV-1 drives DCIR expression in human primary CD4(+ T cells isolated from patients (from both aviremic/treated and viremic/treatment naive persons and cells acutely infected in vitro (seen in both virus-infected and uninfected cells. Soluble factors produced by virus-infected cells are responsible for the noticed DCIR up-regulation on uninfected cells. Infection studies with Vpr- or Nef-deleted viruses revealed that these two viral genes are not contributing to the mechanism of DCIR induction that is seen following acute infection of CD4(+ T cells with HIV-1. Moreover, we report that DCIR is linked to caspase-dependent (induced by a mitochondria-mediated generation of free radicals and -independent intrinsic apoptotic pathways (involving the death effector AIF. Finally, we demonstrate that the higher surface expression of DCIR in CD4(+ T cells is accompanied by an enhancement of virus attachment/entry, replication and transfer. This study shows for the first time that HIV-1 induces DCIR membrane expression in CD4(+ T cells, a process that might promote virus dissemination throughout the infected organism.

  13. Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination

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    Deborah A. Lewinsohn

    2017-10-01

    Full Text Available Tuberculosis (TB, caused by Mycobacterium tuberculosis (Mtb, remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG. Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4+ T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2 as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4+ T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4+ T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4+ T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4+ T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4+ T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in

  14. Prevalence of Oral Manifestations and Their Association with CD4/CD8 Ratio and HIV Viral Load in South India

    Directory of Open Access Journals (Sweden)

    Sharma Gaurav

    2011-01-01

    Full Text Available The objective of the present research was to determine the prevalence of oral manifestations in an HIV infected population from south India and evaluate their association with HIV viral load and CD4/CD8 ratio. Intraoral examination of 103 patients, whose CD4/CD8 ratio was available, were conducted. HIV viral loads were available for thirty patients only. The prevalence of oral manifestations was 80.6% (83/103. The most common oromucosal lesion was erythematous candidiasis (EC (38.8% followed by melanotic hyperpigmentation (35.9%. Patients having any oral manifestation had a mean CD4/CD8 ratio of 0.24. EC had positive predictive value of 85.0% for CD4/CD8 ratio 20,000 copies/mL (20,000 copies/mL.

  15. Binding of the mannose-specific lectin, griffithsin, to HIV-1 gp120 exposes the CD4-binding site

    CSIR Research Space (South Africa)

    Alexandre, Kabamba B

    2011-09-01

    Full Text Available Reference and Reagent Program. The subtype C 12 specific anti-V3 mAb, 3468L was isolated from an HIV-positive patient (22). The 13 anti-CCR5 inhibitor PRO140, the CD4 receptor surrogate CD4-IgG2 and the soluble 14 CD4 (sCD4) were generously provided... was measured as for 20 b12 except that here ID50 and ID80 were calculated. Since PRO140 is a CCR5 21 inhibitor, TZM-bl cells were first incubated with a dilution series of this compound 22 prior to the addition of the virus with or without GRFT (in a...

  16. Disturbed CD4+ T Cell Homeostasis and In Vitro HIV-1 Susceptibility in Transgenic Mice Expressing T Cell Line–tropic HIV-1 Receptors

    OpenAIRE

    Sawada, Shinichiro; Gowrishankar, Kavitha; Kitamura, Rui; Suzuki, Misao; Suzuki, Gen; Tahara, Satoko; Koito, Atsushi

    1998-01-01

    T cell line–tropic (T-tropic) HIV type 1 strains enter cells by interacting with the cell-surface molecules CD4 and CXCR4. We have generated transgenic mice predominantly expressing human CD4 and CXCR4 on their CD4-positive T lymphocytes (CD4+ T cells). Their primary thymocytes are susceptible to T-tropic but not to macrophage-tropic HIV-1 infection in vitro, albeit with a viral antigen production less efficient than human peripheral blood mononuclear cells. Interestingly, even without HIV in...

  17. [Changes of CD(4)(+) Foxp3+ regulatory T cells and CD(4)(+)IL-17+T cells in acrolein exposure rats].

    Science.gov (United States)

    Wei, Ming; Tu, Ling; Liang, Yinghong; Li, Jia; Gong, Yanjie; Zhang, Yihua; Yang, Lu

    2015-09-01

    To evaluate the changes of CD(4)(+) IL-17+T (Th17) and CD(4)(+)Foxp3+regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF) , and therefore to explore the role of Th17 and Treg in acrolein exposure airway inflammation in rats. Forty male Wistar rats were randomly divided into 4 groups: a 2 wk acrolein exposure group, a 4 wk acrolein exposure group, a 2 wk control group and a 4 wk control group (n=10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts.IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17+T and CD(4)(+) Foxp3+Treg in peripheral blood and BALF were determined by flow cytometry.The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 2 wk acrolein exposure group and the 4 wk acrolein exposure group in serum [(52.64 ± 1.89) ng/L, (76.73 ± 5.57) ng/L], and BALF [(79.07 ± 5.67) ng/L, (96.61 ± 6.44) ng/L] compared with the 2 wk control group [(40.05 ± 3.12) ng/L, (56.75 ± 4.37) ng/L] and the 4 wk control group [(38.75 ± 3.23) ng/L, (53.27 ± 4.48) ng/L], all Pacrolein exposure group [ (33.28 ± 2.27) ng/L, (46.24 ± 3.16) ng/L] compared with the 2 wk and the 4 wk control group [ (16.37 ± 1.49) ng/L, (17.02 ± 1.43) ng/L] in BALF.Ratio of Th17 was higher in the 2 wk and the 4 wk acrolein exposure groups in peripheral blood (1.82 ± 0.18) %, (3.75 ± 0.48) % and BALF [(7.23 ± 0.27) %, (8.12 ± 0.38) %] compared with the 2 wk [(0.96 ± 0.07) %, (5.64 ± 0.63) %] and the 4 wk control group [(1.01 ± 0.08) %, (5.86 ± 0.57) %]. Ratio of Treg in BALF was higher in the acrolein exposure groups [ (8.83 ± 0.52) %, (12.05 ± 0.74) %] compared with the control groups [(4.37 ± 0.27) %, (5.01 ± 0

  18. Peripheral CD4+ cell prevalence and pleuropulmonary manifestations in systemic lupus erythematosus patients.

    Science.gov (United States)

    Vincze, Krisztina; Kovats, Zsuzsanna; Cseh, Aron; Pasti, Krisztina; Kiss, Emese; Polgar, Anna; Vasarhelyi, Barna; Szabo, Attila J; Bohacs, Aniko; Tamasi, Lilla; Losonczy, György; Müller, Veronika

    2014-05-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease involving several organs, including the lungs. Previous results confirmed changes of peripheral T cell subsets in lupus patients; however no data are available about their possible relationship with pulmonary involvement. To determine pulmonary manifestations and potential relationship in changes of peripheral CD4+ T cell subsets. Patients with SLE (N = 28) were enrolled in complex pulmonary examination. Patients were divided into groups with pleuropulmonary manifestations (SLEpulm N = 13 age: 44.9 ± 3.3 years, female: male = 11:2) or without (SLEc N = 15 age: 27.2 ± 3.7 years, female: male = 12:3). Peripheral blood was taken for T helper (Th)1, Th2, Th17, CD4+CD25hi+ and regulatory T (Treg: CD4+CD25hi+ CD127-) cell analysis from SLE patients and healthy volunteers (controls, N = 40). SLEpulm patients were older, had more pulmonary symptoms and significantly decreased pO2 as compared to SLEc group. Ventilatory disorder was present in 92% of SLEpulm patients, with significantly decreased lung volumes, signs of airway involvement and decrease in DLco. Significant increase in Th1/Th2, while decrease in Th17/Treg ratios was present in all SLE compared to controls. In SLEpulm CD4+CD25hi+ subset without changes in Treg number was significantly increased as compared to SLEc and this subgroup of T cell showed significant positive correlation with dynamic lung function parameters and DLco (p lupus patients pleuropulmonary manifestations are prevalent and lung function and blood gas measurements should be regularly performed in the daily clinical assessment. Significant increase of activated CD4+CD25hi+ T cells, but not Treg is associated with decreased lung function parameters in SLEpulm patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. GM-CSF Production Allows the Identification of Immunoprevalent Antigens Recognized by Human CD4+ T Cells Following Smallpox Vaccination

    Science.gov (United States)

    Judkowski, Valeria; Bunying, Alcinette; Ge, Feng; Appel, Jon R.; Law, Kingyee; Sharma, Atima; Raja- Gabaglia, Claudia; Norori, Patricia; Santos, Radleigh G.; Giulianotti, Marc A.; Slifka, Mark K.; Douek, Daniel C.; Graham, Barney S.; Pinilla, Clemencia

    2011-01-01

    The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a “T cell–driven” methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens. PMID:21931646

  20. GM-CSF production allows the identification of immunoprevalent antigens recognized by human CD4+ T cells following smallpox vaccination.

    Directory of Open Access Journals (Sweden)

    Valeria Judkowski

    Full Text Available The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a "T cell-driven" methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens.

  1. Immunophenotypic enumeration of CD4 + T-lymphocyte values in ...

    African Journals Online (AJOL)

    Background: The enumeration of CD4+ T-lymphocytes in Human Immunodeficiency Virus (HIV)-infected individuals is an essential tool for staging HIV disease, to make decisions for initiation of anti-retroviral therapy (ART), for monitoring response to ART and to initiate chemoprophylaxis against opportunistic infections.

  2. Cellular Plasticity of CD4+ T Cells in the Intestine

    Science.gov (United States)

    Brucklacher-Waldert, Verena; Carr, Edward J.; Linterman, Michelle A.; Veldhoen, Marc

    2014-01-01

    Barrier sites such as the gastrointestinal tract are in constant contact with the environment, which contains both beneficial and harmful components. The immune system at the epithelia must make the distinction between these components to balance tolerance, protection, and immunopathology. This is achieved via multifaceted immune recognition, highly organized lymphoid structures, and the interaction of many types of immune cells. The adaptive immune response in the gut is orchestrated by CD4+ helper T (Th) cells, which are integral to gut immunity. In recent years, it has become apparent that the functional identity of these Th cells is not as fixed as initially thought. Plasticity in differentiated T cell subsets has now been firmly established, in both health and disease. The gut, in particular, utilizes CD4+ T cell plasticity to mold CD4+ T cell phenotypes to maintain its finely poised balance of tolerance and inflammation and to encourage biodiversity within the enteric microbiome. In this review, we will discuss intestinal helper T cell plasticity and our current understanding of its mechanisms, including our growing knowledge of an evolutionarily ancient symbiosis between microbiota and malleable CD4+ T cell effectors. PMID:25339956

  3. Cellular plasticity of CD4+ T cells in the intestine

    Directory of Open Access Journals (Sweden)

    Verena eBrucklacher-Waldert

    2014-10-01

    Full Text Available Barrier sites such as the gastrointestinal tract are in constant contact with the environment which contains both beneficial and harmful components. The immune system at the epithelia must make the distinction between these components to balance tolerance, protection and immunopathology. This is achieved via multifaceted immune recognition, highly organised lymphoid structures and the interaction of many types of immune cells. The adaptive immune response in the gut is orchestrated by CD4+ helper T (Th cells which are integral to gut immunity. In recent years it has become apparent that the functional identity of these Th cells is not as fixed as initially thought. Plasticity in differentiated T cell subsets has now been firmly established, in both health and disease. The gut, in particular, utilises CD4+ T cell plasticity to mould CD4+ T cell phenotypes to maintain its finely poised balance of tolerance and inflammation and to encourage biodiversity within the enteric microbiome. In this review we will discuss intestinal helper T cell plasticity and our current understanding of its mechanisms, including our growing knowledge of an evolutionarily ancient symbiosis between microbiota and malleable CD4+ T cell effectors.

  4. Enumeration of CD4 and CD8 T-cells in HIV infection in Zimbabwe using a manual immunocytochemical method

    DEFF Research Database (Denmark)

    Gomo, E; Ndhlovu, P; Vennervald, B J

    2001-01-01

    Laboratory, Harare, Zimbabwe. SUBJECTS: 41 HIV positive and 11 HIV negative men and women from Harare participating in HIV studies at Blair Research Laboratory, Zimbabwe. MAIN OUTCOME MEASURES: CD4 and CD8 T-cell counts by FC and the IA method. RESULTS: The IA method and FC were highly correlated for CD4......OBJECTIVES: To enumerate CD4 and CD8 T-cells using the simple and cheap immuno-alkaline phosphatase (IA) method and to compare it with flow cytometry (FC); and to study the effects of duration of sample storage on the IA method results. DESIGN: Method comparison study. SETTING: Blair Research...... counts (Spearman rs = 0.91), CD4 percentage (rs = 0.84), CD8 count (rs = 0.83), CD8 percentage (rs = 0.96) and CD4/CD8 ratio (rs = 0.89). However, CD4 cell counts and percentage measured by the IA method were (mean difference +/- SE) 133 +/- 24 cells/microL [corrected] and 6.7 +/- 1.1% higher than those...

  5. The role of CD4 T cell memory in generating protective immunity to novel and potentially pandemic strains of influenza

    Directory of Open Access Journals (Sweden)

    Anthony eDiPiazza

    2016-01-01

    Full Text Available Recent events have made it clear that potentially pandemic strains of influenza regularly pose a threat to human populations. Therefore, it is essential that we develop better strategies to enhance vaccine design and evaluation, to predict those that will be poor responders to vaccination and to identify those that are at particular risk of disease-associated complications following infection. Simplified animal models have revealed the discrete functions that CD4 T cells play in the developing immune response and to influenza immunity. However, humans have a complex immunological history with influenza through periodic infection and vaccination with seasonal variants, leading to the establishment of heterogeneous memory populations of CD4 T cells that participate in subsequent responses. The continual evolution of the influenza-specific CD4 T cell repertoire involves both specificity and function and overlays other restrictions on CD4 T cell activity derived from viral antigen handling and MHC class II:peptide epitope display. Together, these complexities in the influenza-specific CD4 T cell repertoire constitute a formidable obstacle to predicting protective immune response to potentially pandemic strains of influenza and in devising optimal vaccine strategies to potentiate these responses. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors within the CD4 T cell compartment will aid significantly in achievement of these goals.

  6. A higher frequency of circulating IL-22(+CD4(+ T cells in Chinese patients with newly diagnosed Hashimoto's thyroiditis.

    Directory of Open Access Journals (Sweden)

    Hui Guo

    Full Text Available BACKGROUND: IL-22 and IL-17A are implicated in the pathogenesis of autoimmune diseases. However, the role of IL-22(+ and IL-17A(+ CD4(+ T cells in the pathogenesis of Hashimoto's thyroiditis (HT is not fully understood. This study investigates serum IL-22 and IL-17A levels and determines the frequency of circulating IL-22(+ CD4(+ T cells in HT patients to understand their roles in the pathogenesis of HT. METHODS: The levels of serum IL-22, IL-17A and IFN-γ and the frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells in 17 HT patients and 17 healthy controls (HC were determined by enzyme-linked immunosorbent assay (ELISA and flow cytometry. The levels of serum free triiodothyronine (FT4, free thyroxine (FT3, thyroid stimulating hormone (TSH, anti-thyroid peroxidase (TPO and anti-thyroglobulin antibodies (TgAb by chemiluminescent enzyme immunoassay and radioimmunoassay. RESULTS: The percentages of circulating IL-22(+CD4(+ and IL-17(+CD4(+ T cells (p<0.0001, p<0.0001 and the levels of serum IL-22, IL-17A and IFN-γ (p<0.0001, p<0.0001, p = 0.0210 in the HT patients were significantly higher than that in the HC. The percentages of IL-22(+CD4(+ T cells were positively correlated with Th17 cells (r = 0.8815, p<0.0001 and IL-17A(+IL-22(+CD4(+ T cells (r = 0.8914, p<0.0001, but were negatively correlated with Th1 cells (r = -0.6110, p<0.0092 in the HT patients. The percentages of Th22 cells, Th17 cells and IL-17A(+IL-22(+CD4(+ T cells were negatively correlated with the levels of serum TSH in the HT patients (r = -0.8402, p<0.0001; r = -0.8589, p<0.0001; r = -0.8289 p<0.0001, respectively. CONCLUSIONS: A higher frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells may be associated with the development of HT in Chinese patients.

  7. Correlation of CD4 counts and CD4/CD8 ratio with HIV-infection associated oral manifestations.

    Science.gov (United States)

    Butt, F M A; Vaghela, V P; Chindia, M L

    2007-08-01

    The relationship between oral lesions arising from HIV infection and CD4/CD8 cell ratios is of relevance in clinical assessment of immune suppression. To correlate the prevalence of oral manifestations arising from HIV infection and the levels of CD4/CD8 cell ratios. A cross-sectional study. Kenyatta National Hospital, Nairobi, Kenya. Two hundred and seven HIV-infected patients in medical wards were recruited in the study. Seventy eight (37.7%) were male and 129 (62.3%) female, with an age range of 18-73 years (mean=34.81 years). Oral manifestations encountered with highest prevalence in the oral cavity included: hyperplastic candidosis (labial mucosa) 15%, erythematous candidosis (gingival) 5%, angular cheilitis 32.4%, herpes simplex (corner of the mouth) 0.5%, persistent oral ulceration (labial mucosa) 0.5%, Parotid enlargement 2% and Kaposis sarcoma (hard/soft palate) 2.9%. The prevalence of oral manifestations was higher with low CD4 count <200 cell/mm3 and mean CD4/CD8<0.39(95%CI 0.32-0.48).

  8. The performance of BD FACSPresto™ for CD4 T-cell count, CD4% and hemoglobin concentration test in Ethiopia.

    Directory of Open Access Journals (Sweden)

    Gebremedhin Gebremicael

    Full Text Available In Ethiopia, CD4+ T-cell counting is still required for all patients at baseline before antiretroviral therapy (ART and to determine eligibility and follow-up of opportunistic infection prophylaxis. However, access to CD4+ T cell count in rural health facilities remains a major challenge in Ethiopia like other resource-limited settings.Both capillary and venous blood was drawn from each of 325 study participant recruited in Addis Ababa and surroundings. The CD4+ T-cell count, CD4%, and hemoglobin (Hgb were tested at one of the four study health facilities using capillary blood and BD FACSPresto™ device. These tests were also done at the national HIV reference laboratory, using venous blood with BD FACSCalibur™, Sysmex XT-1800i™, and BD FACSPresto™.BD FACSPresto™ had an absolute mean bias of -13.3 cells/ul (-2.99% and 28.3 cells/μl (6.4% using venous and capillary blood, respectively, compared with BD FACSCalibur™. The absolute CD4 assay on the BD FACSPresto™ had a regression coefficient (R2 of 0.87 and 0.92 using capillary blood and venous blood samples, respectively, compared with BD FACSCalibur™. The percentage similarity of the BD FACSPresto™ using capillary and venous blood was 105.2% and 99.3%, respectively. The sensitivity of the FACSPresto™ using threshold of 500 cells/μl for ART eligibility using capillary and venous blood was 87.9 and 94.3%, while the specificity was 91.4 and 83.8%, respectively. Furthermore, the BD FACSPresto™ had an absolute mean bias of -0.2 dl/μl (0.0% (95% LOA: -1.7, 1.3 and -0.59 dl/μl (0.1% (95% LOA: -1.49, 0.31 for Hgb using capillary and venous blood compared with the Sysmex XT-1800i™, respectively.Our results showed acceptable agreement between the BD FACSPresto™ and BD FACSCalibur™ for CD4+ T-cell counting and CD4%; and between the BD FACSPresto™ and Sysmex XT-1800i™for measuring Hgb concentration.

  9. CD4+ T-cell alloreactivity toward mismatched HLA class II alleles early after double umbilical cord blood transplantation.

    Science.gov (United States)

    Lamers, Cor H J; Wijers, Rebecca; van Bergen, Cornelis A M; Somers, Judith A E; Braakman, Eric; Gratama, Jan Willem; Debets, Reno; Falkenburg, J H Frederik; Cornelissen, Jan J

    2016-10-27

    Although double umbilical cord blood transplantation (dUCBT) in adult patients may be associated with less graft failure compared with single UCBT, hematopoietic recovery generally originates from a single cord blood unit (CBU). CBU predominance is still incompletely understood. We recently showed that blood CD4 + T-cell numbers rapidly increase after dUCBT, and early CD4 + T-cell chimerism predicts for graft predominance. Given the frequent HLA class II allele mismatches between CBUs in dUCBT, we hypothesized that alloreactive HLA class II-specific CD4 + T cells from the "winning" CBU may contribute to rejection of the "loser" CBU. We evaluated whether CD4 + T cells originating from the predominant (PD)-CBU would recognize HLA class II allele mismatches, expressed by the nonengrafting (NE)-CBU. Alloreactive effector CD4 + T cells toward 1 or more mismatched HLA class II alleles of the NE-CBU were detected in 11 of 11 patients, with reactivity toward 29 of 33 (88%) tested mismatches, and the strongest reactivity toward DR and DQ alleles early after dUCBT. Mismatched HLA class II allele-specific CD4 + T cells recognized primary leukemic cells when the mismatched HLA class II allele was shared between NE-CBU and patient. Our results suggest that cytotoxicity exerted by CD4 + T cells from the PD-CBU drives the rapid rejection of the NE-CBU, whose alloreactive effect might also contribute to graft-versus-leukemia. © 2016 by The American Society of Hematology.

  10. Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.

    Directory of Open Access Journals (Sweden)

    David Beauparlant

    2017-03-01

    Full Text Available A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.

  11. Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.

    Science.gov (United States)

    Beauparlant, David; Rusert, Peter; Magnus, Carsten; Kadelka, Claus; Weber, Jacqueline; Uhr, Therese; Zagordi, Osvaldo; Oberle, Corinna; Duenas-Decamp, Maria J; Clapham, Paul R; Metzner, Karin J; Günthard, Huldrych F; Trkola, Alexandra

    2017-03-01

    A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.

  12. Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.

    Directory of Open Access Journals (Sweden)

    Alastair Heffernan

    Full Text Available Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3% of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.

  13. Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.

    Science.gov (United States)

    Heffernan, Alastair; Barber, Ella; Thomas, Ranjeeta; Fraser, Christophe; Pickles, Michael; Cori, Anne

    2016-01-01

    Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC) CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs) were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3%) of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.

  14. Multifunctional Analysis of CD4+ T-Cell Response as Immune-Based Model for Tuberculosis Detection

    Directory of Open Access Journals (Sweden)

    Miriam Lichtner

    2015-01-01

    Full Text Available Mono- and multifunctional specific CD4+ and CD8+ T-cell responses were evaluated to improve the immune-based detection of active tuberculosis (TB and latent infection (LTBI. We applied flow cytometry to investigate cytokines profile (IFN-γ, TNF-α, and IL-2 of T cells after stimulation with TB antigens in 28 TB-infected subjects (18 active TB and 10 LTBI and 10 uninfected controls. Cytokines production by CD4+ T cells at single-cell levels was higher in TB-infected subjects than uninfected controls P0.45%, it was possible to differentiate TB-infected (>0.45% by uninfected subjects (0.182%. The magnitude of CD8+ T-cell responses showed no differences between active TB and LTBI. Multifunctional CD4+ T-cell responses could have the potential to identify at single time point subjects without TB infection and patients having active or latent TB.

  15. Positioning and joining of organic single-crystalline wires

    Science.gov (United States)

    Wu, Yuchen; Feng, Jiangang; Jiang, Xiangyu; Zhang, Zhen; Wang, Xuedong; Su, Bin; Jiang, Lei

    2015-01-01

    Organic single-crystal, one-dimensional materials can effectively carry charges and/or excitons due to their highly ordered molecule packing, minimized defects and eliminated grain boundaries. Controlling the alignment/position of organic single-crystal one-dimensional architectures would allow on-demand photon/electron transport, which is a prerequisite in waveguides and other optoelectronic applications. Here we report a guided physical vapour transport technique to control the growth, alignment and positioning of organic single-crystal wires with the guidance of pillar-structured substrates. Submicrometre-wide, hundreds of micrometres long, highly aligned, organic single-crystal wire arrays are generated. Furthermore, these organic single-crystal wires can be joined within controlled angles by varying the pillar geometries. Owing to the controllable growth of organic single-crystal one-dimensional architectures, we can present proof-of-principle demonstrations utilizing joined wires to allow optical waveguide through small radii of curvature (internal angles of ~90–120°). Our methodology may open a route to control the growth of organic single-crystal one-dimensional materials with potential applications in optoelectronics. PMID:25814032

  16. Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

    DEFF Research Database (Denmark)

    Kristiansen, O P; Karlsen, A E; Larsen, Z M

    2004-01-01

    promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP...

  17. Transcriptional regulation of CD4 gene expression by T cell factor-1/beta-catenin pathway.

    NARCIS (Netherlands)

    Huang, Z.; Xie, H.; Ioannidis, V.; Held, W.; Clevers, J.C.; Sadim, M.S.; Sun, Z.

    2006-01-01

    By interacting with MHC class II molecules, CD4 facilitates lineage development as well as activation of Th cells. Expression of physiological levels of CD4 requires a proximal CD4 enhancer to stimulate basic CD4 promoter activity. T cell factor (TCF)-1/beta-catenin pathway has previously been shown

  18. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    NARCIS (Netherlands)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-01-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is

  19. An integrated tiered service delivery model (ITSDM based on local CD4 testing demands can improve turn-around times and save costs whilst ensuring accessible and scalable CD4 services across a national programme.

    Directory of Open Access Journals (Sweden)

    Deborah K Glencross

    Full Text Available The South African National Health Laboratory Service (NHLS responded to HIV treatment initiatives with two-tiered CD4 laboratory services in 2004. Increasing programmatic burden, as more patients access anti-retroviral therapy (ART, has demanded extending CD4 services to meet increasing clinical needs. The aim of this study was to review existing services and develop a service-model that integrated laboratory-based and point-of-care testing (POCT, to extend national coverage, improve local turn-around/(TAT and contain programmatic costs.NHLS Corporate Data Warehouse CD4 data, from 60-70 laboratories and 4756 referring health facilities was reviewed for referral laboratory workload, respective referring facility volumes and related TAT, from 2009-2012.An integrated tiered service delivery model (ITSDM is proposed. Tier-1/POCT delivers CD4 testing at single health-clinics providing ART in hard-to-reach areas (350-1500 tests/day, serving ≥ 200 health-clinics. Tier-6 provides national support for standardisation, harmonization and quality across the organization.The ITSDM offers improved local TAT by extending CD4 services into rural/remote areas with new Tier-3 or Tier-2/POC-Hub services installed in existing community laboratories, most with developed infrastructure. The advantage of lower laboratory CD4 costs and use of existing infrastructure enables subsidization of delivery of more expensive POC services, into hard-to-reach districts without reasonable access to a local CD4 laboratory. Full ITSDM implementation across 5 service tiers (as opposed to widespread implementation of POC testing to extend service can facilitate sustainable 'full service coverage' across South Africa, and save>than R125 million in HIV/AIDS programmatic costs. ITSDM hierarchical parental-support also assures laboratory/POC management, equipment maintenance, quality control and on-going training between tiers.

  20. An Integrated Tiered Service Delivery Model (ITSDM) Based on Local CD4 Testing Demands Can Improve Turn-Around Times and Save Costs whilst Ensuring Accessible and Scalable CD4 Services across a National Programme

    Science.gov (United States)

    Glencross, Deborah K.; Coetzee, Lindi M.; Cassim, Naseem

    2014-01-01

    Background The South African National Health Laboratory Service (NHLS) responded to HIV treatment initiatives with two-tiered CD4 laboratory services in 2004. Increasing programmatic burden, as more patients access anti-retroviral therapy (ART), has demanded extending CD4 services to meet increasing clinical needs. The aim of this study was to review existing services and develop a service-model that integrated laboratory-based and point-of-care testing (POCT), to extend national coverage, improve local turn-around/(TAT) and contain programmatic costs. Methods NHLS Corporate Data Warehouse CD4 data, from 60–70 laboratories and 4756 referring health facilities was reviewed for referral laboratory workload, respective referring facility volumes and related TAT, from 2009–2012. Results An integrated tiered service delivery model (ITSDM) is proposed. Tier-1/POCT delivers CD4 testing at single health-clinics providing ART in hard-to-reach areas (350–1500 tests/day, serving ≥200 health-clinics). Tier-6 provides national support for standardisation, harmonization and quality across the organization. Conclusion The ITSDM offers improved local TAT by extending CD4 services into rural/remote areas with new Tier-3 or Tier-2/POC-Hub services installed in existing community laboratories, most with developed infrastructure. The advantage of lower laboratory CD4 costs and use of existing infrastructure enables subsidization of delivery of more expensive POC services, into hard-to-reach districts without reasonable access to a local CD4 laboratory. Full ITSDM implementation across 5 service tiers (as opposed to widespread implementation of POC testing to extend service) can facilitate sustainable ‘full service coverage’ across South Africa, and save>than R125 million in HIV/AIDS programmatic costs. ITSDM hierarchical parental-support also assures laboratory/POC management, equipment maintenance, quality control and on-going training between tiers. PMID:25490718

  1. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania

    Directory of Open Access Journals (Sweden)

    Mueller Andreas

    2007-05-01

    Full Text Available Abstract Background Largely due to the lack of diagnostic reagents, the prevalence and clinical presentation of cryptococcal meningitis in Tanzania is poorly understood. This in turn is limiting the impact of increased fluconazole availability. Methods We evaluated a cohort of 149 consecutive HIV-infected adult inpatients presenting with headache or altered mental status for clinical features, CD4 count, cryptococcal infection, and outcome. Cryptococcal meningitis was diagnosed via India ink and latex agglutination assay of CSF (n = 24 and 40 positive, respectively. Associations between cryptococcal meningitis and clinical features were evaluated by t-test. The sensitivity, specificity, and positive likelihood ratio of such features were determined. Results Cryptococcal meningitis was associated with confusion, social withdrawal, seizures, fever, tachycardia, meningismus, oral candidiasis, and low Glasgow coma scales and CD4 count. CD4 count Conclusion Cryptococcal meningitis is common among Tanzanian HIV inpatients presenting with headache or altered mental status. Purely clinical features are insensitive for establishing the diagnosis or prognosis. We advocate expanding laboratory capacity for cryptococcal antigen testing to maximize survival.

  2. Enhancers and Transcriptional Regulation in CD4+ T Cells

    OpenAIRE

    Allison, Karmel Alon

    2015-01-01

    High-throughput sequencing has given us unprecedented insight into the regulatory networks that govern enhancer selection and transcription in mammalian cells, but many open questions remain as to how the mechanics of transcriptional regulation correspond to biological outputs such as gene expression and downstream signaling. In this dissertation, I address the nature of enhancer selection and transcriptional regulation in the context of CD4+ T cell signaling in two parts. The first study des...

  3. Absolute lymphocyte count as a surrogate marker for CD4 counts after six months of HAART initiation in a resource-limited setting in India.

    Science.gov (United States)

    Srirangaraj, S; Venkatesha, D

    2012-06-01

    Owing to the ever-expanding access to HAART (highly active anti-retroviral therapy) in resource-limited settings, there is a need to evaluate alternate markers like absolute lymphocyte count (ALC) as a surrogate for CD4 counts. This study was done to assess the usefulness of ALC as a surrogate marker for CD4 counts in monitoring HIV-infected patients after HAART initiation. In this study, 108 HIV-positive adult patients of both sexes fulfilling the inclusion criteria were included. CD4 and ALC were recorded at baseline. After initiation on HAART, these patients were followed up at three month intervals. ALC and CD4 counts were positively correlated (Spearman correlation coefficient= 0.553). After six months of HAART, the sensitivity of an ALC increase as a marker for CD4 count increase at six months was 82 per cent, specificity was 100 per cent, PPV was 100 per cent and NPV was 31 per cent. Area under the corresponding ROC curve for CD4 increase of >100 cells/μl was 0. 825 ± 0.053. ALC may be a useful surrogate marker in predicting an increase in CD4 counts as a response to HAART, but of questionable value in predicting a decrease in CD4 counts.

  4. CD4 count outperforms World Health Organization clinical algorithm for point-of-care HIV diagnosis among hospitalised HIV-exposed Malawian infants.

    Science.gov (United States)

    Maliwichi, Madalitso; Rosenberg, Nora E; Macfie, Rebekah; Olson, Dan; Hoffman, Irving; van der Horst, Charles M; Kazembe, Peter N; Hosseinipour, Mina C; McCollum, Eric D

    2014-08-01

    To determine, for the WHO algorithm for point-of-care diagnosis of HIV infection, the agreement levels between paediatricians and non-physician clinicians, and to compare sensitivity and specificity profiles of the WHO algorithm and different CD4 thresholds against HIV PCR testing in hospitalised Malawian infants. In 2011, hospitalised HIV-exposed infants CD4 and molecular HIV testing (DNA or RNA PCR). Using molecular testing as the reference, sensitivity, specificity and positive predictive value (PPV) were determined for the WHO algorithm and CD4 count thresholds of 1500 and 2000 cells/mm(3) by paediatricians and clinical officers. We enrolled 166 infants (50% female, 34% CD4 thresholds (CD4 thresholds (CD4 thresholds (CD4 thresholds resulted in many misclassifications. Point-of-care CD4 thresholds of <1500 cells/mm(3) or <2000 cells/mm(3) could identify more HIV-infected infants with fewer false positives than the algorithm. However, a point-of-care option with better performance characteristics is needed for accurate, timely HIV diagnosis. © 2014 John Wiley & Sons Ltd.

  5. A multi-omic analysis of human naïve CD4+ T cells.

    Science.gov (United States)

    Mitchell, Christopher J; Getnet, Derese; Kim, Min-Sik; Manda, Srikanth S; Kumar, Praveen; Huang, Tai-Chung; Pinto, Sneha M; Nirujogi, Raja Sekhar; Iwasaki, Mio; Shaw, Patrick G; Wu, Xinyan; Zhong, Jun; Chaerkady, Raghothama; Marimuthu, Arivusudar; Muthusamy, Babylakshmi; Sahasrabuddhe, Nandini A; Raju, Rajesh; Bowman, Caitlyn; Danilova, Ludmila; Cutler, Jevon; Kelkar, Dhanashree S; Drake, Charles G; Prasad, T S Keshava; Marchionni, Luigi; Murakami, Peter N; Scott, Alan F; Shi, Leming; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Irizarry, Rafael; Cope, Leslie; Ishihama, Yasushi; Wang, Charles; Gowda, Harsha; Pandey, Akhilesh

    2015-11-06

    Cellular function and diversity are orchestrated by complex interactions of fundamental biomolecules including DNA, RNA and proteins. Technological advances in genomics, epigenomics, transcriptomics and proteomics have enabled massively parallel and unbiased measurements. Such high-throughput technologies have been extensively used to carry out broad, unbiased studies, particularly in the context of human diseases. Nevertheless, a unified analysis of the genome, epigenome, transcriptome and proteome of a single human cell type to obtain a coherent view of the complex interplay between various biomolecules has not yet been undertaken. Here, we report the first multi-omic analysis of human primary naïve CD4+ T cells isolated from a single individual. Integrating multi-omics datasets allowed us to investigate genome-wide methylation and its effect on mRNA/protein expression patterns, extent of RNA editing under normal physiological conditions and allele specific expression in naïve CD4+ T cells. In addition, we carried out a multi-omic comparative analysis of naïve with primary resting memory CD4+ T cells to identify molecular changes underlying T cell differentiation. This analysis provided mechanistic insights into how several molecules involved in T cell receptor signaling are regulated at the DNA, RNA and protein levels. Phosphoproteomics revealed downstream signaling events that regulate these two cellular states. Availability of multi-omics data from an identical genetic background also allowed us to employ novel proteogenomics approaches to identify individual-specific variants and putative novel protein coding regions in the human genome. We utilized multiple high-throughput technologies to derive a comprehensive profile of two primary human cell types, naïve CD4+ T cells and memory CD4+ T cells, from a single donor. Through vertical as well as horizontal integration of whole genome sequencing, methylation arrays, RNA-Seq, miRNA-Seq, proteomics, and

  6. CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

    Science.gov (United States)

    Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

    2017-03-01

    Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

  7. Grading of laboratories on CD4+ T-lymphocyte evaluations based on acceptable data boundaries defined by the measurement error.

    Science.gov (United States)

    Kunkl, Annalisa; Risso, Domenico; Terranova, Maria Paola; Girotto, Mauro; Brando, Bruno; Mortara, Lorenzo; Lantieri, Pasquale Bruno

    2002-04-15

    We addressed the definition of limits of error of %CD4+ and CD4+ counts (AbsCD4+) typical of laboratories of excellence, as well as the grading of laboratories based on the decision to take these limits as boundaries of unacceptable data. We studied the 99.9% confidence intervals of the means of 24 human immunodeficiency virus (HIV)+ and HIV- blood samples analyzed by 18 laboratories of the Liguria Region Quality Assessment Program (Liguria Region QALI). Regression equations of lower (L1) and upper (L2) confidence limits over the means of data cleared of unusual results were used to interpolate limits of error for mean values in the tested range. L1 and L2 were symmetric around the mean and a single absolute difference (Abs Res) between the limits and the mean was found. Abs Res significantly increased over mean values (P = 0.0005 for %CD4+, P < 0.0001 for AbsCD4+). Limits were compatible with errors shown with blind replicates. Unacceptable results, outside the limits, accounted for 25% and 30% of %CD4+ and for 18% and 35% AbsCD4+ in the Liguria Region QALI and in the Piemonte Region QA Program, respectively. Limits interpolated over the median showed a similar grading. A comparable fraction of unacceptable data was also found with the method used in the U.K. National External Quality Assessment Scheme (NEQAS) immune monitoring scheme. We propose the general use of these regression equations to determine bounds for unacceptable data in proficiency testing and to identify laboratories of excellence. Published 2002 Wiley-Liss, Inc.

  8. CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

    Science.gov (United States)

    Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

    2018-01-15

    Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4 + T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19 + cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19 + cells than patients who did not show recurrence. Examining cytotoxic CD4 + T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4 + T cells. Also, frequency of cytotoxic CD4 + T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4 + T cells against autologous CD19 + cells was investigated. We found that the cytotoxic potential of CD4 + T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19 + cells presented a significant reduction after longer incubation with cytotoxic CD4 + T cells, suggesting that cytotoxic CD4 + T cells preferentially eliminated MHC II-expressing CD19 + cells. Blocking MHC II on CD19 + cells significantly reduced the cytolytic capacity of CD4 + T cells. Despite these discoveries, the frequency of cytotoxic CD4 + T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4 + T cells presented an MHC II-dependent cytotoxic potential against autologous CD19 + cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Improved employment and education outcomes in households of HIV-infected adults with high CD4 cell counts: evidence from a community health campaign in Uganda.

    Science.gov (United States)

    Thirumurthy, Harsha; Chamie, Gabriel; Jain, Vivek; Kabami, Jane; Kwarisiima, Dalsone; Clark, Tamara D; Geng, Elvin; Petersen, Maya L; Charlebois, Edwin D; Kamya, Moses R; Havlir, Diane V

    2013-02-20

    There is limited evidence on the association between socioeconomic outcomes and CD4 counts in populations that include HIV-infected adults who have high CD4 counts or have not been diagnosed. We examined this association among adults in a rural Ugandan parish. A community health campaign offering diagnostic and treatment services for HIV and other diseases was conducted with Ministry of Health support. Data on campaign participants' education and employment were collected and a detailed household socioeconomic survey was conducted among a subset of participants. Regression analyses were used to assess relationships between CD4 count and employment and education outcomes. A total of 2323 adults (74% of the community) participated in the campaign; 179 of 2282 (7.8%) tested HIV-positive and 46% were newly diagnosed. Among HIV-infected adults not on antiretroviral therapy (ART), those with CD4 at least 500 worked 6.9 more days/month (P < 0.01; 39% more) and 2.5 more h per day (P < 0.05, 44% more) than those with CD4 less than 200. These effects were not significantly different from the effects for those with CD4 350-499. Children aged 6-11 years in households of adults with CD4 at least 350 did not have significantly different school enrollment rates than children in households of adults with CD4 less than 350, but differences were larger among children aged 12-18 years. Outcomes of HIV-infected adults with CD4 at least 350 were better than those of adults with CD4 less than 200 and resembled those of HIV-uninfected adults. The results suggest that early ART initiation may generate economic benefits by preventing a decline in socioeconomic status, but further research is needed to determine the CD4 threshold at which these benefits would be largest.

  10. CD4 and viral load dynamics in antiretroviral-naïve HIV-infected adults from Soweto, South Africa: a prospective cohort.

    Science.gov (United States)

    Martinson, Neil A; Gupte, Nikhil; Msandiwa, Reginah; Moulton, Lawrence H; Barnes, Grace L; Ram, Malathi; Gray, Glenda; Hoffmann, Chris; Chaisson, Richard E

    2014-01-01

    CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003-2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of 100,000 (N = 122) copies/ml. Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.

  11. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+and CD4+T cells.

    Science.gov (United States)

    Boudousquie, Caroline; Bossi, Giovanna; Hurst, Jacob M; Rygiel, Karolina A; Jakobsen, Bent K; Hassan, Namir J

    2017-11-01

    The success of immune system-based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti-CD3 scFv antibody) were previously shown to redirect CD8 + and CD4 + T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma-specific protein, gp100, presented by HLA-A*0201) efficiently redirects and activates effector and memory cells from both CD8 + and CD4 + repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8 + T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4 + effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8 + and CD4 + repertoires secrete key pro-inflammatory cytokines (tumour necrosis factor-α, interferon-γ, interleukin-6) and chemokines (macrophage inflammatory protein-1α-β, interferon-γ-inducible protein-10, monocyte chemoattractant protein-1). At an individual cell level, IMCgp100-redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti-cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8 + T cell-mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  12. CD4+ T-cell epitope prediction using antigen processing constraints.

    Science.gov (United States)

    Mettu, Ramgopal R; Charles, Tysheena; Landry, Samuel J

    2016-05-01

    T-cell CD4+ epitopes are important targets of immunity against infectious diseases and cancer. State-of-the-art methods for MHC class II epitope prediction rely on supervised learning methods in which an implicit or explicit model of sequence specificity is constructed using a training set of peptides with experimentally tested MHC class II binding affinity. In this paper we present a novel method for CD4+ T-cell eptitope prediction based on modeling antigen-processing constraints. Previous work indicates that dominant CD4+ T-cell epitopes tend to occur adjacent to sites of initial proteolytic cleavage. Given an antigen with known three-dimensional structure, our algorithm first aggregates four types of conformational stability data in order to construct a profile of stability that allows us to identify regions of the protein that are most accessible to proteolysis. Using this profile, we then construct a profile of epitope likelihood based on the pattern of transitions from unstable to stable regions. We validate our method using 35 datasets of experimentally measured CD4+ T cell responses of mice bearing I-Ab or HLA-DR4 alleles as well as of human subjects. Overall, our results show that antigen processing constraints provide a significant source of predictive power. For epitope prediction in single-allele systems, our approach can be combined with sequence-based methods, or used in instances where little or no training data is available. In multiple-allele systems, sequence-based methods can only be used if the allele distribution of a population is known. In contrast, our approach does not make use of MHC binding prediction, and is thus agnostic to MHC class II genotypes. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells.

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    Leslie R Cockerham

    Full Text Available The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1 in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.

  14. Neoplasia hematodérmica CD4+ CD56+ en la infancia Hematodermic CD4+ CD56+ neoplasm in childhood

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    Erica A. Rojas Bilbao

    2008-04-01

    Full Text Available La neoplasia hematodérmica CD4+ CD56+ con fenotipo de célula dendrítica plasmocitoide es una rara y agresiva neoplasia recientemente reconocida por la WHO-EORTC classification. Afecta adultos de edad media y ancianos, siendo muy pocos los casos descriptos en niños. Presentamos el caso de una niña de 12 años con grave retraso mental, estigmas genéticos y múltiples lesiones cutáneas localizadas en miembros inferiores y superiores. Histológicamente se observó un infiltrado dérmico difuso de células pequeñas y medianas con expresión de CD4, CD56, CD43 y S100 así como de marcadores dendríticos plasmocitoides: CD 123 y BDCA-2 confirmados por citometría de flujo, sin compromiso de sangre periférica ni médula ósea. Cumpliendo dos semanas de tratamiento para leucemia linfoblástica aguda evolucionó con remisión clínica de las lesiones cutaneas.Hematodermic CD4+ CD56+ neoplasm with plasmacytoid dendritic cell phenotype is a rare and aggressive neoplasm recently recognized by the WHO-EORTC classification. It generally appears in elderly adults, exceptionally in childhood. We present a 12-year-old girl with severe mental retardation, genetic clinical features and multiple nodular cutaneous lesions on legs and arms. Histologically the nodules showed diffuse dermal infiltrate of medium and small cells and expression of CD4, CD56, CD43, S100 and plasmacytoid dendritic markers: CD123, BDCA-2 under flow cytometry study. Peripheral blood and bone marrow were not involved. Clinical remission of cutaneous lesions was observed after two weeks of acute lymphoblastic leukemia therapy.

  15. Association of CD4+ T cell subpopulations and psychological stress measures in women living with HIV.

    Science.gov (United States)

    Rehm, Kristina E; Konkle-Parker, Deborah

    2017-09-01

    Psychological stress is a known immunomodulator. In individuals with HIV, depression, the most common manifestation of increased psychological stress, can affect immune function with lower CD4+ T cell counts correlating with higher levels of depression. It is unknown how other forms of psychological stress can impact immune markers in people living with HIV. We conducted a cross-sectional study to determine how CD4+ T cell subpopulations correlated with different forms of psychological stress. We recruited 50 HIV-positive women as part of the Women's Interagency HIV Study. We assessed perceived stress, worry, acute anxiety, trait anxiety, and depression through self-report questionnaires and CD4+ T cell subpopulations using flow cytometry. Our sample was 96% African-American with a mean ± SD age and body mass index of 42 ± 8.8 years and 36.6 ± 11.5 kg/m 2 , respectively. The mean ± SD scores on the psychological measures were as follows: Perceived Stress Scale (PSS), 16.5 ± 6.4; Penn State Worry Questionnaire (PSWQ), 47.7 ± 13.8; State-Trait Anxiety Inventory - State (STAIS), 39.1 ± 12.3; State-Trait Anxiety Inventory - Trait (STAIT), 40.2 ± 11.4; Center for Epidemiological Studies Depression Scale (CES-D), 15.6 ± 11.4. The mean + SD values for the immune parameters were as follows: regulatory T cells (Treg), 1.25% ± 0.7; T helper 1 (Th1), 14.9% ± 6.1; T helper 2 (Th2), 3.8% ± 2; Th1/Th2 ratio, 4.6 ± 3; and CD4+ T cell count (cells/mm 3 ), 493 ± 251. Treg levels positively correlated with PSS, STAIS, and STAIT. CD4+ T cell count negatively correlated with PSS, PSWQ, STAIS, STAIT, and CES-D. These data suggest that immune function may be impacted by various forms of psychological stress in HIV-positive women. Interventions that target stress reduction may be useful in improving immune parameters and quality of life.

  16. The mechanisms shaping the repertoire of CD4+  Foxp3+ regulatory T cells.

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    Kraj, Piotr; Ignatowicz, Leszek

    2018-03-01

    Regulatory T (Treg) cells expressing Foxp3 transcription factor control homeostasis of the immune system, antigenic responses to commensal and pathogenic microbiota, and immune responses to self and tumour antigens. The Treg cells differentiate in the thymus, along with conventional CD4 + T cells, in processes of positive and negative selection. Another class of Treg cells is generated in peripheral tissues by inducing Foxp3 expression in conventional CD4 + T cells in response to antigenic stimulation. Both thymic and peripheral generation of Treg cells depends on recognition of peptide/MHC ligands by the T-cell receptors (TCR) expressed on thymic Treg precursors or peripheral conventional CD4 + T cells. This review surveys reports describing how thymus Treg cell generation depends on the selecting peptide/MHC ligands and how this process impacts the TCR repertoire expressed by Treg cells. We also describe how Treg cells depend on sustained signalling through the TCR and how they are further regulated by Foxp3 enhancer sequences. Finally, we review the impact of microbiota-derived antigens on the maintenance and functionality of the peripheral pool of Treg cells. © 2017 John Wiley & Sons Ltd.

  17. Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: A small randomized controlled trial

    Science.gov (United States)

    Creswell, J. David; Myers, Hector F.; Cole, Steven W.; Irwin, Michael R.

    2009-01-01

    Mindfulness meditation training has stress reduction benefits in various patient populations, but its effects on biological markers of HIV-1 progression are unknown. The present study tested the efficacy of an 8-week Mindfulness-based stress reduction (MBSR) meditation program compared to a 1-day control seminar on CD4+ T lymphocyte counts in stressed HIV infected adults. A single-blind randomized controlled trial was conducted with enrollment and follow-up occurring between November 2005 and December 2007. A diverse community sample of 48 HIV-1 infected adults was randomized and entered treatment in either an 8-week MBSR or a 1-day control stress reduction education seminar. The primary outcome was circulating counts of CD4+ T lymphocytes. Participants in the 1-day control seminar showed declines in CD4+ T lymphocyte counts whereas counts among participants in the 8-week MBSR program were unchanged from baseline to post-intervention (time × treatment condition interaction, p = .02). This effect was independent of antiretroviral (ARV) medication use. Additional analyses indicated that treatment adherence to the mindfulness meditation program, as measured by class attendance, mediated the effects of mindfulness meditation training on buffering CD4+ T lymphocyte declines. These findings provide an initial indication that mindfulness meditation training can buffer CD4+ T lymphocyte declines in HIV-1 infected adults. PMID:18678242

  18. Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: a small randomized controlled trial.

    Science.gov (United States)

    Creswell, J David; Myers, Hector F; Cole, Steven W; Irwin, Michael R

    2009-02-01

    Mindfulness meditation training has stress reduction benefits in various patient populations, but its effects on biological markers of HIV-1 progression are unknown. The present study tested the efficacy of an 8-week Mindfulness-based stress reduction (MBSR) meditation program compared to a 1-day control seminar on CD4+ T lymphocyte counts in stressed HIV infected adults. A single-blind randomized controlled trial was conducted with enrollment and follow-up occurring between November 2005 and December 2007. A diverse community sample of 48 HIV-1 infected adults was randomized and entered treatment in either an 8-week MBSR or a 1-day control stress reduction education seminar. The primary outcome was circulating counts of CD4+ T lymphocytes. Participants in the 1-day control seminar showed declines in CD4+ T lymphocyte counts whereas counts among participants in the 8-week MBSR program were unchanged from baseline to post-intervention (time x treatment condition interaction, p=.02). This effect was independent of antiretroviral (ARV) medication use. Additional analyses indicated that treatment adherence to the mindfulness meditation program, as measured by class attendance, mediated the effects of mindfulness meditation training on buffering CD4+ T lymphocyte declines. These findings provide an initial indication that mindfulness meditation training can buffer CD4+ T lymphocyte declines in HIV-1 infected adults. clinicaltrials.gov, Identifier: NCT00600561.

  19. Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection.

    Science.gov (United States)

    Fontana, Mary F; de Melo, Gabrielly L; Anidi, Chioma; Hamburger, Rebecca; Kim, Chris Y; Lee, So Youn; Pham, Jennifer; Kim, Charles C

    2016-12-01

    Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is dependent upon both CD4+ T cells and the cytokine Macrophage Colony Stimulating Factor (MCSF). Single-cell RNA-Seq analysis on antigen-experienced T cells revealed robust expression of Csf1, the gene encoding MCSF, in a sub-population of CD4+ T cells with distinct transcriptional and surface phenotypes. Selective deletion of Csf1 in CD4+ cells during P. chabaudi infection diminished proliferation and activation of certain myeloid subsets, most notably lymph node-resident CD169+ macrophages, and resulted in increased parasite burden and impaired recovery of infected mice. Depletion of CD169+ macrophages during infection also led to increased parasitemia and significant host mortality, confirming a previously unappreciated role for these cells in control of P. chabaudi. This work establishes the CD4+ T cell as a physiologically relevant source of MCSF in vivo; probes the complexity of the CD4+ T cell response during type 1 infection; and delineates a novel mechanism by which T helper cells regulate myeloid cells to limit growth of a blood-borne intracellular pathogen.

  20. [Effect of total glucosides of peony on expression and DNA methylation status of ITGAL gene in CD4(+) T cells of systemic lupus erythematosus].

    Science.gov (United States)

    Zhao, Ming; Liang, Gongping; Luo, Shuangyan; Lu, Qianjin

    2012-05-01

    To investigate the effect of total glucosides of peony (TGP) on expression and DNA methylation status of ITGAL gene (CD11a) in CD4(+) T cells from patients with systemic lupus erythematosus (SLE). CD4(+) T cells were isolated by positive selection using CD4 beads. CD4(+) T cells were treated by TGP at 0, 62.5, 312.5 and 1562.5 mg/L for 48 h. The MTT method was used to assess cell viability; mRNA expression level was measured by realtime-PCR; protein level of CD11a was measured by flow cytometric analysis; DNA methylation status was assayed by bisulfite sequencing. No significant change in cell viability was found in CD4(+) T cells among the different concentration groups (P>0.05). Compared with control, the mRNA and protein levels of ITGAL were down-regulated significantly in SLE CD4(+) T cells treated with TGP (1562.5 mg/L) (PTGP (1562.5 mg/L) treated CD4(+) T cells compared with control group (PTGP can repress CD11a gene expression through enhancing DNA methylation of ITGAL promoter in CD4(+) T cells from patients with SLE. This observation represents a preliminary step in understanding the mechanism of TGP in SLE therapy.

  1. CD4 and viral load dynamics in antiretroviral-naive HIV-infected adults from Soweto, South Africa: a prospective cohort.

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    Neil A Martinson

    Full Text Available BACKGROUND: CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. METHODS: HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV treatment were randomized to a trial of preventive treatment from 2003-2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to 100,000 (N = 122 copies/ml. CONCLUSIONS: Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.

  2. HIV dynamics linked to memory CD4+ T cell homeostasis.

    Science.gov (United States)

    Murray, John M; Zaunders, John; Emery, Sean; Cooper, David A; Hey-Nguyen, William J; Koelsch, Kersten K; Kelleher, Anthony D

    2017-01-01

    The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART). We investigated whether plasma viral level (pVL) and HIV DNA dynamics could be explained by HIV's impact on memory CD4+ T cell homeostasis. Median total, 2-LTR and integrated HIV DNA levels per μL of peripheral blood, for 8 primary (PHI) and 8 chronic HIV infected (CHI) individuals enrolled on a raltegravir (RAL) based regimen, exhibited greatest changes over the 1st year of ART. Dynamics slowed over the following 2 years so that total HIV DNA levels were equivalent to reported values for individuals after 10 years of ART. The mathematical model reproduced the multiphasic dynamics of pVL, and levels of total, 2-LTR and integrated HIV DNA in both PHI and CHI over 3 years of ART. Under these simulations, residual viremia originated from reactivated latently infected cells where most of these cells arose from clonal expansion within the resting phenotype. Since virion production from clonally expanded cells will not be affected by antiretroviral drugs, simulations of ART intensification had little impact on pVL. HIV DNA decay over the first year of ART followed the loss of activated memory cells (120 day half-life) while the 5.9 year half-life of total HIV DNA after this point mirrored the slower decay of resting memory cells. Simulations had difficulty reproducing the fast early HIV DNA dynamics, including 2-LTR levels peaking at week 12, and the later slow loss of total and 2-LTR HIV DNA, suggesting some ongoing infection. In summary, our modelling indicates that much of the dynamical behavior of HIV can be explained by its impact on memory CD4+ T cell homeostasis.

  3. HIV dynamics linked to memory CD4+ T cell homeostasis.

    Directory of Open Access Journals (Sweden)

    John M Murray

    Full Text Available The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART. We investigated whether plasma viral level (pVL and HIV DNA dynamics could be explained by HIV's impact on memory CD4+ T cell homeostasis. Median total, 2-LTR and integrated HIV DNA levels per μL of peripheral blood, for 8 primary (PHI and 8 chronic HIV infected (CHI individuals enrolled on a raltegravir (RAL based regimen, exhibited greatest changes over the 1st year of ART. Dynamics slowed over the following 2 years so that total HIV DNA levels were equivalent to reported values for individuals after 10 years of ART. The mathematical model reproduced the multiphasic dynamics of pVL, and levels of total, 2-LTR and integrated HIV DNA in both PHI and CHI over 3 years of ART. Under these simulations, residual viremia originated from reactivated latently infected cells where most of these cells arose from clonal expansion within the resting phenotype. Since virion production from clonally expanded cells will not be affected by antiretroviral drugs, simulations of ART intensification had little impact on pVL. HIV DNA decay over the first year of ART followed the loss of activated memory cells (120 day half-life while the 5.9 year half-life of total HIV DNA after this point mirrored the slower decay of resting memory cells. Simulations had difficulty reproducing the fast early HIV DNA dynamics, including 2-LTR levels peaking at week 12, and the later slow loss of total and 2-LTR HIV DNA, suggesting some ongoing infection. In summary, our modelling indicates that much of the dynamical behavior of HIV can be explained by its impact on memory CD4+ T cell homeostasis.

  4. Memory T follicular helper CD4 T cells

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    J. Scott eHale

    2015-02-01

    Full Text Available T follicular helper (Tfh cells are the subset of CD4 T helper cells that are required for generation and maintenance of germinal center reactions and the generation of long-lived humoral immunity. This specialized T helper subset provides help to cognate B cells via their expression of CD40 ligand, IL-21, IL-4, and other molecules. Tfh cells are characterized by their expression of the chemokine receptor CXCR5, expression of the transcriptional repressor Bcl6, and their capacity to migrate to the follicle and promote germinal center B cell responses. Until recently, it remained unclear whether Tfh cells differentiated into memory cells and whether they maintain their Tfh commitment at the memory phase. This review will highlight several recent studies that support the idea of Tfh-committed CD4 T cells at the memory stage of the immune response. The implication of these findings is that memory Tfh cells retain their capacity to recall their Tfh-specific effector functions upon reactivation to provide help for B cell responses and play an important role in prime and boost vaccination or during recall responses to infection. The markers that are useful for distinguishing Tfh effector and memory cells, as well as the limitations of using these markers will be discussed. Tfh effector and memory generation, lineage maintenance, and plasticity relative to other T helper lineages (Th1, Th2, Th17, etc will also be discussed. Ongoing discoveries regarding the maintenance and lineage stability versus plasticity of memory Tfh cells will improve strategies that utilize CD4 T cell memory to modulate antibody responses during prime and boost vaccination.

  5. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.

    Science.gov (United States)

    Heit, Antje; Gebhardt, Friedemann; Lahl, Katharina; Neuenhahn, Michael; Schmitz, Frank; Anderl, Florian; Wagner, Hermann; Sparwasser, Tim; Busch, Dirk H; Kastenmüller, Kathrin

    2008-06-01

    Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.

  6. Oral manifestations in a patient with idiopathic CD4+ lymphocytopenia.

    Science.gov (United States)

    Reichart, P A; Pohle, H D; Gelderblom, H R

    1996-08-01

    A 56-year-old patient with idiopathic CD4+ lymphocytopenia (ICL) is described. In addition to a complex medical history and clinical course, he presented with oral manifestations including episodic erythematous candidiasis, persistent angular cheilitis, lingua exfoliativa areata, and teleangiectasia of facial skin and buccal mucosa. Light microscopy and transmission electron microscopy (TEM) revealed vascular structures similar to findings in clinically uninvolved oral mucosa of patients with HIV infection. Further observations of patients with ICL are warranted to clarify the significance of oral findings made in the present case.

  7. Kaposi sarcoma: no longer an AIDS-defining illness? A retrospective study of Kaposi sarcoma cases with CD4 counts above 300/mm³ at presentation.

    Science.gov (United States)

    Daly, M-L; Fogo, A; McDonald, C; Morris-Jones, R

    2014-01-01

    Historically, Kaposi sarcoma (KS) has been considered to occur in patients infected with human immunodeficiency virus (HIV) who have low CD4 counts and high viral loads. However, merging data show that KS also occurs in HIV-positive patients with CD4 counts of > 300/mm(3) and undetectable viral loads. To investigate the characteristics of HIV-positive patients with CD4 counts of > 300 cells/mm(3) and presence of KS. This was a retrospective study of 23 cases of histologically confirmed KS in HIV-positive patients presenting to King's College Hospital between 2005 and 2011. Of the 23 cases, 7 (30%) had a CD4 count of > 300 cells/mm(3) at diagnosis of KS; 2 were being treated with highly active antiretroviral therapy (HAART) at the time of KS diagnosis, while the remaining 5 patients were HAART-naïve. All 7 patients were men, and all had a lower median age, higher recorded CD4 counts and more recent HIV diagnosis than the 16 patients with lower CD4 counts (count > 300/mm(3) , most of whom were HAART-naïve at the time of KS diagnosis. Contemporary data indicate that KS presenting with CD4 counts > 300/mm(3) usually occurs in patients established on HAART, which is not borne out by the results of our study. © 2013 British Association of Dermatologists.

  8. Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis

    DEFF Research Database (Denmark)

    Solti, Izabella; Kvell, Krisztian; Talaber, Gergely

    2015-01-01

    Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first......- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged...

  9. Utility of the point of care CD4 analyzer, PIMA, to enumerate CD4 counts in the field settings in India

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    Thakar Madhuri

    2012-09-01

    Full Text Available Abstract Background In resource limited settings non-availability of CD4 count facility at the site could adversely affect the ART roll out programme. Point of care CD4 enumerating equipments can make the CD4 count available at the site of care and improve the patients’ management considerably. This study is aimed at determining the utility of a Point of Care PIMA CD4 analyzer (Alere, Germany in the field settings in India. Method The blood samples were collected from 1790 participants at 21 ART centers from different parts of the country and tested using PIMA and the reference methods (FACSCalibur, FACSCount and CyFlow SL3. The paired finger prick and venous blood samples from 175 participants were tested by the PIMA CD4 Analyzer and then by FACSCalibur. Result The CD4 counts obtained by PIMA CD4 analyzer showed excellent correlation with the counts obtained by the reference methods; for venous blood the Pearson’s r was 0.921, p 500 cells/mm3, the differences in the median CD4 counts obtained by the reference method and the PIMA analyzer were not significant (P > 0.05 and the relative bias were low (−7 to 5.1%. The Intermachine comparison showed variation within the acceptable limit of%CV of 10%. Conclusion In the field settings, the POC PIMA CD4 analyzer gave CD4 counts comparable to the reference methods for all CD4 ranges. The POC equipment could identify the patients eligible for ART in 91% cases. Adequate training is necessary for finger prick sample collection for optimum results. Decentralization of CD4 testing by making the CD4 counts available at primary health centers, especially in remote areas with minimum or no infrastructure would reduce the missed visits and improve adherence of the patients.

  10. Intrinsic tolerance in autologous collagen-induced arthritis is generated by CD152-dependent CD4+ suppressor cells

    DEFF Research Database (Denmark)

    Treschow, Alexandra P; Bäcklund, Johan; Holmdahl, Rikard

    2005-01-01

    . We found that expression of heterologous rat CII sequence in the cartilage of mice positively selects autoreactive CD4(+) T cells with suppressive capacity. Although CD4(+)CD25(+) cells did not play a prominent role in this suppression, CD152-expressing T cells played a crucial role in this tolerance....... MMC CD4(+) T cells were able to suppress proliferation of wild-type cells in vitro where this suppression required cell-to-cell contact. The suppressive capability of MMC cells was also demonstrated in vivo, as transfer of such cells into wild-type arthritis susceptible mice delayed arthritis onset....... This study also determined that both tolerance and disease resistance were CD152-dependent as demonstrated by Ab treatment experiments. These findings could have relevance for RA because the transgenic mice used express the same CII epitope in cartilage as humans and because autoreactive T cells, specific...

  11. Trans-abdominal ultrasonic findings correlated with CD4+ counts in adult HIV-infected patients in Benin, Nigeria

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    B O-E Igbinedion

    2009-06-01

    Full Text Available Objective: The objective of this study is to document the abdominal ultrasound findings in HIV infected patients and compare it with their CD4+ count. Patients and method: 300 confirmed HIV positive patients had abdominal ultrasonography done at the University of Benin Teaching Hospital from November 2007 to January 2008. Each patient’s sonographic findings were correlated with their CD4+ category using the WHO’s HIV classification index. Result: Splenomegaly, hepatomegaly, renomegaly, hyperechoic splenic parenchyma, increased renal echogenicity and lymphadenopathy are among the common sonographic findings. However, few of these findings correlated statistically with the CD4+ count. Conclusion: The versatile diagnostic tool, ultrasound, should continue to be an important imaging equipment in several impoverished communities. In the evaluation of HIV infected patients, its use is invaluable and should be promoted.

  12. Code Single Point Positioning Using Nominal GNSS Constellations (Future Perception)

    Science.gov (United States)

    Farah, A. M. A.

    Global Navigation Satellite Systems (GNSS) have an endless number of applications in industry, science, military, transportation and recreation & sports. Two systems are currently in operation, namely GPS (the USA Global Positioning System) and GLONASS (the Russian GLObal NAvigation Satellite System), and a third is planned, the European satellite navigation system GALILEO. The potential performance improvements achievable through combining these systems could be significant and expectations are high. The need is inevitable to explore the future of positioning from different nominal constellations. In this research paper, Bernese 5.0 software could be modified to simulate and process GNSS observations from three different constellations (GPS, GLONASS and Galileo) using different combinations. This study presents results of code single point positioning for five stations using the three constellations and different combinations.

  13. Positive impedance humidity sensors via single-component materials.

    Science.gov (United States)

    Qian, Jingwen; Peng, Zhijian; Shen, Zhenguang; Zhao, Zengying; Zhang, Guoliang; Fu, Xiuli

    2016-05-06

    Resistivity-type humidity sensors have been investigated with great interest due to the increasing demands in industry, agriculture and daily life. To date, most of the available humidity sensors have been fabricated based on negative humidity impedance, in which the electrical resistance decreases as the humidity increases, and only several carbon composites have been reported to present positive humidity impedance. However, here we fabricate positive impedance humidity sensors only via single-component WO3-x crystals. The resistance of WO3-x crystal sensors in response to relative humidity could be tuned from a negative to positive one by increasing the compositional x. And it was revealed that the positive humidity impedance was driven by the defects of oxygen vacancy. This result will extend the application field of humidity sensors, because the positive humidity impedance sensors would be more energy-efficient, easier to be miniaturized and electrically safer than their negative counterparts for their lower operation voltages. And we believe that constructing vacancies in semiconducting materials is a universal way to fabricate positive impedance humidity sensors.

  14. Cycling Memory CD4+ T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

    Science.gov (United States)

    Jiang, Wei; Younes, Souheil-Antoine; Funderburg, Nicholas T.; Mudd, Joseph C.; Espinosa, Enrique; Davenport, Miles P.; Babineau, Denise C.; Sieg, Scott F.

    2014-01-01

    ABSTRACT The mechanisms of increased memory CD4+ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and Vβ family distribution in cycling memory CD4+ T cells among 52 healthy and 59 HIV-positive (HIV+) donors. Cycling memory CD4+ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4+ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV+ donors, memory CD4+ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8+ T cell cycling and was inversely related to peripheral blood CD4+ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4+ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV+ donors, cycling memory CD4+ T cells had a broad distribution of Vβ families comparable to that of noncycling cells. Increased memory CD4+ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines. IMPORTANCE This work provides evidence that the increased memory CD4+ T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection. PMID:24522925

  15. Contribution of CD4+ T cells to the early mechanisms of ischemia- reperfusion injury in a mouse model of acute renal failure

    Directory of Open Access Journals (Sweden)

    H.S. Pinheiro

    2007-04-01

    Full Text Available Renal ischemia-reperfusion (IR injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 µ, ip, and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of ßC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-g and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.

  16. CD4+ T-cell lines used to evaluate a Mycobacterium avium subsp. paratuberculosis (MAP) peptide vaccine

    DEFF Research Database (Denmark)

    Lybeck, Kari; Sjurseth, Siri K.; Al-Touama, Zainab

    The aim of the study was to establish a protocol for generation of MAP-specific T-cell lines and to use these lines for evaluation of a peptide vaccine. A protocol for culturing T-cell lines from peripheral blood of goats naturally infected with MAP was established. CD4+ T cells were positively s...

  17. No Neurocognitive Advantage for Immediate Antiretroviral Treatment in adults with greater than 500 CD4+ T Cell Counts

    DEFF Research Database (Denmark)

    Wright, Edwina J; Grund, Birgit; Robertson, Kevin R

    2018-01-01

    OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with >500 CD4+ cells/μL. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immedia...

  18. Inhibition of T Cell Receptor Expression and Function in Immature CD4+CD8+ Cells by CD4

    Science.gov (United States)

    1990-09-28

    8217 SYNIOL Phyllis Blum, Information Services Division 0L-295-2188 IsD/ADMIN/NNRI DD FORM 1473, 84 MAR 83 APR ecoiton may oe usea until exnaulted...TCR surface expres- determined by electrophoresis of detergent-solubilized cell sion, decreased TCR- phosphorylation, or lvsates and immunoblotting...MAb to CI)3t (A) Purified B6 CD4’CD8’ thvlmocvltcs were SDS-polvacvlaxnide gel electrophoresis (SDS- (MAb 145-2C01), 13% SDS-PAGE in reducing cultured

  19. Are Mucosa CD4+/CD8+ T-Cells Expressions Correlated with the Endoscopic Appearance of Chronic Gastritis Related with Helicobacter pylori Infection?

    Science.gov (United States)

    Ratnasari, Neneng; Bayupurnama, Putut; Maduseno, Sutanto; Indrarti, Fahmi; Triwikatmani, Catharina; Harijadi, Achmad; Nurdjanah, Siti

    2016-06-01

    Local inflammatory processes in the gastric mucosa are followed by extensive immune cell infiltration, resulting in chronic active gastritis characterized by a marked infiltration of T(h)1 cytokine-producing CD4+ and CD8+T-cells Objective. To investigate the correlation between CD4+/CD8+ T-cells in gastric mucosa with endoscopic appearance in chronic gastritis with or without H.pylori infection. Prospective, cross sectional study is performed in a chronic dyspepsia population in July-November 2009 at Dr. Sardjito General Hospital Yogyakarta, Indonesia. The update Sydney system was used to analyze the gastroscopy appearance. Biopsy specimens were stained with HE-stain and IHC-stain. Data were analyzed by t-test, Mann-Whitney and Spearman correlation test. Number of 88 consecutive subjects are enrolled the study (50% male; 50% female), age 46±15 years; 25% H.pylori positive. The expression of CD4+ and CD8+ were higher in H.pylori negative subjects, but only the CD4+ was significant (P=0.011). A significant correlation was found between CD4+ and CD8+ in both subjects (r(Hp+)=0.62 and r(Hp-)=0.68; Ppylori positive showed a significant correlation with gastric lesions (r(CD4+)=-0.60; r(CD8+)=-0.42 ; Ppylori infection, and a negative correlation was only found between gastric lesion with CD4+ and CD8+ infiltration in H.pylori subject.

  20. A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs.

    Directory of Open Access Journals (Sweden)

    Kara G Lassen

    Full Text Available Latently infected cells form the major obstacle to HIV eradication. Studies of HIV latency have been generally hindered by the lack of a robust and rapidly deployable cell model that involves primary human CD4 T lymphocytes. Latently infected cell lines have proven useful, but it is unclear how closely these proliferating cells recapitulate the conditions of viral latency in non-dividing CD4 T lymphocytes in vivo. Current primary lymphocyte models more closely reflect the in vivo state of HIV latency, but they are limited by protracted culture periods and often low cell yields. Additionally, these models are always established in a single latently infected cell type that may not reflect the heterogeneous nature of the latent reservoir. Here we describe a rapid, sensitive, and quantitative primary cell model of HIV-1 latency with replication competent proviruses and multiple reporters to enhance the flexibility of the system. In this model, post-integration HIV-1 latency can be established in all populations of CD4 T cells, and reactivation of latent provirus assessed within 7 days. The kinetics and magnitude of reactivation were evaluated after stimulation with various cytokines, small molecules, and T-cell receptor agonists. Reactivation of latent HIV proviruses was readily detected in the presence of strong activators of NF-κB. Latently infected transitional memory CD4 T cells proved more responsive to these T-cell activators than latently infected central memory cells. These findings reveal potentially important biological differences within the latently infected pool of memory CD4 T cells and describe a flexible primary CD4 T-cell system to evaluate novel antagonists of HIV latency.

  1. DX5+ CD4+ T cells modulate CD4+ T-cell response via inhibition of IL-12 production by DCs.

    Science.gov (United States)

    el Bannoudi, Hanane; Han, Wanda G H; Stoop, Jeroen N; Louis-Plence, Pascale; Huizinga, Tom W J; Toes, René E M

    2013-02-01

    DX5(+) CD4(+) T cells have been shown to dampen collagen-induced arthritis and delayed-type hypersensitivity reactions in mice. These cells are also potent modulators of T-helper cell responses through direct effects on CD4(+) T cells in an IL-4 dependent manner. To further characterize this T-cell population, we studied their effect on DCs and the potential consequences on T-cell activation. Here, we show that mouse DX5(+) CD4(+) T cells modulate DCs by robustly inhibiting IL-12 production. This modulation is IL-10 dependent and does not require cell contact. Furthermore, DX5(+) CD4(+) T cells modulate the surface phenotype of LPS-matured DCs. DCs modulated by DX5(+) CD4(+) T-cell supernatant express high levels of the co-inhibitor molecules PDL-1 and PDL-2. OVA-specific CD4(+) T cells primed with DCs exposed to DX5(+) CD4(+) T-cell supernatant produce less IFN-γ than CD4(+) T cells primed by DCs exposed to either medium or DX5(-) CD4(+) T-cell supernatant. The addition of IL-12 to the co-culture with DX5(+) DCs restores IFN-γ production. When IL-10 present in the DX5(+) CD4(+) T-cell supernatant is blocked, DCs re-establish their ability to produce IL-12 and to efficiently prime CD4(+) T cells. These data show that DX5(+) CD4(+) T cells can indirectly affect the outcome of the T-cell response by inducing DCs that have poor Th1 stimulatory function. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Changes in Reactivity In Vitro of CD4+CD25+ and CD4+CD25− T Cell Subsets in Transplant Tolerance

    Directory of Open Access Journals (Sweden)

    Bruce M. Hall

    2017-08-01

    Full Text Available Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4+CD25+ T cells, yet in many models, proliferation of CD4+ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4+, CD4+CD25+, and CD4+CD25− T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG cardiac allografts and from naïve DA rats were examined. Proliferation of CD4+ T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4+CD25− T cells was greater than naïve CD4+ T cells. In contrast, proliferation of CD4+CD25− T cells from tolerant hosts to specific-donor PVG was not greater than CD4+ T cells, whereas their response to Lewis and self-DA was greater than CD4+ T cells. Paradoxically, CD4+CD25+ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4+CD25+ T cells proliferate to both PVG and Lewis but not to self-DA. CD4+CD25+ T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4+CD25+ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4+CD25+ T cells that mediate transplant tolerance depend on IFN−γ or IL-5 from alloactivated Th1 and Th2 cells.

  3. Intestinal parasitic infections in relation to HIV/AIDS status, diarrhea and CD4 T-cell count

    Directory of Open Access Journals (Sweden)

    Assefa Zelalem

    2009-09-01

    Full Text Available Abstract Background HIV infection has been modifying both the epidemiology and outcome of parasitic infections. Hence, this study was undertaken to determine the prevalence of intestinal parasitic infection among people with and without HIV infection and its association with diarrhea and CD4 T-cell count. Methods A cross-sectional study was conducted at Hawassa Teaching and Referral Hospital focusing on HIV positive individuals, who gave blood for CD4 T-cell count at their first enrolment and clients tested HIV negative from November, 2008 to March, 2009. Data on socio-demographic factors and diarrhea status were obtained by interviewing 378 consecutive participants (214 HIV positive and 164 HIV negative. Stool samples were collected from all study subjects and examined for parasites using direct, formol-ether and modified acid fast stain techniques. Results The prevalence of any intestinal parasitic infection was significantly higher among HIV positive participants. Specifically, rate of infection with Cryptosporidium, I. belli, and S. stercoralis were higher, particularly in those with CD4 count less than 200 cells/μL. Diarrhea was more frequent also at the same lower CD4 T-cell counts. Conclusion Immunodeficiency increased the risk of having opportunistic parasites and diarrhea. Therefore; raising patient immune status and screening at least for those treatable parasites is important.

  4. Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma.

    Science.gov (United States)

    Hoesli, Rebecca; Birkeland, Andrew C; Rosko, Andrew J; Issa, Mohamad; Chow, Kelsey L; Michmerhuizen, Nicole L; Mann, Jacqueline E; Chinn, Steven B; Shuman, Andrew G; Prince, Mark E; Wolf, Gregory T; Bradford, Carol R; McHugh, Jonathan B; Brenner, J Chad; Spector, Matthew E

    2018-02-01

    Tumor infiltrating lymphocytes (TILs) have been shown to be an important prognostic factor in patients with previously untreated head and neck cancer. After organ preservation therapy for laryngeal cancer and subsequent persistence/recurrence, the prognostic value of TILs is unknown. Our goal was to determine if TILs have value as a prognostic biomarker in patients with surgically salvageable persistent/recurrent laryngeal squamous cell carcinoma. Levels of TILs were quantified on tissue microarrays from 183 patients undergoing salvage total laryngectomy for persistent/recurrent laryngeal cancer after radiation or chemoradiation between 1997 and 2014. Demographic and clinical data were abstracted. Immunohistology evaluation included CD4, CD8, PDL-1, p16, CD31, Vimentin, EGFR, and p53. Elevated levels of either CD8 or CD4 positive TILs were associated with improved disease specific survival (CD8: HR 0.46, 95% CI 0.24-0.88, CD4: HR 0.43; 95% CI 0.21-0.89) and disease free survival (CD8: HR 0.53, 95% CI 0.29-0.94, CD4: HR 0.52; 95% CI 0.27-0.99). Levels of CD8 (HR 0.74; 95% CI 0.47-1.17) or CD4 (HR 0.66; 95% CI 0.40-1.08) TILs were not significantly associated with overall survival. In bivariate analysis, patients with elevated CD4 and/or CD8 TILs had significantly improved disease specific survival (HR 0.42; 95% CI 0.21-0.83) and disease free survival (HR 0.45; 95% CI 0.24-0.84) compared to patients with low levels of CD4 and CD8. PDL-1, p16, CD31, Vimentin, EGFR, and p53 were not significant prognostic factors. On multivariate analysis, elevated CD8 TILs were associated with improved disease specific survival (HR 0.35; 95% CI 0.14-0.88, p = .02) and disease free survival (HR 0.41; 95% CI 0.17-0.96, p = .04). CD8, and possibly CD4, positive TILs are associated with favorable disease free and disease specific survival for recurrent/persistent laryngeal cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. CD4+ T Cells Modified by the Endoribonuclease MazF Are Safe and Can Persist in SHIV-infected Rhesus Macaques

    Directory of Open Access Journals (Sweden)

    Naoki Saito

    2014-01-01

    Full Text Available MazF, an endoribonuclease encoded by Escherichia coli, specifically cleaves the ACA (adenine–cytosine–adenine sequence of single-stranded RNAs. Conditional expression of MazF under the control of the HIV-1 LTR promoter rendered CD4+ T cells resistant to HIV-1 replication without affecting cell growth. To investigate the safety, persistence and efficacy of MazF-modified CD4+ T cells in a nonhuman primate model in vivo, rhesus macaques were infected with a pathogenic simian/human immunodeficiency virus (SHIV and transplanted with autologous MazF-modified CD4+ T cells. MazF-modified CD4+ T cells were clearly detected throughout the experimental period of more than 6 months. The CD4+ T cell count values increased in all four rhesus macaques. Moreover, the transplantation of the MazF-modified CD4+ T cells was not immunogenic, and did not elicit cellular or humoral immune responses. These data suggest that the autologous transplantation of MazF-modified CD4+ T cells in the presence of SHIV is effective, safe and not immunogenic, indicating that this is an attractive strategy for HIV-1 gene therapy.

  6. Short synthetic peptides derived from viral proteins compete with HIV gp120 for the binding to CD4 receptors.

    Science.gov (United States)

    Chersi, A; Pugliese, O; Federico, A; Viora, M

    2000-01-01

    In the complex mechanism of adhesion, internalization, and infection of cells by human immunodeficiency virus (HIV) viral particles, a determinant role is played by the viral envelope glycoprotein gp120, which binds to CD4 receptors of T cells and monocytes. We tested the ability of a panel of 7- to 12-residue synthetic peptides, selected from the region 414-434 of the HIV-1 gp120, to inhibit the binding of the viral protein to CD4 receptors of cultured human lymphoid cells. The assay was based on the observation that the binding of gp120 to the receptors interferes with the binding of a specific anti-CD4 monoclonal antibody, as a result of the masking of the antibody epitope; thus, we tested whether preincubation of cells with the peptides before gp120 addition might restore the recognition of the CD4 molecule by the antibody. High expression of CD4 receptors was thus assumed as indication that the binding of the viral protein had been inhibited. Maximum activity was displayed by a 9-residue peptide located near the amino terminal end of the 414-434 fragment. In addition, several fragments deduced from other viral proteins, possessing partial amino acid sequence homology with the HIV gp120 fragment, exhibited a similar type of interaction with the CD4 receptor. All active peptides contain the Cys residue (position 423 of gp120). This residue is essential, although not sufficient, for inhibiting gp120 binding, as few other amino acid residues within the fragment play a complementary role in increasing or decreasing the inhibitory ability.

  7. The endocrine milieu and CD4 T-lymphocyte polarisation during pregnancy

    Directory of Open Access Journals (Sweden)

    Barbara ePolese

    2014-07-01

    Full Text Available Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg and Th17 cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T-cell polarisation during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones (progesterone, estradiol on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG. The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uNK cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. LH immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse.

  8. Single-baseline RTK GNSS Positioning for Hydrographic Surveying

    Science.gov (United States)

    Metin Alkan, Reha; Murat Ozulu, I.; Ilçi, Veli; Kahveci, Muzaffer

    2015-04-01

    Positioning with GNSS technique can be carried out in two ways, absolute and relative. It has been possible to reach a few meters absolute point positioning accuracies in real time after disabling SA permanently in May 2000. Today, accuracies obtainable from absolute point positioning using code observations are not sufficient for most surveying applications. Thus to meet higher accuracy requirements, differential methods using single or dual frequency geodetic-grade GNSS receivers that measure carrier phase have to be used. However, this method requires time-cost field and office works and if the measurement is not carried out with conventional RTK method, user needs a GNSS data processing software to estimate the coordinates. If RTK is used, at least two or more GNSS receivers are required, one as a reference and the other as a rover. Moreover, the distance between the receivers must not exceed 15-20 km in order to be able to rapidly and reliably resolve the carrier phase ambiguities. On the other hand, based on the innovations and improvements in satellite geodesy and GNSS modernization studies occurred within the last decade, many new positioning methods and new approaches have been developed. One of them is Network-RTK (or commonly known as CORS) and the other is Single-baseline RTK. These methods are widely used for many surveying applications in many countries. The user of the system can obtain his/her position within a few cm level of accuracy in real-time with only a single GNSS receiver that has Network RTK (CORS) capability. When compared with the conventional differential and RTK methods, this technique has several significant advantages as it is easy to use and it produces accurate, cost-effective and rapid solutions. In Turkey, establishment of a multi-base RTK network was completed and opened for civilian use in 2009. This network is called CORS-TR and consists of 146 reference stations having about 80-100 km interstation distances. It is possible

  9. Quantitative variations of CD4 + CD25 + cells in Peking duckwhite ...

    African Journals Online (AJOL)

    Purpose: To develop a chimera via microinjection of poultry xenogeneic bone marrow mesenchymal stem cells (BMMSCs), and to assess its immune tolerance based on variations in proportion of CD4+CD25+ cells in CD4+ cells (specific CD4+CD25+ cells). Methods: BMMSCs were flush out from femurs and tibias of ...

  10. Circulating CD4+CD28null T Cells May Increase the Risk of an Atherosclerotic Vascular Event Shortly after Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Michiel G. H. Betjes

    2013-01-01

    Full Text Available Proinflammatory CD4+ T cells without the costimulatory molecule CD28 (CD4+CD28null T cells are expanded in patients with end-stage renal disease (ESRD and associated with atherosclerotic vascular events (AVE. In a prospective study, the number of circulating CD4+CD28null T cells was established in 295 ESRD patients prior to receiving a kidney allograft. Within the first year after transplantation, an AVE occurred in 20 patients. Univariate analysis showed that besides a history of cardiovascular disease (CVDpos, HR 8.1, , age (HR 1.04, , dyslipidaemia (HR 8.8, , and the % of CD4+CD28null T cells (HR 1.04 per % increase, 95% CI 1.00–1.09, were significantly associated with the occurrence of a posttransplantation AVE. In a multivariate analysis, only CVDpos remained a significant risk factor with a significant and positive interaction between the terms CVDpos and the % of CD4+CD28null T cells (HR 1.05, 95% CI 1.03–1.11, . Within the CVDpos group, the incidence of an AVE was 13% in the lowest tertile compared to 25% in the highest tertile of % of CD4+CD28null T cells. In conclusion, the presence of circulating CD4+CD28null T cells is associated with an increased risk for a cardiovascular event shortly after kidney transplantation.

  11. Genome-wide expression profiling analysis to identify key genes in the anti-HIV mechanism of CD4+and CD8+T cells.

    Science.gov (United States)

    Gao, Lijie; Wang, Yunqi; Li, Yi; Dong, Ya; Yang, Aimin; Zhang, Jie; Li, Fengying; Zhang, Rongqiang

    2018-03-06

    Comprehensive bioinformatics analyses were performed to explore the key biomarkers in response to HIV infection of CD4 + and CD8 + T cells. The numbers of CD4 + and CD8 + T cells of HIV infected individuals were analyzed and the GEO database (GSE6740) was screened for differentially expressed genes (DEGs) in HIV infected CD4 + and CD8 + T cells. Gene Ontology enrichment, KEGG pathway analyses, and protein-protein interaction (PPI) network were performed to identify the key pathway and core proteins in anti-HIV virus process of CD4 + and CD8 + T cells. Finally, we analyzed the expressions of key proteins in HIV-infected T cells (GSE6740 dataset) and peripheral blood mononuclear cells(PBMCs) (GSE511 dataset). 1) CD4 + T cells counts and ratio of CD4 + /CD8 + T cells decreased while CD8 + T cells counts increased in HIV positive individuals; 2) 517 DEGs were found in HIV infected CD4 + and CD8 + T cells at acute and chronic stage with the criterial of P-value CD8 + T cells changed significantly in HIV infection, in which ISG15 gene may play a central role in activating the natural antiviral process of immune cells. © 2018 Wiley Periodicals, Inc.

  12. Elicitation of neutralizing antibodies directed against CD4-induced epitope(s using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein.

    Directory of Open Access Journals (Sweden)

    Antu K Dey

    Full Text Available The identification of HIV-1 envelope glycoprotein (Env structures that can generate broadly neutralizing antibodies (BNAbs is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4 receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i epitope(s known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH, was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140 using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1 complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s. These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s here, and its potential role in vaccine application.

  13. HIV-1 Infection Is Associated with Depletion and Functional Impairment of Mycobacterium tuberculosis-Specific CD4 T Cells in Individuals with Latent Tuberculosis Infection.

    Science.gov (United States)

    Day, Cheryl L; Abrahams, Deborah A; Harris, Levelle D; van Rooyen, Michele; Stone, Lynnett; de Kock, Marwou; Hanekom, Willem A

    2017-09-15

    Coinfection with HIV is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell-mediated control of M. tuberculosis have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to M. tuberculosis , we evaluated the frequency, phenotype, and functional capacity of M. tuberculosis -specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI. HIV infection was associated with a lower total frequency of cytokine-producing M. tuberculosis -specific CD4 T cells, and preferential depletion of a discrete subset of M. tuberculosis -specific IFN-γ + IL-2 - TNF-α + CD4 T cells. M. tuberculosis -specific CD4 T cells in HIV-infected individuals expressed significantly higher levels of Ki67, compared with HIV-uninfected individuals, thus indicating recent activation and turnover of these cells in vivo. The ex vivo proliferative capacity of M. tuberculosis -specific CD4 T cells was markedly impaired in HIV-infected individuals, compared with HIV-uninfected individuals. Moreover, HIV infection was associated with increased M. tuberculosis Ag-induced CD4 T cell death ex vivo, indicating a possible mechanism contributing to impaired proliferative capacity of M. tuberculosis -specific CD4 T cells in HIV-infected individuals. These data provide new insights into the parameters of M. tuberculosis -specific CD4 T cell immunity that are impaired in HIV-infected individuals with LTBI, which may contribute to their increased risk of developing active tuberculosis disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  14. Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9.

    Science.gov (United States)

    Li, Chang; Guan, Xinmeng; Du, Tao; Jin, Wei; Wu, Biao; Liu, Yalan; Wang, Ping; Hu, Bodan; Griffin, George E; Shattock, Robin J; Hu, Qinxue

    2015-08-01

    CCR5 serves as an essential coreceptor for human immunodeficiency virus type 1 (HIV-1) entry, and individuals with a CCR5(Δ32) variant appear to be healthy, making CCR5 an attractive target for control of HIV-1 infection. The CRISPR/Cas9, which functions as a naturally existing adaptive immune system in prokaryotes, has been recently harnessed as a novel nuclease system for genome editing in mammalian cells. Although CRISPR/Cas9 can be readily delivered into cell lines, due to the large size of the Cas9 protein, efficient delivery of CCR5-targeting CRISPR/Cas9 components into primary cells, including CD4(+) T-cells, the primary target for HIV-1 infection in vivo, remains a challenge. In the current study, following design of a panel of top-ranked single-guided RNAs (sgRNAs) targeting the ORF of CCR5, we demonstrate that CRISPR/Cas9 can efficiently mediate the editing of the CCR5 locus in cell lines, resulting in the knockout of CCR5 expression on the cell surface. Next-generation sequencing revealed that various mutations were introduced around the predicted cleavage site of CCR5. For each of the three most effective sgRNAs that we analysed, no significant off-target effects were detected at the 15 top-scoring potential sites. More importantly, by constructing chimeric Ad5F35 adenoviruses carrying CRISPR/Cas9 components, we efficiently transduced primary CD4(+) T-lymphocytes and disrupted CCR5 expression, and the positively transduced cells were conferred with HIV-1 resistance. To our knowledge, this is the first study establishing HIV-1 resistance in primary CD4(+) T-cells utilizing adenovirus-delivered CRISPR/Cas9.

  15. Effector memory CD4(+) T cells differentially express activation associated molecules depending on the duration of American cutaneous leishmaniasis lesions.

    Science.gov (United States)

    de Oliveira Mendes-Aguiar, C; Vieira-Gonçalves, R; Guimarães, L H; de Oliveira-Neto, M P; Carvalho, E M; Da-Cruz, A M

    2016-08-01

    A high number of Leishmania-responder T cells is found in cutaneous leishmaniasis lesions, suggesting that important immunological events occur at the site of infection. Although activated, cytotoxic and regulatory T cells infiltrating into lesions may influence disease pathogenesis, the role of the T cell differentiation pattern of lymphocytes in lesions is unknown. Our aim was to investigate whether the phase of lesion development (early or late) is influenced by the functional status of cells present in inflammatory infiltrate. Activation, cytotoxity and T cell differentiation molecules were evaluated in lesion mononuclear cells by flow cytometry. The frequency of T cells was correlated with the lesion area (r = 0·68; P = 0·020). CD4(+) CD25(+) T cells predominated over CD4(+) CD69(+) T cells in early lesions (less than 30 days), whereas late lesions (more than 60 days) exhibited more CD4(+) CD69(+) T cells than CD4(+) CD25(+) T cells. The duration of illness was correlated positively with CD4(+) CD69(+) (r = 0·68; P = 0·005) and negatively with CD4(+) CD25(+) T cells (r = -0·45; P = 0·046). Most CD8(+) T cells expressed cytotoxic-associated molecules (CD244(+) ), and the percentages were correlated with the lesion area (r = 0·52; P = 0·04). Both CD4(+) and CD8(+) effector memory T cells (TEM -CD45RO(+) CCR7(-) ) predominated in CL lesions and were significantly higher than central memory (TCM -CD45RO(+) CCR7(+) ) or naive T cells (CD45RO(-) CCR7(+) ). An enrichment of TEM cells and contraction of naive T cells were observed in lesions in comparison to blood (P = 0·006) for both CD4(+) and CD8(+) T cells. Lesion chronicity is associated with a shift in activation phenotype. The enrichment of TEM and activated cytotoxic cells can contribute to immune-mediated tissue damage. © 2016 British Society for Immunology.

  16. Studies on positive conveying in helically channeled single screw extruders

    Directory of Open Access Journals (Sweden)

    L. Pan

    2012-07-01

    Full Text Available A solids conveying theory called double-flight driving theory was proposed for helically channeled single screw extruders. In the extruder, screw channel rotates against static barrel channel, which behaves as cooperative embedded twin-screws for the positive conveying. They turn as two parallel arc plates, between which an arc-plate solid-plug was assumed. By analyzing the forces on the solid-plug in the barrel channel and screw channel, the boundary conditions when the solid-plug is waived of being cut off on barrel wall, were found to have the capacity of the positive conveying. Experimental data were obtained using a specially designed extruder with a helically channeled barrel in the feeding zone and a pressure-adjustable die. The effects of the barrel channel geometry and friction coefficients on the conveying mechanism were presented and compared with the experimental results. The simulations showed that the positive conveying could be achieved after optimizing extruder designs. Compared with the traditional design with the friction-drag conveying, the throughput is higher while screw torque and energy consumption are decreased. Besides, the design criteria of the barrel channel were also discussed.

  17. Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

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    Kristin Kassler

    2011-01-01

    Full Text Available The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4. Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120.

  18. IL-15 augments TCR-induced CD4+ T cell expansion in vitro by inhibiting the suppressive function of CD25 High CD4+ T cells.

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    Tom L Van Belle

    Full Text Available Due to its critical role in NK cell differentiation and CD8(+ T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+ T cells. The increased levels of IL-15 found in several CD4(+ T cell-driven (auto- immune diseases prompted us to examine how IL-15 influences murine CD4(+ T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+ and CD8(+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+ T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+ T cell suppression by a gradually expanding CD25(HighCD4(+ T cell subset that expresses Foxp3 and originates from CD4(+CD25(+ Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.

  19. Comparison of oral manifestations with CD4 count in HIV-infected patients

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    Subodh Arun Sontakke

    2011-01-01

    Full Text Available Aim and Objective: This study was carried out with the primary aim of correlating oral changes and general changes of HIV-infected patients with their CD4 count. Materials and Methods: 124 patients were selected, and after taking their informed consent, they were subjected to detailed history taking and thorough clinical examination. Specific oral lesions and general physical changes were recorded. Every patient was subjected to laboratory investigation for CD4 count. All these findings were tabulated. The clinical observation and laboratory findings were subjected to critical analysis and correlated. Statistical test, i.e. Student′s " t" test, was applied and objective conclusions were drawn. Result: Out of 124 patients, 40 had oral candidiasis, 6 had oral hairy leukoplakia, 12 had periodontal disease, 20 had xerostomia, 30 had melanin pigmentation, while 4 had HSV2, and atypical ulceration. Out of 40 patients with oral candidiasis, 28 patients had CD4 count 500 cell/mm 3 . Oral hairy leukoplakia occurred in equal proportions in group A and B. These periodontal diseases were more commonly in group B; xerostomia and melanin pigmentation was equally seen in group A and B. Conclusion: Oral candidiasis, oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis are specific oral indicators which will definitely suggest to the dental surgeon that the disease is running a rapid downhill course and due to this the oral physician is in a position to raise a suspicion and alert the general physician regarding the declining immune status of patient.

  20. Manifestations of tuberculosis in HIV/AIDS patients and its relationship with CD4 count

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    Ajay Jaryal

    2011-01-01

    Full Text Available Background: HIV/AIDS pandemic is responsible for the resurgence of TB worldwide, resulting in increased morbidity and mortality. HIV and Mycobacterium tuberculosis have a synergistic interaction; each propagates progression of the other. Coinfection with HIV infection leads to difficulties in both the diagnosis and treatment of tuberculosis, increase risk of death, treatment failure and relapse. Objective: The aim of the present study is to study the clinical, radiological profile of pulmonary and extrapulmonary tuberculosis (EPTB in HIV-seropositive patients and their relationship to CD4 counts. Materials and Methods: It was a prospective study conducted over a period of 1 year in the department of medicine, Indira Gandhi Medical College, Shimla. We examined 87 HIV-infected patients with associated tuberculosis recruited from the department of medicine and antiretroviral center and were subjected to thorough clinical examination, X-ray chest, tuberculin testing and sputum examination for AFB and necessary relevant investigations for EPTB. Results: Most common affected age group was 31-40 years. EPTB is the commonest form of TB in our study detected in 65 patients. Commonest EPTB was CNS tuberculosis. Disseminated tuberculosis was only found in patient with CD4 count less than 200/cmm. Majority of lymph node TB was diagnosed by fine needle aspiration cytology (FNAC examination. All patients with AFB-positive lymph node had CD4 count below 200/cum. Conclusions: The results of this study provide information regarding the various forms of TB and their presentation in HIV-infected persons. Early diagnosis of tuberculosis and prompt institution of antitubercular treatment (ATT reduces mortality and morbidity significantly. In resource-poor areas, the diagnosis can be established with cytological/biochemical analysis of fluid, histopathological examination and ZN staining of tissue coupled with radiological features and response to ATT. Therefore

  1. Auditing national HIV guidelines and policies: The United Kingdom CD4 Surveillance Scheme.

    Science.gov (United States)

    Brown, Alison E; Kall, Meaghan M; Smith, Ruth D; Yin, Zheng; Hunter, Alan; Hunter, Alan; Delpech, Valerie C

    2012-01-01

    The United Kingdom's CD4 surveillance scheme monitors CD4 cell counts among HIV patients and is a national resource for HIV surveillance. It has driven public health policy and allowed auditing of national HIV testing, treatment and care guidelines. WE DEMONSTRATE ITS UTILITY THROUGH FOUR EXAMPLE OUTPUTS: median CD4 count at HIV diagnosis; late HIV diagnosis and short-term mortality; the timing of first CD4 count to indicate entry into HIV care; and the proportion of patients with CD4 counts auditing of policies and guidelines. These routine surveillance outputs can be generated at national and local levels to drive and monitor public health policy and prevention efforts.

  2. Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway.

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    Seema M Thayil

    Full Text Available Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC(2155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01. Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.

  3. 1-D position sensitive single carrier semiconductor detectors

    International Nuclear Information System (INIS)

    Zhong He; Knoll, G.F.; Wehe, D.K.; Rojeski, R.; Mastrangelo, C.H.; Hammig, M.; Barrett, C.; Uritani, A.

    1996-01-01

    A single polarity charge sensing method has been studied using coplanar electrodes on 5 mm cubes of CdZnTe γ-ray detectors. This method can ameliorate the hole trapping problem of room-temperature semiconductor detectors. Our experimental results confirm that the energy resolution is dramatically improved compared with that obtained using the conventional readout method, but is still about an order of magnitude worse than the theoretical limit. A method to obtain the γ-ray interaction depth between the cathode and the anode is presented here. This technique could be used to correct for the electron trapping as a function of distance from the coplanar electrodes. Experimental results showed that a position resolution of about 0.9 mm FWHM at 122 keV can be obtained. These results will be of interest in the design of higher performance room-temperature semiconductor γ-ray detectors. (orig.)

  4. Short communication: Longitudinal changes in peripheral blood NK cells during the first year of HIV-1 Infection in CD4Low and CD4High patient groups.

    Science.gov (United States)

    Jiao, Yanmei; Song, Jingjing; Zhang, Yonghong; Li, Wei; Zhang, Tong; Qi, Shwan M; Wu, Hao

    2015-02-01

    Natural killer (NK) cells may modulate the pathogenesis of primary HIV-1 infection. However, the relationship between the number and function of NK cells during an acute HIV-1 infection and HIV-1 disease progression remains to be elucidated. In this study, we enrolled two distinct patient groups. One group progressed to where their CD4 cell counts fell below 200 cells/μl within 2 years (CD4Low group), while the CD4 cell counts of the other group remained above 500 cells/μl for over 2 years (CD4High group). We compared the number and function of NK cells during the first year of HIV-1 infection between the two distinct groups. We found that the number of total NK cells and the number of cells in the CD56(dim)CD16(pos) subset rapidly decreased in both groups during early HIV-1 infection. The absolute number of total NK cells and CD56(dim)CD16(pos) NK cells was significantly higher in the CD4High group when compared to the CD4Low group during the first month of infection. No significant difference between the numbers of CD56(bright)CD16(neg) NK cells of the two groups was observed. However, more CD56(neg)CD16(pos) NK cells were found in the CD4Low group than in the CD4High group. We also found that NK cell function increased within the first 3 months of HIV-1 infection in the CD4High group and then exhibited a decreasing trend. However, in the CD4Low group, NK cell function did not increase significantly within the first 3 months of HIV-1 infection but then gradually increased. We concluded, therefore, that robust NK functioning cells that are present during an acute HIV-1 infection might be beneficial in controlling HIV-1 disease progression.

  5. Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets.

    Science.gov (United States)

    Ryan, John F; Hovde, Rachel; Glanville, Jacob; Lyu, Shu-Chen; Ji, Xuhuai; Gupta, Sheena; Tibshirani, Robert J; Jay, David C; Boyd, Scott D; Chinthrajah, R Sharon; Davis, Mark M; Galli, Stephen J; Maecker, Holden T; Nadeau, Kari C

    2016-03-01

    Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

  6. Single-frequency, single-receiver terrestrial and spaceborne point positioning

    Science.gov (United States)

    Beran, Tomas

    High-accuracy, point positioning has been an attractive research topic in the GPS community for a number of years. The overall quality of precise point positioning results is also dependent on the quality of the GPS measurements and the user's processing software. Dual-frequency, geodetic-quality GPS receivers are routinely used both in static and kinematic applications for high-accuracy point positioning. However, use of low-cost, single-frequency GPS receivers in similar applications creates a challenge because of difficulty of handling the ionosphere, multipath and other measurement error sources. Potential use of such receivers to provide horizontal positioning accuracies of a few decimetres, and vertical accuracies of less than two metres, will be examined in this dissertation. Practical applications of post-processed, high-accuracy, single-frequency point positioning include a myriad of terrestrial and space-borne applications, where the size and cost of the GPS unit is an issue. The processing technique uses pseudorange and time-differenced carrier-phase measurements in a sequential least-squares filter. In developing the approach, different techniques were investigated. Ionospheric delay grid maps are used to remove the bulk of the ionospheric error, while tropospheric error is handled by a prediction model. Pseudorange multipath errors are mitigated by means of stochastic modelling and carrier-phase cycle slips are detected and corrupted measurements are removed in a quality-control algorithm. The technique was first tested on L1 measurements extracted from datasets from static, high-quality GPS receivers. Accuracies better than two-decimetres in horizontal components (northing and easting r.m.s.), and three-decimetre accuracies in the vertical component (up-component r.m.s.), were obtained. A test dataset from a stationary low-cost GPS receiver has been processed to demonstrate the difference in data quality. Positioning results obtained are worse than

  7. CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression

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    Luyan Mu

    2017-11-01

    Full Text Available BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA recurred as DA, DA recurred as glioblastomas (GBM, and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors. Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS (HR = 4.199, 95% CI 1.522–11.584, p = 0.006.ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3

  8. Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells.

    Science.gov (United States)

    Fazal, Nadeem; Shelip, Alla; Alzahrani, Alhusain J

    2013-01-01

    After scald burn-injury, the intestinal immune system responds to maintain immune balance. In this regard CD4+T cells in Gut-Associated Lymphoid Tissues (GALT), like mesenteric lymph nodes (MLN) and Peyer's patches (PP) respond to avoid immune suppression following major injury such as burn. Therefore, we hypothesized that the gut CD4+T cells become dysfunctional and turn the immune homeostasis towards depression of CD4+ T cell-mediated adaptive immune responses. In the current study we show down regulation of mucosal CD4+ T cell proliferation, IL-2 production and cell surface marker expression of mucosal CD4+ T cells moving towards suppressive-type. Acute burn-injury lead to up-regulation of regulatory marker (CD25+), down regulation of adhesion (CD62L, CD11a) and homing receptor (CD49d) expression, and up-regulation of negative co-stimulatory (CTLA-4) molecule. Moreover, CD4+CD25+ T cells of intestinal origin showed resistance to spontaneous as well as induced apoptosis that may contribute to suppression of effector CD4+ T cells. Furthermore, gut CD4+CD25+ T cells obtained from burn-injured animals were able to down-regulate naïve CD4+ T cell proliferation following adoptive transfer of burn-injured CD4+CD25+ T cells into sham control animals, without any significant effect on cell surface activation markers. Together, these data demonstrate that the intestinal CD4+ T cells evolve a strategy to promote suppressive CD4+ T cell effector responses, as evidenced by enhanced CD4+CD25+ T cells, up-regulated CTLA-4 expression, reduced IL-2 production, tendency towards diminished apoptosis of suppressive CD4+ T cells, and thus lose their natural ability to regulate immune homeostasis following acute burn-injury and prevent immune paralysis.

  9. Technical performance evaluation of the MyT4 point of care technology for CD4+ T cell enumeration.

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    Matilu Mwau

    Full Text Available Though absolute CD4+ T cell enumeration is the primary gateway to antiretroviral therapy initiation for HIV-positive patients in all developing countries, patient access to this critical diagnostic test is relatively poor. We technically evaluated the performance of a newly developed point-of-care CD4+ T cell technology, the MyT4, compared with conventional CD4+ T cell testing technologies.Over 250 HIV-positive patients were consecutively enrolled and their blood tested on the MyT4, BD FACSCalibur, and BD FACSCount.Compared with the BD FACSCount, the MyT4 had an r2 of 0.7269 and a mean bias of -23.37 cells/µl. Compared with the BD FACSCalibur, the MyT4 had an r2 of 0.5825 and a mean bias of -46.58 cells/µl. Kenya currently uses a CD4+ T cell test threshold of 350 cells/µl to determine patient eligibility for antiretroviral therapy. At this threshold, the MyT4 had a sensitivity of 95.3% (95% CI: 88.4-98.7% and a specificity of 87.9% (95% CI: 82.3-92.3% compared with the BD FACSCount and sensitivity and specificity of 88.2% (95% CI: 79.4-94.2% and 84.2% (95% CI: 78.2-89.2%, respectively, compared with the BD FACSCalibur. Finally, the MyT4 had a coefficient of variation of 12.80% compared with 14.03% for the BD FACSCalibur.We conclude that the MyT4 performed well at the current 350 cells/µl ART initiation eligibility threshold when used by lower cadres of health care facility staff in rural clinics compared to conventional CD4+ T cell technologies.

  10. IFNA-AS1 regulates CD4+T cell activation in myasthenia gravis though HLA-DRB1.

    Science.gov (United States)

    Luo, Mengchuan; Liu, Xiaofang; Meng, Huanyu; Xu, Liqun; Li, Yi; Li, Zhibin; Liu, Chang; Luo, Yue-Bei; Hu, Bo; Xue, Yuanyuan; Liu, Yu; Luo, Zhaohui; Yang, Huan

    2017-10-01

    Abnormal CD4 + T cell activation is known to play roles in the pathogenesis of myasthenia gravis (MG). However, little is known about the mechanisms underlying the roles of lncRNAs in regulating CD4 + T cell. In this study, we discovered that the lncRNA IFNG-AS1 is abnormally expressed in MG patients associated with quantitative myasthenia gravis (QMG) and the positive anti-AchR Ab levels patients. IFNG-AS1 influenced Th1/Treg cell proliferation and regulated the expression levels of their transcription factors in an experimental autoimmune myasthenia gravis (EAMG)model. IFNG-AS1 could reduce the expression of HLA-DRB and HLA-DOB and they had a negative correlation in MG. Furthermore IFNG-AS1 influenced the expression levels of CD40L and CD4 + T cells activation in MG patient partly depend on effecting the HLA-DRB1 expression. It suggests that IFNG-AS1 may be involved in CD4 + T cell-mediated immune responses in MG. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals

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    Satou Yorifumi

    2012-05-01

    Full Text Available Abstract Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4+ T cells. Infection of CD4+ T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4+ T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4+ T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4+ T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC, 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP, 10 patients with adult T-cell leukemia (ATL, and 10 healthy donors. The frequency of FoxP3+ cells in CD4+ T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4+ T cells that were FoxP3+. The CD4+FoxP3+ T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3+ T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the Treg associated molecules CTLA-4 and GITR were decreased in CD4+FoxP3+ T cells. Further we characterized FoxP3+CD4+ T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA−FoxP3low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3+ cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression

  12. Statins Increase the Frequency of Circulating CD4+FOXP3+ Regulatory T Cells in Healthy Individuals

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    Ana Lucía Rodríguez-Perea

    2015-01-01

    Full Text Available Statins have been shown to modulate the number and the suppressive function of CD4+FOXP3+ T cells (Treg in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4+ T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c, suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

  13. Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells

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    Khoury Gabriela

    2011-10-01

    Full Text Available Abstract Background We recently described that HIV latent infection can be established in vitro following incubation of resting CD4+ T-cells with chemokines that bind to CCR7. The main aim of this study was to fully define the post-integration blocks to virus replication in this model of CCL19-induced HIV latency. Results High levels of integrated HIV DNA but low production of reverse transcriptase (RT was found in CCL19-treated CD4+ T-cells infected with either wild type (WT NL4.3 or single round envelope deleted NL4.3 pseudotyped virus (NL4.3- Δenv. Supernatants from CCL19-treated cells infected with either WT NL4.3 or NL4.3- Δenv did not induce luciferase expression in TZM-bl cells, and there was no expression of intracellular p24. Following infection of CCL19-treated CD4+ T-cells with NL4.3 with enhanced green fluorescent protein (EGFP inserted into the nef open reading frame (NL4.3- Δnef-EGFP, there was no EGFP expression detected. These data are consistent with non-productive latent infection of CCL19-treated infected CD4+ T-cells. Treatment of cells with phytohemagluttinin (PHA/IL-2 or CCL19, prior to infection with WT NL4.3, resulted in a mean fold change in unspliced (US RNA at day 4 compared to day 0 of 21.2 and 1.1 respectively (p = 0.01; n = 5, and the mean expression of multiply spliced (MS RNA was 56,000, and 5,000 copies/million cells respectively (p = 0.01; n = 5. In CCL19-treated infected CD4+ T-cells, MS-RNA was detected in the nucleus and not in the cytoplasm; in contrast to PHA/IL-2 activated infected cells where MS RNA was detected in both. Virus could be recovered from CCL19-treated infected CD4+ T-cells following mitogen stimulation (with PHA and phorbyl myristate acetate (PMA as well as TNFα, IL-7, prostratin and vorinostat. Conclusions In this model of CCL19-induced HIV latency, we demonstrate HIV integration without spontaneous production of infectious virus, detection of MS RNA in the nucleus only, and the

  14. Micro-magnet arrays for specific single bacterial cell positioning

    Energy Technology Data Exchange (ETDEWEB)

    Pivetal, Jérémy, E-mail: jeremy.piv@netcmail.com [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Royet, David [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Ciuta, Georgeta [Univ. Grenoble Alpes, Inst NEEL, F-38042 Grenoble (France); CNRS, Inst NEEL, F-38042 Grenoble (France); Frenea-Robin, Marie [Université de Lyon, Université Lyon 1, CNRS UMR 5005, Laboratoire Ampère, F-69622 Villeurbanne (France); Haddour, Naoufel [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France); Dempsey, Nora M. [Univ. Grenoble Alpes, Inst NEEL, F-38042 Grenoble (France); CNRS, Inst NEEL, F-38042 Grenoble (France); Dumas-Bouchiat, Frédéric [Univ Limoges, CNRS, SPCTS UMR 7513, 12 Rue Atlantis, F-87068 Limoges (France); Simonet, Pascal [Ecole Centrale de Lyon, CNRS UMR 5005, Laboratoire Ampère, F-69134 Écully (France)

    2015-04-15

    In various contexts such as pathogen detection or analysis of microbial diversity where cellular heterogeneity must be taken into account, there is a growing need for tools and methods that enable microbiologists to analyze bacterial cells individually. One of the main challenges in the development of new platforms for single cell studies is to perform precise cell positioning, but the ability to specifically target cells is also important in many applications. In this work, we report the development of new strategies to selectively trap single bacterial cells upon large arrays, based on the use of micro-magnets. Escherichia coli bacteria were used to demonstrate magnetically driven bacterial cell organization. In order to provide a flexible approach adaptable to several applications in the field of microbiology, cells were magnetically and specifically labeled using two different strategies, namely immunomagnetic labeling and magnetic in situ hybridization. Results show that centimeter-sized arrays of targeted, isolated bacteria can be successfully created upon the surface of a flat magnetically patterned hard magnetic film. Efforts are now being directed towards the integration of a detection tool to provide a complete micro-system device for a variety of microbiological applications. - Highlights: 1.We report a new approach to selectively micropattern bacterial cells individually upon micro-magnet arrays. 2.Permanent micro-magnets of a size approaching that of bacteria could be fabricated using a Thermo-Magnetic Patterning process. 3.Bacterial cells were labeled using two different magnetic labeling strategies providing flexible approach adaptable to several applications in the field of microbiology.

  15. Crystal Structure of HIV-1 Primary Receptor CD4 i Complex with a Potent Antiviral Antibody

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, M.M.; Hong, X.; Seaman, M.S.; Rits-Vollock, S.p Kao, C.Y.; Ho, D.D.; Chen, B.

    2010-06-18

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 {angstrom} resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  16. HIV-1/HSV-2 co-infected adults in early HIV-1 infection have elevated CD4+ T cell counts.

    Directory of Open Access Journals (Sweden)

    Jason D Barbour

    2007-10-01

    Full Text Available HIV-1 is often acquired in the presence of pre-existing co-infections, such as Herpes Simplex Virus 2 (HSV-2. We examined the impact of HSV-2 status at the time of HIV-1 acquisition for its impact on subsequent clinical course, and total CD4+ T cell phenotypes.We assessed the relationship of HSV-1/HSV-2 co-infection status on CD4+ T cell counts and HIV-1 RNA levels over time prior in a cohort of 186 treatment naïve adults identified during early HIV-1 infection. We assessed the activation and differentiation state of total CD4+ T cells at study entry by HSV-2 status.Of 186 recently HIV-1 infected persons, 101 (54% were sero-positive for HSV-2. There was no difference in initial CD8+ T cell count, or differences between the groups for age, gender, or race based on HSV-2 status. Persons with HIV-1/HSV-2 co-infection sustained higher CD4+ T cell counts over time (+69 cells/ul greater (SD = 33.7, p = 0.04 than those with HIV-1 infection alone (Figure 1, after adjustment for HIV-1 RNA levels (-57 cells per 1 log(10 higher HIV-1 RNA, p<0.0001. We did not observe a relationship between HSV-2 infection status with plasma HIV-1 RNA levels over time. HSV-2 acquisition after HIV-1 acquisition had no impact on CD4+ count or viral load. We did not detect differences in CD4+ T cell activation or differentiation state by HSV-2+ status.We observed no effect of HSV-2 status on viral load. However, we did observe that treatment naïve, recently HIV-1 infected adults co-infected with HSV-2+ at the time of HIV-1 acquisition had higher CD4+ T cell counts over time. If verified in other cohorts, this result poses a striking paradox, and its public health implications are not immediately clear.

  17. The T-cell accessory molecule CD4 recognizes a monomorphic determinant on isolated Ia

    DEFF Research Database (Denmark)

    Gay, D; Buus, S; Pasternak, J

    1988-01-01

    The membrane protein CD4 is commonly found on mature T cells specific for antigen in association with class II major histocompatibility complex (MHC; Ia) proteins. This correlation has led to the suggestion that CD4 binds to a monomorphic region of the Ia molecule on the antigen-presenting cell...... proteins into a planar membrane system, we show that different Ia molecules can greatly enhance the ability of a CD4+ but not a CD4- variant of this class I-restricted T hybrid to respond to isolated class I molecules. T-cell responses can be strongly augmented by the concurrent expression of CD4 on the T...... cell and any of four different Ia proteins on planar membranes, thus supporting the idea that CD4 binds to a monomorphic region of the Ia molecule and increases the avidity with which the T cell can interact with its target....

  18. Bystander CD4+ T lymphocytes survive in HIV-infected human lymphoid tissue

    Science.gov (United States)

    Grivel, Jean-Charles; Biancotto, Angelique; Ito, Yoshinori; Lima, Rosangela G.; Margolis, Leonid B.

    2003-01-01

    HIV infection is associated with depletion of CD4(+) T cells. The mechanisms of this phenomenon remain to be understood. In particular, it remains controversial whether and to what extent uninfected ("bystander") CD4(+) T cells die in HIV-infected individuals. We address this question using a system of human lymphoid tissue ex vivo. Tissue blocks were inoculated with HIV-1. After productive infection was established, they were treated with the reverse transcriptase inhibitor nevirapine to protect from infection those CD4(+) T cells that had not yet been infected. These CD4(+) T cells residing in HIV-infected tissue are by definition bystanders. Our results demonstrate that after nevirapine application the number of bystander CD4(+) T cells is conserved. Thus, in the context of HIV-infected human lymphoid tissue, productive HIV infection kills infected cells but is not sufficient to cause the death of a significant number of uninfected CD4(+) T cells.

  19. Genetic subspecies diversity of the chimpanzee CD4 virus-receptor gene

    DEFF Research Database (Denmark)

    Hvilsom, Christina; Carlsen, Frands; Siegismund, Hans R

    2008-01-01

    Chimpanzees are naturally and asymptomatically infected by simian immunodeficiency virus (SIV). Pathogenic properties of SIV/HIV vary and differences in susceptibility and pathogenicity of SIV/HIV depend in part on host-specific factors such as virus-receptor/co-receptor interactions. Since CD4...... plays a primary role in virus binding and since SIVcpz have been found only in two African chimpanzee subspecies, we characterized the genetic diversity of CD4 receptors in all four recognized subspecies of chimpanzees. We found noticeable variation in the first variable region V1 of CD4 and in intron...... six among the subspecies of chimpanzees. We found the CD4 receptor to be conserved in individuals belonging to the P. t. verus subspecies and divergent from the other three subspecies, which harbored highly variable CD4 receptors. The CD4 receptor of chimpanzees differed from that of humans. We...

  20. Production of Autoantibodies in Chronic Hepatitis B Virus Infection Is Associated with the Augmented Function of Blood CXCR5+CD4+ T Cells.

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    Yu Lei

    Full Text Available T follicular helper cells (Tfh provide help to B cells to support their activation, expansion and differentiation. However, the role of Tfh cells in chronic HBV infection is poorly defined. The aim of this research was to examine the function of Tfh cells and whether they are involved in HBV related disease. Blood CXCR5+CD4+T cells and B cells in 85 patients with chronic HBV infection (HBV patients and health controls (HC were examined by flow cytometry. The molecule expression in blood CXCR5+CD4+ T cells was detected by real-time PCR. Blood CXCR5+CD4+ T cells and B cells were co-cultured and the production of Ig and cytokines was detected by ELISA. Autoantibodies were detected by indirect immunofluorescence and immunospot assay. We found that blood CXCR5+CD4+ T cells in patients with chronic HBV infection (HBV patients expressed higher level of activation related molecules and cytokines than that from health controls (HC.In HBV patients, the frequency of blood CXCR5+CD4+ T cells was significantly correlated with serum ALT and AST. We also found that blood CXCR5+CD4+ T cells from HBV patients could induce B cells to secret higher level of immunoglobulin than that from HC. Several autoantibodies, including ANA, ss-A, ss-B, Scl-70, Jo-1, ect, were indeed positive in 65% HBV patients. Among HBV patients, expression of function related molecules was significantly higher in blood CXCR5+CD4+ T cells from patients with autoantibodies than that without autoantibodies. Our research indicated that blood CXCR5+CD4+ T cells from HBV patients were over activated and show augmented capacity to help B cells for antibody secreting, which might correlated with liver inflammation and the production of autoantibodies in extrahepatic manifestations.

  1. Evaluation of the Association between CD4, CD8 and CD25 Cell Counts and SLE in Active Disease and in Remission.

    Science.gov (United States)

    Sonawale, Archana; Bohara, Vinay; Bichile, L S

    2017-04-01

    To evaluate the correlation between the levels of CD4, CD8 and CD25 cells and SLE disease in active phase and in remission. A total of 25 SLE patients, aged between 18-60 years, and fulfilling the ACR criteria with preferential Renal and CNS involvement were included in this study. Baseline CD4/CD8 and CD25 counts, lab parameters etc were conducted. Approximately at the end of 6 months with the settlement of the disease activity blood sample was drawn for the CD4, CD8 and CD25 counts and other lab parameters. ESR showed a statistical significant decrease while the SLEDAI score and proteinuria showed a decreasing trend as the patients underwent remission. The C3 showed an increasing trend, while the C4 showed more or less a stable pattern. Rise in %CD4 and %CD25 count was statistically significant. There was negative correlation between % CD4 count and SLEDAI score, while positive correlation between % CD25 count and SLEDAI score. %CD4 count is a sensitive, specific, reliable and valid marker of active disease in SLE and can be used to follow disease activity. %CD25 count can also be used as a marker to follow disease activity.

  2. Association between CD8 T-cell subsets and CD4/CD8 ratio with HS-CRP level in HIV-infected patients on antiretroviral therapy

    Science.gov (United States)

    Isabela, S.; Nugroho, A.; Harijanto, P. N.

    2018-03-01

    Due to improved access and adherence to antiretroviral therapy (ART), most HIV-infected persons worldwide are predicted to live longer. Nowadays the cause of death for most HIV-infected persons has changed to serious non-AIDS events (SNAEs) which is due to low-grade viremia. HIV patients with ART who had undergone CD4 cell count above 500/uL and there is an increase in hs-CRP despite an undetectable viral load. Some conditions CD8 cells count do not decrease with CD4 cells repairs. We researched in Prof Kandou General Hospital with a total sample of 35 HIV patients who had received ART with the level of CD4>350/uL. CD8 levels, CD4/CD8 ratio, and hs-CRP were assessed. This research is analytic descriptive with cross-sectional study design and analysis uses Spearman correlation. The mean CD8 during the study was 1291.8 (IQR 319-2610cells/uL), the mean ratio of CD4:CD8 was 0.57 (IQR 0.16-1.24) and median hs-CRP is 2.18 (IQR 0.3-6.6mg/dL). There was a significant positive correlation between CD8 and increased hs-CRP (r=0.369, p<0.05). There was a negative correlation between CD4/CD8 ratio and hs-CRP (r=-0.370, p<0.05).

  3. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion

    International Nuclear Information System (INIS)

    Thomas, Elaine R.; Dunfee, Rebecca L.; Stanton, Jennifer; Bogdan, Derek; Taylor, Joann; Kunstman, Kevin; Bell, Jeanne E.; Wolinsky, Steven M.; Gabuzda, Dana

    2007-01-01

    HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion

  4. T cell antigen receptor expression by subsets of Ly-2-L3T4- (CD8-CD4-) thymocytes

    DEFF Research Database (Denmark)

    Wilson, A; Ewing, T; Owens, T

    1988-01-01

    The V beta 8-specific mAb F23.1 and KJ16 were used as fluorescent stains to test for TCR expression on the surface of subpopulations of early, CD4-CD8- (L3T4-Ly-2-) thymocytes from adult CBA mice. A surprisingly high proportion (27%) of Ly-2-L3T4- thymocytes were strongly F23.1 and KJ16 positive...

  5. Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells☆

    OpenAIRE

    Fazal, Nadeem; Shelip, Alla; Alzahrani, Alhusain J.

    2013-01-01

    After scald burn-injury, the intestinal immune system responds to maintain immune balance. In this regard CD4+T cells in Gut-Associated Lymphoid Tissues (GALT), like mesenteric lymph nodes (MLN) and Peyer's patches (PP) respond to avoid immune suppression following major injury such as burn. Therefore, we hypothesized that the gut CD4+T cells become dysfunctional and turn the immune homeostasis towards depression of CD4+ T cell-mediated adaptive immune responses. In the current study we show ...

  6. Enteroantigen-presenting B cells efficiently stimulate CD4(+) T cells in vitro

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Kristensen, Nanna Ny; Claesson, Mogens Helweg

    2011-01-01

    Presentation of enterobacterial antigens by antigen-presenting cells and activation of enteroantigen-specific CD4(+) T cells are considered crucial steps in inflammatory bowel disease (IBD) pathology. The detrimental effects of such CD4(+) T cells have been thoroughly demonstrated in models...... of colitis. Also, we have previously established an in vitro assay where murine enteroantigen-specific colitogenic CD4(+) CD25(-) T cells are activated by splenocytes pulsed with an enterobacterial extract....

  7. A DNA vaccine encoding multiple HIV CD4 epitopes elicits vigorous polyfunctional, long-lived CD4+ and CD8+ T cell responses.

    Directory of Open Access Journals (Sweden)

    Daniela Santoro Rosa

    Full Text Available T-cell based vaccines against HIV have the goal of limiting both transmission and disease progression by inducing broad and functionally relevant T cell responses. Moreover, polyfunctional and long-lived specific memory T cells have been associated to vaccine-induced protection. CD4(+ T cells are important for the generation and maintenance of functional CD8(+ cytotoxic T cells. We have recently developed a DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18, capable of eliciting broad CD4(+ T cell responses in multiple HLA class II transgenic mice. Here, we evaluated the breadth and functional profile of HIVBr18-induced immune responses in BALB/c mice. Immunized mice displayed high-magnitude, broad CD4(+/CD8(+ T cell responses, and 8/18 vaccine-encoded peptides were recognized. In addition, HIVBr18 immunization was able to induce polyfunctional CD4(+ and CD8(+ T cells that proliferate and produce any two cytokines (IFNγ/TNFα, IFNγ/IL-2 or TNFα/IL-2 simultaneously in response to HIV-1 peptides. For CD4(+ T cells exclusively, we also detected cells that proliferate and produce all three tested cytokines simultaneously (IFNγ/TNFα/IL-2. The vaccine also generated long-lived central and effector memory CD4(+ T cells, a desirable feature for T-cell based vaccines. By virtue of inducing broad, polyfunctional and long-lived T cell responses against conserved CD4(+ T cell epitopes, combined administration of this vaccine concept may provide sustained help for CD8(+ T cells and antibody responses- elicited by other HIV immunogens.

  8. Improvement in CD4 lymphocyte count in HIV-Reiter's syndrome after treatment with sulfasalazine.

    Science.gov (United States)

    Disla, E; Rhim, H R; Reddy, A; Taranta, A

    1994-04-01

    To describe an observed improvement in CD4 lymphocytes in patients with Reiter's syndrome (RS) and human immunodeficiency virus (HIV) infection, after treatment with sulfasalazine (SFSZ). METHODS . Care series. We analyzed CD4 lymphocyte counts in 4 consecutive patients with RS and HIV disease before and after treatment with SFSZ. CD4+ lymphocyte counts increased from a mean of 315 +/- 179 before treatment to 542 +/- 231 x 10(6)/l on followup (p < 0.03), in the absence of antiretroviral therapy. The significance of these observations is discussed. Treatment of RS with SFSZ in HIV disease appears to be associated with an improvement in CD4 count.

  9. Combination effect on HIV infection in vitro of soluble CD4 and HIV-neutralizing antibodies

    DEFF Research Database (Denmark)

    Hansen, J E; Sørensen, A M; Olofsson, S

    1994-01-01

    In combination with HIV gp120 V3-loop antibody, two carbohydrate specific neutralizing antibodies (83D4 and 2G12) had a synergistic neutralizing effect on HIV infection. However, sCD4 and an antibody which blocks gp 120/CD4 binding (1B1) both displayed antagonism.......In combination with HIV gp120 V3-loop antibody, two carbohydrate specific neutralizing antibodies (83D4 and 2G12) had a synergistic neutralizing effect on HIV infection. However, sCD4 and an antibody which blocks gp 120/CD4 binding (1B1) both displayed antagonism....

  10. Regulatory function of cytomegalovirus-specific CD4+CD27-CD28- T cells

    International Nuclear Information System (INIS)

    Tovar-Salazar, Adriana; Patterson-Bartlett, Julie; Jesser, Renee; Weinberg, Adriana

    2010-01-01

    CMV infection is characterized by high of frequencies of CD27 - CD28 - T cells. Here we demonstrate that CMV-specific CD4 + CD27 - CD28 - cells are regulatory T cells (T R ). CD4 + CD27 - CD28 - cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose-dependent fashion. Compared with the entire CMV-stimulated CD4 + T-cell population, higher proportions of CD4 + CD27 - CD28 - T R expressed FoxP3, TGFβ, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, Fas-L and GITR-L. CMV-CD4 + CD27 - CD28 - T R expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4 + CD27 - CD28 - T R significantly decreased after granzyme B or TGFβ inhibition. The CMV-CD4 + CD27 - CD28 - T R of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4 + CD27 - CD28 - T R . The CMV-CD4 + CD27 - CD28 - T R may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.

  11. The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy

    Science.gov (United States)

    Polese, Barbara; Gridelet, Virginie; Araklioti, Eleni; Martens, Henri; Perrier d’Hauterive, Sophie; Geenen, Vincent

    2014-01-01

    Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse. PMID

  12. Effect of highly active anti-retroviral therapy on CD3+/CD4+/CD8+ T lymphocyte counts in HIV seropositive Kashmiri patients: a follow up study.

    Science.gov (United States)

    Shah, Zafar A; Rasool, Roohi; Siddiqi, Mushtaq A

    2007-07-01

    Antiretroviral therapy has played an important role in improving the quality of life and extending the life span of HIV positive patients. In the present study 17 naive HIV positive patients out of a total of 23 positive cases from local population who had absolute CD4+ counts below 300 were given ARV therapy and followed for 1 year. The patients showed an overall improvement in CD4+T lymphocyte counts at one year survival. The values of CD3+ & CD8+ T lymphocytes also changed as expected.

  13. Demonstration of strong enterobacterial reactivity of CD4+CD25- T cells from conventional and germ-free mice which is counter-regulated by CD4+CD25+ T cells

    DEFF Research Database (Denmark)

    Gad, Monika; Pedersen, Anders Elm; Kristensen, Nanna N

    2004-01-01

    Unfractionated CD4+ T cells from the gut-associated lymphoid tissue (GALT) and peripheral lymph nodes are unresponsive when exposed to enterobacterial antigens in vitro. Under similar conditions, CD4+ T cells depleted in vivo or in vitro of CD4+CD25+ T cells proliferate extensively. The CD4+CD25- T...

  14. IDENTIFICATION OF BACTERIA CAUSING DIARRHOEA IN HIV/AIDS PATIENTS AND ITS CORRELATION WITH CD4 COUNT

    Directory of Open Access Journals (Sweden)

    Anand Premanand

    2016-05-01

    Full Text Available BACKGROUND The number of HIV-positive patients is increasing in India. Data on the prevalence of diarrhoea and the spectrum of bacteria responsible for diarrhoea in HIV- positive patients is lacking in our area. The identification of enteric pathogens in patients with HIV/AIDS is important because an increasing array of therapeutic regimens is becoming available to treat many of these infections. Thus, an attempt is done to elucidate the associations between causative bacteria of acute and chronic diarrhoea and CD4 count. METHODS Stool specimens were obtained over a period of eighteen months from HIV infected adults with diarrhoea presenting to Shri B M Patil Medical College Hospital and Research Centre, Vijayapura. In all patients with diarrhoea, stool specimens were examined by microscopy and cultures to identify bacterial pathogens and blood sample was analysed for CD4 count. RESULTS A total of 80 individuals were enrolled in this study. Cases included 46 males and 34 females. Among the cases, maximum subjects were found to be in the age group of 30-40 years in which 23 (62.2% were males and 14 (37.8% were females. 56 had acute and 24 had chronic diarrhoea. The percentages of bacteria isolated were 5 (8.9% in acute and 16 (66.7% in chronic diarrhoea respectively. The most common bacteria isolated was E. Coli (17.5% followed by Klebsiella (5% and Shigella Sps (3.75%. Patients with chronic diarrhoea had lower CD4 cell counts. The maximum bacterial isolation was in the patients whose CD4 cell counts were below 200 cells/mm3. CONCLUSION Bacterial isolation was most strongly associated with low CD4 counts and chronic diarrhoea. E. coli was isolated maximum among all the bacteria in the HIV patients. Over two-thirds of diarrhoeal episodes were undiagnosed, suggesting that unidentified agents or primary HIV enteropathy are important causes of diarrhoea in this population. There is a strong negative association between duration of diarrhoea and CD4

  15. Evaluation of the FACSPresto, a New Point of Care Device for the Enumeration of CD4% and Absolute CD4+ T Cell Counts in HIV Infection.

    Directory of Open Access Journals (Sweden)

    Azure Tariro Makadzange

    Full Text Available Enumeration of CD4+ T lymphocytes is important for pre-ART disease staging and screening for opportunistic infections, however access to CD4 testing in resource limited settings is poor. Point of care (POC technologies can facilitate improved access to CD4 testing. We evaluated the analytical performance of a novel POC device the FACSPresto compared to the FACSCalibur as a reference standard and to the PIMA, a POC device in widespread use in sub-Saharan Africa.Specimens were obtained from 253 HIV infected adults. Venous blood samples were analyzed on the FACSPresto and the FACSCalibur, in a subset of 41 samples additional analysis was done on the PIMA.The absolute CD4 count results obtained on the FACSPresto were comparable to those on the FACSCalibur with low absolute (9.5cells/μl and relative bias (3.2%. Bias in CD4% values was also low (1.06% with a relative bias of 4.9%. The sensitivity was lower at a CD4 count threshold of ≤350cells/μl compared with ≤500cells/μl (84.9% vs. 92.8% resulting in a high upward misclassification rate at low CD4 counts. Specificity at thresholds of ≤350cells/μl and ≤500cells/μl were 96.6% and 96.8% respectively. The PIMA had a high absolute (-68.6cells/μl and relative bias (-10.5% when compared with the FACSCalibur. At thresholds of ≤350cells/μl and ≤500cells/μl the sensitivity was 100% and 95.5% respectively; specificity was 85.7% and 84.2% respectively. The coefficients of repeatability were 4.13%, 5.29% and 9.8% respectively.The analytic performance of the FACSPresto against the reference standard was very good with better agreement and precision than the PIMA. The FACSPresto had comparable sensitivity at a threshold of 500 cells/μl and better specificity than the PIMA. However the FACSPresto showed reduced sensitivity at low CD4 count thresholds.The FACSPresto can be reliably used as a POC device for enumerating absolute CD4 count and CD4% values.

  16. Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

    Directory of Open Access Journals (Sweden)

    Weihong Zeng

    2017-06-01

    Full Text Available Decidual CD4+ T (dCD4 T cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy.

  17. The influence of CD 4+t cells, hiv disease stage and zidovudine on hiv isolation in Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Carlos Brites

    1996-02-01

    Full Text Available HIV-l isolation was attempted on 72 individuais, including persons with knoum HIV infection and five without proven HIV infection but with indeterminate Western blot patterns, as well as on low-risk HIV seronegative persons. The ahility to detect HIV- 1 frorn culture supernatant by p24 antigen capture assay was evaluated by segregating patients by absolute CD4+ cell counts, clinicai stage of disease, p24 antigenemia and zidovudine use. The likelihood of a p24 positive HIV culture was highest among patients with CD4+ T-cell counts below 200/ul and patients with advanced clinical disease. Use of zidovudine did not affect the rate ofHIV positwity in cultures.

  18. McCoy cell line as a possible model containing CD4+ receptors for the study of HIV-1 replication

    Directory of Open Access Journals (Sweden)

    Nogueira Yeda L.

    2003-01-01

    Full Text Available Several studies have recently shown the use of recombinant rabies virus as potential vector-viral vaccine for HIV-1. The sequence homology between gp 120 and rabies virus glycoprotein has been reported. The McCoy cell line has therefore been used to show CD4+ or CD4+ like receptors. Samples of HIV-1 were isolated, when plasma of HIV-1 positive patients was inoculated in the McCoy cell line. The virus infection was then studied during successive virus passages. The proteins released in the extra cellular medium were checked for protein activity, by exposure to SDS Electrophoresis and blotting to nitro-cellulose filter, then reacting with sera of HIV positive and negative patients. Successive passages were performed, and showed viral replication, membrane permeabilization, the syncytium formation, and the cellular lysis (cytopathic effect. Flow cytometry analysis shows clear evidence that CD4+ receptors are present in this cell line, which enhances the likelihood of easy isolation and replication of HIV. The results observed allow the use of this cell line as a possible model for isolating HIV, as well as for carrying out studies of the dynamics of viral infection in several situations, including exposure to drugs in pharmacological studies, and possibly studies and analyses of the immune response in vaccine therapies.

  19. HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeirão Preto, Brazil

    Directory of Open Access Journals (Sweden)

    Andre Minhoto Lanca

    2012-02-01

    Full Text Available While human immunodeficiency virus (HIV-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1 over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm³ [standard deviation (SD = 99] and a mean viral load of 5.09 log10 copies/mL (SD = 0.49. The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno[clinical20%] algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05. Moreover, higher false-positive rates (FPR values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001. Transmitted drug resistance mutations, documented in 3/41 (7.3% cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, naÏve HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

  20. The influence of CD 4+t cells, hiv disease stage and zidovudine on hiv isolation in Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Carlos Brites

    1996-02-01

    Full Text Available HIV-l isolation was attempted on 72 individuais, including persons with knoum HIV infection and five without proven HIV infection but with indeterminate Western blot patterns, as well as on low-risk HIV seronegative persons. The ahility to detect HIV- 1 frorn culture supernatant by p24 antigen capture assay was evaluated by segregating patients by absolute CD4+ cell counts, clinicai stage of disease, p24 antigenemia and zidovudine use. The likelihood of a p24 positive HIV culture was highest among patients with CD4+ T-cell counts below 200/ul and patients with advanced clinical disease. Use of zidovudine did not affect the rate ofHIV positwity in cultures.Tentativa de isolamento do vírus tipo 1 da imunodeficiência adquirida (VIH-1 foi realizada em 72 indivíduos sendo 51 pacientes com sorologia positiva para o VIH-1, confirmada por Western blot; 5 doadores de sangue com padrão indeterminado ao Western blot; 3 indivíduos com diagnóstico clínico de AIDS, porém com sorologia negativa, e 13 profissionais de saúde soronegativos. Os pacientes foram estratificados de acordo com a contagem de células CD4+, estágio clínico , antigenemia (p24 e uso de zidovudine. As culturas para o VIH-1 foram positivas em 45/50 (90% tentativas. Houve uma correlação inversa entre o número de células CD4+ e a freqüência de isolamento do VIH-1. As culturas foram positivas em 84% dos indivíduos com CD4+ <200, contra 48% d positividade naqueles com contagem de célula CD4+ acima deste valor. O uso de zidovudine não interferiu na positividade das culturas. Concluímo. que a sensibilidade dos métodos de culture qualitativo e quantitativo é similar para a detecção do VIH-1. A taxa de positividade das culturas não foi afetada pelo uso prévio de zidovudine, mas foi diretamente proporcional ao grau de imunodeficiência dos pacientes.

  1. Trigger-happy resident memory CD4(+) T cells inhabit the human lungs

    NARCIS (Netherlands)

    Oja, A. E.; Piet, B.; Helbig, C.; Stark, R.; van der Zwan, D.; Blaauwgeers, H.; Remmerswaal, E. B. M.; Amsen, D.; Jonkers, R. E.; Moerland, P. D.; Nolte, M. A.; van Lier, R. A. W.; Hombrink, P.

    2017-01-01

    Resident memory T cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. Although lung CD8(+) TRM have been extensively characterized, the properties of CD4(+) TRM remain unclear. Here we determined the transcriptional signature of CD4(+) TRM,

  2. In situ depletion of CD4(+) T cells in human skin by Zanolimumab

    DEFF Research Database (Denmark)

    Villadsen, L.S.; Skov, L.; Dam, T.N.

    2007-01-01

    -driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis...

  3. Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure

    DEFF Research Database (Denmark)

    Schultze, Anna; Paredes, Roger; Sabin, Caroline

    2014-01-01

    mutations on CD4 slopes in patients undergoing episodes of viral failure. MATERIALS AND METHODS: Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test...

  4. The impact of pregnancy and menopause on CD4 lymphocyte counts in HIV-infected women

    NARCIS (Netherlands)

    van Benthem, Birgit H. B.; Vernazza, Pietro; Coutinho, Roel A.; Prins, Maria

    2002-01-01

    OBJECTIVES: To determine indirectly the effect of changes in levels of reproductive hormones on CD4 lymphocyte counts by investigating the impact of pregnancy and menopause on CD4 lymphocyte counts in HIV-infected women. METHODS: Participants were 382 women with a known interval of HIV

  5. Predictors of CD4+ lymphocyte count among HIV-Seropositive and ...

    African Journals Online (AJOL)

    ... the CD4+ lymphocyte count increased by about 16 cells/mm3 for each increment of 1000 WBC cells/mm3, while each 10 mm/hr increase in ESR was associated with a reduction of CD4+ lymphocyte count of about 8 cells/mm3. Conclusion: These results show that simple and inexpensive haematological indices cannot be ...

  6. Reactivity of naive CD4+CD25- T cells against gut microflora in healthy mice

    DEFF Research Database (Denmark)

    Gad, Monika; Lundsgaard, Dorthe; Kjellev, Stine

    2006-01-01

    We have previously shown that conventional as well as germ-free CD4+ T cells depleted of CD25+ cells from the gut-associated lymphoid tissue and the periphery proliferate specifically in response to enterobacterial antigen exposure whereas unfractionated CD4+ T cells are not reactive under...

  7. Inverted CD4+/CD8+ ratio associated with AIDS event and death in ...

    African Journals Online (AJOL)

    The current guidelines for the use of antiretroviral therapy in Nigeria places emphasis on the use of CD4+ enumeration to take decision of initiating antiretroviral therapy and HIV disease monitoring. CD4+ counts are known to be inherently inconsistent and therefore could be misleading. This study was undertaken to ...

  8. IFNγ-producing CD4+T lymphocytes: the double-edged swords in tuberculosis.

    Science.gov (United States)

    Kumar, Pawan

    2017-12-01

    IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb-coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB-IRIS and in Mtb-infected PD-1 -/- mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.

  9. HIV-specific CD4+ T cells and viremia: who's in control?

    NARCIS (Netherlands)

    Jansen, Christine A.; van Baarle, Debbie; Miedema, Frank

    2006-01-01

    It has been proposed that HIV-specific CD4+ T cells with a central memory phenotype might be involved in controlling HIV replication. Based on recent data (lack of protective effects of HIV-specific CD4+ T-cell responses in acutely infected patients undergoing treatment interruptions; loss of

  10. Inter- and intra-laboratory variability of CD4 cell counts in Swaziland ...

    African Journals Online (AJOL)

    The samples were further subdivided at each laboratory: one was run at 12 hours and the second at 24 hours after venepuncture. The results of absolute CD4 count and CD4 percentage testing were compared within (intra-laboratory) and between (inter-laboratory) laboratories. Results. Among 53 participants, the mean ...

  11. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells

    DEFF Research Database (Denmark)

    Baslund, B; Gregers, J; Nielsen, Claus Henrik

    2008-01-01

    To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.......To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells....

  12. predictors of cd4+ lymphocyte count among hiv-seropositive and hiv

    African Journals Online (AJOL)

    hi-tech

    2000-04-04

    Apr 4, 2000 ... abnormal programme of cell death(2). Consequently, there is progressive reduction in the number of CD4+ lymphocytes in HIV-infected individuals. Although the CD4+ lymphocyte count provides important prognostic information, determination of lymphocyte subsets requires resources and technical.

  13. Applying machine learning to predict patient-specific current CD 4 ...

    African Journals Online (AJOL)

    ... respectively, proving that a CD4 cell count measure may be accurately predicted using machine learning on genotype, viral load and time. Keywords: Human immunodeficiency virus (HIV), antigens, CD4, computational biology, artificial intelligence, data mining, pattern recognition. African Journal of Biotechnology Vol.

  14. Relaxation of adaptive evolution during the HIV-1 infection owing to reduction of CD4+ T cell counts.

    Directory of Open Access Journals (Sweden)

    Élcio Leal

    Full Text Available The first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. In order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. The diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection.Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N/d(S>1 was detected in the viruses within each host in all time points. In the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. In both patients X4 variants never reached high frequencies during infection time. The recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time.Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. The dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection.

  15. CD4+ and CD8+ T cells can act separately in tumour rejection after immunization with murine pneumotropic virus chimeric Her2/neu virus-like particles.

    Directory of Open Access Journals (Sweden)

    Kalle Andreasson

    Full Text Available BACKGROUND: Immunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained. METHODOLOGY AND RESULTS: During the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4-/-CD8-/- and CD4-/-, but not in CD8-/- mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNgamma response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge. CONCLUSION: Her2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together.

  16. CD4+ and CD8+ T cells can act separately in tumour rejection after immunization with murine pneumotropic virus chimeric Her2/neu virus-like particles.

    Science.gov (United States)

    Andreasson, Kalle; Eriksson, Mathilda; Tegerstedt, Karin; Ramqvist, Torbjörn; Dalianis, Tina

    2010-07-19

    Immunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs) prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained. During the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4-/-CD8-/- and CD4-/-, but not in CD8-/- mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNgamma response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge. Her2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together.

  17. CD4 T cell knockout does not protect against kidney injury and worsens cancer.

    Science.gov (United States)

    Ravichandran, Kameswaran; Wang, Qian; Ozkok, Abdullah; Jani, Alkesh; Li, Howard; He, Zhibin; Ljubanovic, Danica; Weiser-Evans, Mary C; Nemenoff, Raphael A; Edelstein, Charles L

    2016-04-01

    Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-α, mediators of AKI and fibrosis, in both cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer. A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 -/- mice had an impaired therapeutic effect of cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.

  18. CD4-independent use of the CCR5 receptor by sequential primary SIVsm isolates

    Directory of Open Access Journals (Sweden)

    Thorstensson Rigmor

    2007-07-01

    Full Text Available Abstract Background CD4-independence has been taken as a sign of a more open envelope structure that is more accessible to neutralizing antibodies and may confer altered cell tropism. In the present study, we analyzed SIVsm isolates for CD4-independent use of CCR5, mode of CCR5-use and macrophage tropism. The isolates have been collected sequentially from 13 experimentally infected cynomolgus macaques and have previously been shown to use CCR5 together with CD4. Furthermore, viruses obtained early after infection were neutralization sensitive, while neutralization resistance appeared already three months after infection in monkeys with progressive immunodeficiency. Results Depending whether isolated early or late in infection, two phenotypes of CD4-independent use of CCR5 could be observed. The inoculum virus (SIVsm isolate SMM-3 and reisolates obtained early in infection often showed a pronounced CD4-independence since virus production and/or syncytia induction could be detected directly in NP-2 cells expressing CCR5 but not CD4 (CD4-independent-HIGH. Conversely, late isolates were often more CD4-dependent in that productive infection in NP-2/CCR5 cells was in most cases weak and was revealed only after cocultivation of infected NP-2/CCR5 cells with peripheral blood mononuclear cells (CD4-independent-LOW. Considering neutralization sensitivity of these isolates, newly infected macaques often harbored virus populations with a CD4-independent-HIGH and neutralization sensitive phenotype that changed to a CD4-independent-LOW and neutralization resistant virus population in the course of infection. Phenotype changes occurred faster in progressor than long-term non-progressor macaques. The phenotypes were not reflected by macrophage tropism, since all isolates replicated efficiently in macrophages. Infection of cells expressing CCR5/CXCR4 chimeric receptors revealed that SIVsm used the CCR5 receptor in a different mode than HIV-1. Conclusion Our

  19. Household point of care CD4 testing and isoniazid preventive therapy initiation in a household TB contact tracing programme in two districts of South Africa.

    Science.gov (United States)

    Page-Shipp, Liesl; Lewis, James J; Velen, Kavindhran; Senoge, Sedikanelo; Zishiri, Elizabeth; Popane, Flora; Chihota, Violet N; Clark, Dave; Churchyard, Gavin J; Charalambous, Salome

    2018-01-01

    In South Africa, TB household contact tracing provides an opportunity for increased TB and HIV case finding. We aimed to determine the effect of two new potential interventions for TB contact tracing programmes: Point of Care CD4 (PoC CD4) on HIV linkage to care and household Isoniazid Preventive Therapy (IPT) provision on uptake and retention of IPT. A pragmatic, three-arm, cluster-randomized trial was undertaken. TB Household contacts were randomised to 3 arms: 1) Standard of Care TB and HIV testing (SOC); 2) SOC with POC CD4 for those testing HIV positive; 3) SOC with POC CD4 and IPT for eligible household members. Linkage to care within 90 days was assessed either through patient visits (at 10 weeks and 6 months) or via telephonic contact. 2,243 index TB patients and 3,012 contacts (64,3% female, median age 30 years) were enrolled. On self-report, 26(1.2%) were currently receiving TB treatment and 1816 (60.3%) reported a prior HIV test. HIV testing uptake was 34.7% in the SoC arm, 40.2% in the PoC CD4 arm (RR1.16, CI 0.99-1.36, p-value = 0.060) and 39.9% in the PoC CD4 + HH-IPT arm (RR = 1.15, CI 0.99-1.35, p-value = 0.075). Linkage to care within 3 months was 30.8% in the SoC arm and 42.1% in the POC CD4 arms (RR 1.37; CI: 0.68-2.76, p-value = 0.382). 20/21 contacts (95.2%) initiated IPT in the PoC CD4 + HH-IPT arm, compared to 3/20 (15.0%) in the PoC CD4 arm (p = 0.004; p-value from Fisher's exact test TB with an overall yield of TB of 0.5% (95% CI: 0.3%, 0.8%). Household PoC CD4 testing and IPT initiation is feasible. There was only weak evidence that PoCCD4 led to a small increase in HCT uptake and no evidence for an increase in linkage-to-care. IPT initiation and completion was increased by the household intervention. Although feasible, these interventions had low impact due to the low uptake of HIV testing in households.

  20. Non-traditional CD4+CD25-CD69+ regulatory T cells are correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Zhao, Xiao-su; Wang, Xu-hua; Zhao, Xiang-yu; Chang, Ying-jun; Xu, Lan-ping; Zhang, Xiao-hui; Huang, Xiao-jun

    2014-07-01

    Non-traditional CD4+CD25-CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT). The frequency of CD4+CD25-CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion. The results showed that the frequency of CD4+CD25-CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25-CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion. This study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.

  1. Development and function of protective and pathologic memory CD4 T cells

    Directory of Open Access Journals (Sweden)

    Megan KL Macleod

    2015-09-01

    Full Text Available IImmunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

  2. In situ depletion of CD4(+) T cells in human skin by Zanolimumab

    DEFF Research Database (Denmark)

    Villadsen, L.S.; Skov, L.; Dam, T.N.

    2007-01-01

    CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease......-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis...... xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4...

  3. CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function

    Science.gov (United States)

    Bernstein, Helene B.; Wang, Guangwu; Plasterer, Mary C.; Zack, Jerome A.; Ramasastry, Parthasarathy; Mumenthaler, Shannon M.; Kitchen, Christina M. R.

    2009-01-01

    NK cells mediate the innate immune response, and HIV-infected individuals demonstrate altered NK cell phenotype and function. We find that CD4+ NK cells are susceptible to HIV infection; this could account for the NK cell dysfunction seen in HIV-infected individuals. CD4+ NK cells express CXCR4 and can be infected with X4-tropic viruses and some primary R5-utilizing viral isolates. Treatment with the CXCR4 ligands AMD3100 and SDF-1α partially blocks infection with X4-tropic virus, treatment with anti-CCL Igs upregulates CCR5 surface expression and enables infection with HIV-Bal. HIV infection of NK cells results in CD4 downregulation and the production of infectious virus. HIV-infected CD4+ NK cells mediate NK cell cytotoxicity, however, HIV infection is associated with decreased chemotaxis towards IL-16. Thus, HIV infection of CD4+ NK cells could account for the NK cell dysfunction observed in HIV-infected individuals. Furthermore infected NK cells could serve as a viral reservoir of HIV in vivo. PMID:19251297

  4. A novel differentiation pathway from CD4⁺ T cells to CD4⁻ T cells for maintaining immune system homeostasis.

    Science.gov (United States)

    Zhao, X; Sun, G; Sun, X; Tian, D; Liu, K; Liu, T; Cong, M; Xu, H; Li, X; Shi, W; Tian, Y; Yao, J; Guo, H; Zhang, D

    2016-04-14

    CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases.

  5. Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

    Directory of Open Access Journals (Sweden)

    C Scott Mahan

    2010-02-01

    Full Text Available Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone.This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3 and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB.Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period.TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.

  6. Immunity to experimental Salmonella typhimurium infections in rats. Transfer of immunity with primed CD4+CD25high and CD4+CD25low T lymphocytes

    DEFF Research Database (Denmark)

    Thygesen, P; Brandt, L; Jørgensen, T

    1994-01-01

    M and IgG antibodies. Cell sorting revealed that 2/3 of the primed CD4+ T lymphocytes expressed high levels of CD25. Cell transfer revealed that both CD25high and CD25low expression populations could induce immunity against a lethal dose of S. typhimurium, whilst antibody analysis revealed that antibody...... levels were not correlated with protection against S. typhimurium infections, although it showed that a higher and more persistent level of specific IgG antibodies was produced in animals receiving the CD4+CD25high fraction. It is concluded that 10(4) primed CD4+ T lymphocytes can induce immunity......The protective effect of primed CD4+ T lymphocytes against a lethal dose of 10(8) viable Salmonella typhimurium was studied in Lewis rats. Primed CD4+ T lymphocytes were obtained by inoculating Lewis rats with a non-lethal dose of 10(6) viable S. typhimurium. Four weeks after the infection, spleen...

  7. Immunity to experimental Salmonella typhimurium infections in rats. Transfer of immunity with primed CD4+CD25high and CD4+CD25low T lymphocytes

    DEFF Research Database (Denmark)

    Thygesen, P; Brandt, L; Jørgensen, T

    1994-01-01

    levels were not correlated with protection against S. typhimurium infections, although it showed that a higher and more persistent level of specific IgG antibodies was produced in animals receiving the CD4+CD25high fraction. It is concluded that 10(4) primed CD4+ T lymphocytes can induce immunity......The protective effect of primed CD4+ T lymphocytes against a lethal dose of 10(8) viable Salmonella typhimurium was studied in Lewis rats. Primed CD4+ T lymphocytes were obtained by inoculating Lewis rats with a non-lethal dose of 10(6) viable S. typhimurium. Four weeks after the infection, spleen...... by a fluorescence-activated cell sorter. Untreated Lewis rats were injected with 10(4) different primed CD4+ T-cell populations 24 h prior to the lethal dose of 10(8) viable S. typhimurium. Blood samples were drawn from the orbital plexus 1, 2, 3, and 4 weeks after the infection, and analysed for specific Ig...

  8. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection

    Directory of Open Access Journals (Sweden)

    Deborah M. Brown

    2016-03-01

    Full Text Available CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL play a role in chronic, as well as, acute infections such as influenza A virus (IAV infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections such as HIV, mouse pox, murine gamma herpes virus, CMV, EBV and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and anti-tumor immunity through their ability to acquire perforin mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other anti-viral and anti-tumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell mediated immune protection against heterosubtypic IAV infection.

  9. CD4 + T cells promote renal cell carcinoma proliferation via modulating YBX1.

    Science.gov (United States)

    Wang, Yong; Wang, Yiting; Xu, Liang; Lu, Xianqi; Fu, Donghe; Su, Jing; Geng, Hua; Qin, Guoxuan; Chen, Ruibing; Quan, Changyi; Niu, Yuanjie; Yue, Dan

    2018-02-01

    Renal cell carcinoma (RCC) is a common urologic tumor and the third leading cause of death among urological tumors. Recent studies demonstrate that RCC tumors are more heavily infiltrated by lymphocytes than other cancers. However, the exact roles played by CD4 + T cells in RCC proliferation remain unknown. In this study, we cocultured RCC cells with CD4 + T cells. Stable knockdown of YBX1 in RCC cells was constructed. The effects of CD4 + T cells, TGFβ1 and YBX1 on RCC cells were investigated using cell viability assays. In situ RCC nude mouse model was used to observe the tumor growth. The potential mechanisms of CD4 + T cells and YBX1 in RCC cells proliferation were explored by qRT-PCR and western blot. Expression of CD4, Foxp3 and TGFβ1 in RCC were quantified by immunohistochemical staining. The results indicated that CD4, Foxp3 and TGFβ1 were significantly up-regulated in RCC tissues. Human clinical sample and in vitro cell lines studies showed that RCC cells had better capacity than its surrounding normal kidney epithelial cells to recruit the CD4 + T cells. In vivo mouse model studies were consistent with the results by in vitro cell lines studies showing infiltrating T cells enhanced RCC cell proliferation. qRT-PCR and western blot exhibited that CD4 + T cells could enhance RCC cell proliferation via activating YBX1/HIF2α signaling pathway. Furthermore, CD4 + T cells functioned through inducing TGFβ1 expression. In a word, infiltrating CD4 + T cells promoted TGFβ1 expression in both RCC and T cells and regulated RCC cells proliferation via modulating TGFβ1/YBX1/ HIF2α signals. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells

    Science.gov (United States)

    Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye; Koreth, John; Kim, Haesook T.; Paul, Nicole E.; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana C.; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Blazar, Bruce R.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    CD4+ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+ CD4Tregs and CD56brightCD16– NK cells in vitro. Preferential activation and expansion of Helios+ CD4Tregs and CD56brightCD16– NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios– CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+ T cells and CD8+ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+ CD4Tregs and CD56bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo. PMID:27812545

  11. Positive impedance humidity sensors via single-component materials

    OpenAIRE

    Qian, Jingwen; Peng, Zhijian; Shen, Zhenguang; Zhao, Zengying; Zhang, Guoliang; Fu, Xiuli

    2016-01-01

    Resistivity-type humidity sensors have been investigated with great interest due to the increasing demands in industry, agriculture and daily life. To date, most of the available humidity sensors have been fabricated based on negative humidity impedance, in which the electrical resistance decreases as the humidity increases, and only several carbon composites have been reported to present positive humidity impedance. However, here we fabricate positive impedance humidity sensors only via sing...

  12. Alternative Th17 and CD4+ CD25+ FoxP3+ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy.

    Science.gov (United States)

    Almeida, M S; Lorena, V M B; Medeiros, C de A; Junior, W O; Cavalcanti, M da G A M; Martins, S M; de Morais, C N L

    2018-04-01

    Immune homeostasis has been suggested to play an important role in the clinical evolution of chronic Chagas disease; however, the immunopathologic factors involved have not been fully elucidated. Therefore, our study aimed to analyse the frequency of CD4 + CD25 + FoxP3 + cells, classic Th17 cells, alternative Th17 cells and IL-17 + B cells from peripheral blood of chronic cardiac patients after in vitro stimulation with Trypanosoma cruzi soluble EPI antigen. Patients were selected and classified according to clinical evaluation of cardiac involvement: mild, B1 (CARD1) (n = 20) and severe, C (CARD2) (n = 11). Patients with the indeterminate form of CD were included as the control group A (IND) (n = 17). Blood samples were collected and cultured in the presence of EPI antigen. Cells frequency and median fluorescence intensity (MFI) were obtained by flow cytometry. Our results showed that only CD4 + CD25 + FoxP3 + , CD4 + CD25 high FoxP3 + , CD4 + IL-17 + IFN-γ - and CD4 + IL-17 + IFN-γ + cells are more frequent in patients with severe cardiac disease and correlate with worse global cardiac function. However, while indeterminate patients demonstrated a positive correlation between CD4 + CD25 + FoxP3 + and CD4 + IL-17 + IFN-γ - Th17 cells, this relationship was not observed in cardiac patients. IL-17 expression by Th17 cells and B cells correlated with disease progression. Altogether our results suggest that the clinical progression of Chagas cardiomyopathy involves worsening of inflammation and impairment of immunoregulatory mechanisms. © 2018 The Foundation for the Scandinavian Journal of Immunology.

  13. Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-analysis.

    Science.gov (United States)

    Shen, Yongchun; Pang, Caishuang; Wu, Yanqiu; Li, Diandian; Wan, Chun; Liao, Zenglin; Yang, Ting; Chen, Lei; Wen, Fuqiang

    2016-06-01

    The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deeks's funnel plot was used to detect publication bias. Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64-0.75); specificity, 0.83 (95%CI 0.78-0.86); PLR, 4.04 (95%CI 3.13-5.20); NLR, 0.36 (95%CI 0.30-0.44); and DOR, 11.17 (95%CI 7.31-17.07). The area under the SROC curve was 0.84 (95%CI 0.81-0.87). There was no evidence of publication bias. Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Gene variation in IL-7 receptor (IL-7R)α affects IL-7R response in CD4+ T cells in HIV-infected individuals

    DEFF Research Database (Denmark)

    Hartling, Hans Jakob; Ryder, Lars P.; Ullum, Henrik

    2017-01-01

    Optimal CD4+ T cell recovery after initiating combination antiretroviral treatment (cART) in HIV infection reduces risk of morbidity and mortality. T-allele homozygosity (‘TT’) in the single nucleotide polymorphism, rs6897932(C/T), in the IL-7 receptor α (IL-7RA) is associated with faster CD4+ T...... cell recovery after cART initiation compared to C-allele homozygosity in rs6897932 (‘CC’). However, underlying mechanisms are unknown. We aimed to examine potential mechanisms explaining the association between rs6897932 and CD4+ T cell recovery. Ten ‘TT’ and 10 ‘CC’ HIV-infected individuals matched...... on gender, age, and nadir and current CD4+ T cell counts were included in a cross-sectional study. ‘TT’ individuals had higher proportion of CD4+ T cells expressing pSTAT5 compared to ‘CC’ individuals after stimulating with IL-7, especially when co-stimulated with soluble IL7-RA (sIL-7RA). Furthermore, ‘TT...

  15. Mycobacterium avium and purified protein derivative-specific cytotoxicity mediated by CD4+ lymphocytes from healthy HIV-seropositive and-seronegative individuals

    DEFF Research Database (Denmark)

    Ravn, P; Pedersen, B K

    1996-01-01

    HIV is the greatest single risk factor for the development of tuberculosis. Diseases caused by M. tuberculosis and mycobacteria are the most common opportunistic infections in HIV-infected persons, which may stem from a functional defect of the CD4+ T-cell-mediated killing of macrophages harborin...

  16. Polymorphism in interleukin-7 receptor α gene is associated with faster CD4 T-cell recovery after initiation of combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Hartling, Hans J; Thørner, Lise W; Erikstrup, Christian

    2014-01-01

    OBJECTIVES: To investigate single-nucleotide polymorphisms (SNPs) in the gene encoding interleukin-7 receptor α (IL7RA) as predictors for CD4⁺ T-cell change after initiation of combination antiretroviral therapy (cART) in HIV-infected whites. DESIGN: SNPs in IL7RA were determined in the Danish HIV...

  17. Increased sensitivity of CD4+ T-effector cells to CD4+CD25+ Treg suppression compensates for reduced Treg number in asymptomatic HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Georgina Thorborn

    Full Text Available BACKGROUND: In HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue. METHODOLOGY/PRINCIPAL FINDINGS: A classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25- effectors cells (E following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27 and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14. HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047. Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25- effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV. CONCLUSIONS/SIGNIFICANCE: Together, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection.

  18. Analysis of HIV disease burden by calculating the percentages of patients with CD4 counts <100 cells/µL across 52 districts reveals hot spots for intensified commitment to programmatic support

    Directory of Open Access Journals (Sweden)

    Lindi Marie Coetzee

    2017-06-01

    Full Text Available Background. South Africa (SA’s Comprehensive HIV and AIDS Care, Management and Treatment (CCMT programme has reduced new HIV infections and HIV-related deaths. In spite of progress made, 11.2% of South Africans (4.02 million were living with HIV in 2015. Objective. The National Health Laboratory Service (NHLS in SA performs CD4 testing in support of the CCMT programme and collates data through the NHLS Corporate Data Warehouse. The objective of this study was to assess the distribution of CD4 counts 500 cells/µL (as an HIV-positive ‘wellness’ indicator. Methods. CD4 data were extracted for the financial years 2010/11 and 2014/15, according to the district where the test was ordered, for predefined CD4 ranges. National and provincial averages of CD4 counts 500 cells/µL were calculated. Data were analysed using Stata 12 and mapping was done with ArcGIS software, reporting percentages of CD4 counts 500 cells/µL by district. Results. The national average percentage of patients with CD4 counts 500 cells/µL (by 57%. District-by-district analysis showed that in 2010/11, 44/52 districts had >10% of CD4 samples with counts 500 cells/µL. In contrast, in 2014/15, the highest percentages of CD4 counts 500 cells/µL were also noted. Conclusions. The percentages of CD4 counts <100 cells/µL highlighted here reveal districts with positive change suggestive of programmatic improvements, and also highlight districts requiring local interventions to achieve the UNAIDS/SA National Department of Health 90-90-90 HIV treatment goals. The study further underscores the value of using NHLS laboratory data, an underutilised national resource, to leverage laboratory test data to enable a more comprehensive understanding of programme-specific health indicators.

  19. Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery.

    Science.gov (United States)

    Hermans, Sabine M; van Leth, Frank; Kiragga, Agnes N; Hoepelman, Andy I M; Lange, Joep M A; Manabe, Yukari C

    2012-12-01

    To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution. © 2012 Blackwell Publishing Ltd.

  20. A quality management systems approach for CD4 testing in resource-poor settings.

    Science.gov (United States)

    Westerman, Larry E; Kohatsu, Luciana; Ortiz, Astrid; McClain, Bernice; Kaplan, Jonathan; Spira, Thomas; Marston, Barbara; Jani, Ilesh V; Nkengasong, John; Parsons, Linda M

    2010-10-01

    Quality assurance (QA) is a systematic process to monitor and improve clinical laboratory practices. The fundamental components of a laboratory QA program include providing a functional and safe laboratory environment, trained and competent personnel, maintained equipment, adequate supplies and reagents, testing of appropriate specimens, internal monitoring of quality, accurate reporting, and external quality assessments. These components are necessary to provide accurate and precise CD4 T-cell counts, an essential test to evaluate start of and monitor effectiveness of antiretroviral therapy for HIV-infected patients. In recent years, CD4 testing has expanded dramatically in resource-limited settings. Information on a CD4 QA program as described in this article will provide guidelines not only for clinical laboratory staff but also for managers of programs responsible for supporting CD4 testing. All agencies involved in implementing CD4 testing must understand the needs of the laboratory and provide advocacy, guidance, and financial support to established CD4 testing sites and programs. This article describes and explains the procedures that must be put in place to provide reliable CD4 determinations in a variety of settings.

  1. The genotype of early-transmitting HIV gp120s promotes α (4 β(7-reactivity, revealing α (4 β(7 +/CD4+ T cells as key targets in mucosal transmission.

    Directory of Open Access Journals (Sweden)

    Fatima Nawaz

    2011-02-01

    Full Text Available Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α₄β₇/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin-α₄β₇. High-affinity for integrin α₄β₇, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α₄β₇ affinity is mediated by sequences encoded in gp120 V1/V2. α₄β₇-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α₄β₇+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s

  2. A study of anemia in human immunodeficiency virus patients: Estimating the prevalence, analyzing the causative effect of nutritional deficiencies, and correlating the degree of severity with CD4 cell counts

    Directory of Open Access Journals (Sweden)

    Ajay Panwar

    2016-01-01

    Full Text Available Background: Anemia is a common complication of human immunodeficiency virus (HIV infection. The role of iron, Vitamin B12, and folate deficiencies, which are otherwise most common causes of anemia, is not well-established in HIV patients. Several studies in India have shown that severe immunodeficiency is associated with higher grade of anemia, but correlation of CD4 cell counts with severity of anemia is not well-documented. Aims: The aims of the present study were: To estimate the point prevalence of anemia in HIV patients, to analyze the causative role of iron, Vitamin B12, and folate deficiencies in anemic HIV patients, and correlating the degree of severity of anemia with CD4 cell counts. Materials and Methods: This study was a cross-sectional study. The study group enrolled 103 consecutive HIV patients attending medical emergency, medical outpatient department, medical wards, and anti-retroviral therapy (ART center at a tertiary care medical center in North India. Study participation consisted of a single visit during which relevant data, including medical history, current medications, CD4 T-lymphocyte count, complete hemogram with red blood cell indices, peripheral smear picture, iron studies, serum Vitamin B12, serum folate and bone marrow studies, were recorded on a case report form. Anemia was classified according to the World Health Organization criteria. Data analysis was carried out using Microsoft Excel and Statistical Package for the Social Sciences software. Results: 86.4% (89/103 patients were found to be anemic. There was no significant difference in prevalence of anemia in ART-naive patients from those who were on ART (P > 0.05. Pearson′s correlation had shown a highly significant positive correlation of hemoglobin and CD4 cell counts in male patients (r = 0.418 as well as female patients (r = 0.565. Normocytic normochromic was the most common type of anemia in males (46% as well as females (42%. Significant iron deficiency

  3. Total lymphocyte count as a surrogate marker to predict CD4 count in human immunodeficiency virus-infected children: a retrospective evaluation.

    Science.gov (United States)

    Wang, Yuming; Li, Yuqian; Wang, Chongjian; Liang, Shuying; Guo, Jinling; Li, Zizhao; Zhang, Meixi; Li, Wenjie

    2012-01-01

    A retrospective study was conducted, and 576 human immunodeficiency virus-infected children with total lymphocyte count (TLC) and CD4 count were recruited from China. Spearman rank order correlation and receiver-operating characteristic were used. An overall positive correlation was noted between TLC and CD4 count (prehighly active antiretroviral therapy [pre-HAART], r = 0.789, 6 months of HAART, r = 0.642, 12 months of HAART, r = 0.691, P = 0.001). TLC ≤ 2600 cells/mm(3) predicted a CD4 count of ≤ 350 cells/mm(3) with 82.9% sensitivity, 79.6% specificity pre-HAART. Meanwhile, the optimum prediction for CD4 count of ≤ 350 cells/mm(3) was a TLC of ≤ 2400 cells/mm at 6 months (73.6% sensitivity and 74.1% specificity) and 12 months (81.7% sensitivity and 76.5% specificity) of HAART. TLC can be used as a surrogate marker for predicting CD4 count of human immunodeficiency virus-infected children before and during HAART in resource-limited countries.

  4. Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  5. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent.

    Directory of Open Access Journals (Sweden)

    Christine M Freeman

    Full Text Available Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry; by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent. Aberrant lung CD4+ T cells polarization appears to be common in advanced

  6. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent.

    Science.gov (United States)

    Freeman, Christine M; McCubbrey, Alexandra L; Crudgington, Sean; Nelson, Joshua; Martinez, Fernando J; Han, MeiLan K; Washko, George R; Chensue, Stephen W; Arenberg, Douglas A; Meldrum, Catherine A; McCloskey, Lisa; Curtis, Jeffrey L

    2014-01-01

    Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also

  7. The impact of HIV infection and CD4 cell count on the performance of an interferon gamma release assay in patients with pulmonary tuberculosis

    DEFF Research Database (Denmark)

    Aabye, Martine G.; Ravn, Pernille; PrayGod, George

    2009-01-01

    -out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV...... pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance. METHODOLOGY/PRINCIPAL FINDINGS: 161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT......-IT was positive in 74% (119/161; 95% CI: 67-81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion...

  8. Long-term Maintenance of CD4 T Cell Memory Responses to Malaria Antigens in Malian Children Coinfected with Schistosoma haematobium

    Directory of Open Access Journals (Sweden)

    Kirsten E. Lyke

    2018-02-01

    Full Text Available Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP Malian children, aged 4–8 years, are protected from malaria compared to matched schistosomiasis-negative (SN children. The effect of concomitant schistosomiasis upon acquisition of T cell memory is unknown. We examined antigen-specific T cell frequencies in 48 Malian children aged 4–14 to a pool of malaria blood stage antigens, and a pool of schistosomal antigens, at a time point during a malaria episode and at a convalescent time point ~6 months later, following cessation of malaria transmission. CD4+ T cell-derived memory responses, defined as one or more significant cytokine (IFN-γ, TNF-α, IL-2, and/or IL-17A responses, was measured to schistoma antigens in 18/23 SP children at one or both time points, compared to 4/23 SN children (P < 0.0001. At the time of malaria infection, 12/24 SN children and 15/23 SP children (P = 0.29 stimulated with malaria antigens demonstrated memory recall as defined by CD4-derived cytokine production. This compares to 7/23 SN children and 16/23 SP children (P = 0.009 at the convalescent timepoint. 46.2% of cytokine-producing CD4+ T cells expressed a single cytokine after stimulation with malaria antigen during the malaria episode. This fell to 40.9% at follow-up with a compensatory rise of multifunctional cytokine secretion over time, a phenomenon consistent with memory maturation. The majority (53.2–59.5% of responses derived from CD45RA−CD62L− effector memory T cells with little variation in the phenotype depending upon the time point or the study cohort. We conclude that detectable T cell memory responses can be measured against both malaria and schistosoma antigens and that the presence of Schistosoma haematobium may be associated with long-term maintenance of T memory to malaria.

  9. A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups.

    Science.gov (United States)

    Parathyras, John; Gebhardt, Stefan; Hillermann-Rebello, Renate; Grobbelaar, Nelis; Venter, Mauritz; Warnich, Louise

    2009-05-01

    South Africa, like many other Southern African countries, has one of the highest HIV infection rates in the world and many individuals consequently receive antiretroviral therapy (ART). However, knowledge regarding (i) the prevalence of functional single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes, and (ii) variance in pharmacotherapy both within and between different populations and ethnic groups is limited. The aim of this study was to determine whether selected polymorphisms in cytochrome P450 (CYP) genes (CYP2B6 and CYP3A4) and the multidrug-resistance 1 (ABCB1) gene underlie altered antiretroviral (ARV) drug response in two South African populations. DNA samples from 182 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity on ART were genotyped for the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in ABCB1. Univariate two-way analysis of variance (ANOVA) testing revealed no apparent effect of ethnicity on immune recovery (in terms of CD4-cell count) in response to ART. Univariate one-way ANOVA testing revealed a discernible effect of genotype on immune recovery in the cases of the T-129C (P=0.03) and G2677A (P<0.01) polymorphisms in the ABCB1 gene. This study serves as a basis for better understanding and possible prediction of pharmacogenetic risk profiles and drug response in individuals and ethnic groups in South Africa.

  10. Progressive multifocal leucoencephalopathy in a patient with idiopathic CD4+ lymphocytopenia.

    LENUS (Irish Health Repository)

    Moloney, F

    2012-03-01

    Progressive multifocal leucoencephalopathy (PML) is an opportunistic, demyelinating neurological disease caused by reactivation of the JC polyomavirus. PML occurs almost exclusively in immunosuppressed individuals, with only isolated case reports of PML occurring in patients without apparent immunosuppression. Idiopathic CD4+ lymohocytopenia (ICL) is a syndrome defined by the Centre for Disease Control and Prevention as a CD4+ count <300 cells\\/uL or <20% of total T cell count on >1 occasion, with no evidence of human immunodeficiency virus (HIV) infection, and the absence of other known immunodeficiency or therapy associated with lymphocytopenia. We describe a case of PML occurring in a patient with idiopathic CD4+ lymphocytopenia.

  11. Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice

    Directory of Open Access Journals (Sweden)

    Shahir Prajakta

    2011-05-01

    Full Text Available Abstract Back ground Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. Method In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. Results The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical compared to the normal lymphocytes. Greater percentage of

  12. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad

    2006-01-01

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  13. The endocrine milieu and CD4 T-lymphocyte polarization during pregnancy

    OpenAIRE

    Polese, Barbara; Gridelet, Virginie; Arakioti, Eleni; Martens, Henri; Perrier d'Hauterive, Sophie; Geenen, Vincent

    2014-01-01

    Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy...

  14. The endocrine milieu and CD4 T-lymphocyte polarisation during pregnancy

    OpenAIRE

    Barbara ePolese; Virginie eGridelet; Eleni eAraklioti; Henri Joseph Martens; Sophie ePerrier d'Hauterive; Vincent eGeenen

    2014-01-01

    Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and Th17 cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T-cell polarisation during pregnancy. We first foc...

  15. The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy

    OpenAIRE

    Polese, Barbara; Gridelet, Virginie; Araklioti, Eleni; Martens, Henri; Perrier d’Hauterive, Sophie; Geenen, Vincent

    2014-01-01

    Acceptance of the fetal semi-allograft by the mother’s immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy...

  16. Psychopatholgy, fundamental assumptions and CD-4 T lymphocyte ...

    African Journals Online (AJOL)

    Received: 06-07-2009. Accepted: 02-09-2009. Correspondence. Ms S Suliman. Department of Psychiatry, University of Stellenbosch and the MRC Unit ... For example, Farber et al. found that individuals who ascribed a more positive meaning to their illness also reported higher levels of psychological well-being and lower ...

  17. sCD4-17b bifunctional protein: Extremely broad and potent neutralization of HIV-1 Env pseudotyped viruses from genetically diverse primary isolates

    Directory of Open Access Journals (Sweden)

    Dey Barna

    2010-02-01

    recombinant forms AE and AG. The neutralization breadth and potency were superior to what have been reported for the broadly neutralizing monoclonal antibodies IgG b12, 2G12, 2F5, and 4E10. The activity of sCD4-17b was found to be similar against isogenic virus particles from infectious molecular clones derived either directly from the transfected producer cell line or after a single passage through PBMCs; this contrasted with the monoclonal antibodies, which were less potent against the PMBC-passaged viruses. Conclusions The results highlight the extremely potent and broad neutralizing activity of sCD4-17b against genetically diverse HIV-1 primary isolates. The bifunctional protein has potential applications for antiviral approaches to combat HIV infection.

  18. Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells.

    Science.gov (United States)

    Zhao, Ming; Liang, Gong-ping; Tang, Mei-ni; Luo, Shuang-yan; Zhang, Jing; Cheng, Wen-jing; Chan, Tak-mao; Lu, Qian-jin

    2012-05-01

    Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy

    DEFF Research Database (Denmark)

    De la Herrán-Arita, Alberto K; Kornum, Birgitte Rahbek; Mahlios, Josh

    2013-01-01

    the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4(+) T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association...

  20. T-cell reprogramming through targeted CD4-coreceptor and T-cell receptor expression on maturing thymocytes by latent Circoviridae family member porcine circovirus type 2 cell infections in the thymus.

    Science.gov (United States)

    Klausmann, Stefanie; Sydler, Titus; Summerfield, Artur; Lewis, Fraser I; Weilenmann, Roseline; Sidler, Xaver; Brugnera, Enrico

    2015-03-01

    Although porcine circovirus type 2 (PCV2)-associated diseases have been evaluated for known immune evasion strategies, the pathogenicity of these viruses remained concealed for decades. Surprisingly, the same viruses that cause panzootics in livestock are widespread in young, unaffected animals. Recently, evidence has emerged that circovirus-like viruses are also linked to complex diseases in humans, including children. We detected PCV2 genome-carrying cells in fetal pig thymi. To elucidate virus pathogenicity, we developed a new pig infection model by in vivo transfection of recombinant PCV2 and the immunosuppressant cofactor cyclosporine A. Using flow cytometry, immunofluorescence and fluorescence in situ hybridization, we found evidence that PCV2 dictates positive and negative selection of maturing T cells in the thymus. We show for the first time that PCV2-infected cells reside at the corticomedullary junction of the thymus. In diseased animals, we found polyclonal deletion of single positive cells (SPs) that may result from a loss of major histocompatibility complex class-II expression at the corticomedullary junction. The percentage of PCV2 antigen-presenting cells correlated with the degree of viremia and, in turn, the severity of the defect in thymocyte maturation. Moreover, the reversed T-cell receptor/CD4-coreceptor expression dichotomy on thymocytes at the CD4(+)CD8(interm) and CD4SP cell stage is viremia-dependent, resulting in a specific hypo-responsiveness of T-helper cells. We compare our results with the only other better-studied member of Circoviridae, chicken anemia virus. Our data show that PCV2 infection leads to thymocyte selection dysregulation, adding a valuable dimension to our understanding of virus pathogenicity.

  1. Molecular pathways regulating CD4(+) T cell differentiation, anergy and memory with implications for vaccines.

    Science.gov (United States)

    Ahlers, Jeffrey D; Belyakov, Igor M

    2010-10-01

    CD4(+) T cells occupy a central role in the induction and regulation of adaptive immune responses. Activated CD4(+) T helper (Th) cells exert immediate effector functions by producing cytokines and chemokines, providing help for the induction of CD8(+) cytotoxic T lymphocyte responses and memory, and providing help for immunoglobulin class switching, affinity maturation of antibody and B cell memory. Inherent in naïve CD4(+) T cells is the flexibility to adopt alternate lineage potentials, which depend upon regulatory mechanisms that change with tissue microenvironment and upon infection. Here, we discuss lineage instructive programs that regulate CD4(+) T cell differentiation and memory and how to translate this knowledge into vaccines and immunotherapies that promote protective immune responses. Published by Elsevier Ltd.

  2. Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis.

    Science.gov (United States)

    Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee; Barreira-Silva, Palmira; Behar, Samuel M

    2017-11-01

    Immunological memory is the key biological process that makes vaccines possible. Although tuberculosis vaccines elicit protective immunity in animals, few provide durable protection. To understand why protection is transient, we evaluated the ability of memory CD4+ T cells to expand, differentiate, and control Mycobacterium tuberculosis. Both naïve and memory CD4+ T cells initially proliferated exponentially, and the accumulation of memory T cells in the lung correlated with early bacterial control. However, later during infection, memory CD4+ T cell proliferation was curtailed and no protection was observed. We show that memory CD4+ T cells are first activated in the LN and their recruitment to the lung attenuates bacterial growth. However, their interaction with Mtb-infected macrophages does not promote continued proliferation. We conclude that a lack of sustained expansion by memory-derived T cells in the lung limits the durability of their protection, linking their slower expansion with transient protection in vaccinated mice.

  3. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.

    Directory of Open Access Journals (Sweden)

    Seung-Joo Lee

    2012-01-01

    Full Text Available Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

  4. Quantifying CD4/CCR5 Usage Efficiency of HIV-1 Env Using the Affinofile System.

    Science.gov (United States)

    Webb, Nicholas E; Lee, Benhur

    2016-01-01

    Entry of HIV-1 into target cells involves the interaction of the HIV envelope (Env) with both a primary receptor (CD4) and a coreceptor (CXCR4 or CCR5). The relative efficiency with which a particular Env uses these receptors is a major component of cellular tropism in the context of entry and is related to a variety of pathological Env phenotypes (Chikere et al. Virology 435:81-91, 2013). The protocols outlined in this chapter describe the use of the Affinofile system, a 293-based dual-inducible cell line that expresses up to 25 distinct combinations of CD4 and CCR5, as well as the associated Viral Entry Receptor Sensitivity Assay (VERSA) metrics used to summarize the CD4/CCR5-dependent infectivity results. This system allows for high-resolution profiling of CD4 and CCR5 usage efficiency in the context of unique viral phenotypes.

  5. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM cells which expand following virulent mycobacterial challenge.

    Directory of Open Access Journals (Sweden)

    Daryan A Kaveh

    Full Text Available To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM cells in vaccinated mice. These CD4+CD44(hiCD62L(loCD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM in the lung may represent a new generation of TB vaccines.

  6. IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

    DEFF Research Database (Denmark)

    Skov, S; Bonyhadi, M; Odum, Niels

    2000-01-01

    The cellular and humoral immune system is critically dependent upon CD40-CD154 (CD40 ligand) interactions between CD40 expressed on B cells, macrophages, and dendritic cells, and CD154 expressed primarily on CD4 T cells. Previous studies have shown that CD154 is transiently expressed on CD4 T cells...... of CD154 expression. This has significant impact on our understanding of the acquired immune response and may provide insight concerning the mechanisms underlying several immunological diseases....

  7. [Coreceptor function of CD4 in response to MHC class I molecule].

    Science.gov (United States)

    Zvezdova, E S; Grinenko, T S; Pobezinskaia, E L; Pobezinskiĭ, L A; Kazanskiĭ, D B

    2008-01-01

    Specificity of T cell receptor (TCR) and its interaction with coreceptor molecules play decisive role in successful passing of T lymphocytes via check-points during their development and finally determine the efficiency of adaptive immunity. Genes encoding alpha- and beta-chains of TCR hybridoma 1D1 have been cloned. The hybridoma 1D1 was established by the fusion of BWZ.36CD8alpha cell line with CD8+ memory cells specific to MHC class I H-2Kb molecule. Exploiting retroviral transduction of thymoma 4G4 cells with TCR genes and coreceptors CD4 and CD8, variants of this cell line expressing on the surface CD3/TCR complex and coreceptors, separately or simultaneously have been obtained. The main function of CD4 is stabilization of interaction between TCR and MHC class II molecule. Nevertheless, we have found that CD4 could successfully participate in the activation of transfectants via TCR specific to MHC class I molecule H-2Kb. Moreover, coreceptor CD4 dominates CDS, because the response of transfectants CD4+CD8+ is blocked by antibodies to CD4 and MHC Class II Ab molecule but not to coreceptor CD8. The response of CD4+ cells was not due to cross-reaction between TCR 1D1 with MHC class II molecules, because transfectants do not respond to splenocytes of H-2b knockouted mice with impaired assembly of TCR/beta2-microglobulin/peptide complexes resulting in their absence on the cell surphace. The effect of domination was not due to sequestration of kinase p56lck, because truncated CD4 with the loss of binding motif for p56lck remained functional in 4G4 cells. Results obtained can explain the number of features of intrathymic selection and represent experimental basis for development of new methods of cancer gene therapy.

  8. Increased expression of CD4 molecules on Jurkat cells mediated by human immunodeficiency virus tat protein.

    OpenAIRE

    Koka, P; Yunis, J; Passarelli, A L; Dubey, D P; Faller, D V; Ynis, E J

    1988-01-01

    The tat gene of the human immunodeficiency virus, tat-III, when introduced into T-lymphoblastoid Jurkat cells by a Moloney retroviral recombinant DNA vector expressed high levels of the functional tat protein as measured by the chloramphenicol acetyltransferase assay. Immunofluorescence analysis with CD4-specific monoclonal antibodies demonstrated that the cell surface levels of the CD4 antigen were increased by 5- to 10-fold in the tat-III-infected Jurkat cells. Cellular cytoplasmic RNA anal...

  9. Cell-contact-dependent activation of CD4+T cells by adhesion molecules on synovial fibroblasts.

    Science.gov (United States)

    Mori, Masato; Hashimoto, Motomu; Matsuo, Takashi; Fujii, Takao; Furu, Moritoshi; Ito, Hiromu; Yoshitomi, Hiroyuki; Hirose, Jun; Ito, Yoshinaga; Akizuki, Shuji; Nakashima, Ran; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Ohmura, Koichiro; Mimori, Tsuneyo

    2017-05-01

    To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4 +  T cells. Naïve CD4 +  T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4 +  T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4 +  T cells, CD161 +  or CD161 - naïve CD4 +  T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. SF enhanced naïve CD4 +  T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4 +  T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161 +  naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CD4 +  T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

  10. The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery

    Science.gov (United States)

    Sakaguchi, Shimon

    2003-01-01

    Naturally arising CD4+ regulatory T cells, which engage in the maintenance of immunologic self-tolerance, specifically express FOXP3, which encodes a transcription-repressor protein. Genetic defects in FOXP3 cause IPEX, an X-linked autoimmune/inflammatory syndrome. With FOXP3 as a specific marker for regulatory CD4+ T cells in humans, it is now possible to determine their origin and developmental pathway . PMID:14597756

  11. Regulation of CD4+ T-Cell Function by Membrane Cholesterol

    Science.gov (United States)

    2012-03-13

    pathogen immune evasion or possibly when a robust CD4 T-cell response is desired in response to vaccination. A potential target for regulating T-cell...Carcinogenesis 1998;19: 287-290. Rouse BT and Sehrawat S. Immunity and immunopathology to viruses : what decided the outcome? Nat Rev Immunol 2010;10:514...the Health Sciences 4301 Jones Bridge Road, Bethesda, Maryland 20814 The CD4 T helper cells play a central role in initiating immune

  12. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

    DEFF Research Database (Denmark)

    Grarup, N; Overvad, M; Sparsø, T

    2011-01-01

    A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432...

  13. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM cells in cattle naturally infected with bovine tuberculosis.

    Directory of Open Access Journals (Sweden)

    Adam O Whelan

    Full Text Available Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-γ, IL-2 and TNF-α. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2. Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-γ(+IL-2(+TNF-α(+ and IFN-γ(+ TNF-α(+ response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hiCD45RO(+CD62L(lo T-effector memory (T(EM phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future.

  14. Relationship between leptin levels and suppressed CD4 counts in HIV patients.

    Science.gov (United States)

    Al-Fadhli, Mariam; Saraya, Mohammad; Qasem, Jafar; Azizieh, Fawaz; Shahab, Shahab; Raghupathy, Raj

    2013-01-01

    To examine the relationship between serum leptin levels and suppression of CD4 count in HIV-infected individuals with highly active antiretroviral therapy (HAART). Thirty seropositive HIV male patients selected from the Infectious Disease Hospital were classified into two groups according to their immunological and virological response to HAART. The first group included 15 male patients with low viral load and low CD4 counts; the second included 15 male patients with low viral load and high CD4 counts. Morning serum leptin and tumor necrosis factor-α levels of HIV patients were measured and correlated with fasting serum insulin, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), HIV viral load and CD4 count. Serum leptin levels were significantly higher in patients with high CD4 counts than in patients with low CD4 counts (mean serum leptin level 47.3 vs. 10.9 ng/ml, respectively; p counts (r = 0.697; p count and correlated with fasting serum insulin and HOMA-IR, thereby indicating that HAART treatment could lead to decreased levels of leptin in HIV patients, which might lead to impaired immunological recovery. Copyright © 2012 S. Karger AG, Basel.

  15. Local and Systemic CD4+ T Cell Exhaustion Reverses with Clinical Resolution of Pulmonary Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Charlene Hawkins

    2017-01-01

    Full Text Available Investigation of the Th1 immune response in sarcoidosis CD4+ T cells has revealed reduced proliferative capacity and cytokine expression upon TCR stimulation. In other disease models, such cellular dysfunction has been associated with a step-wise, progressive loss of T cell function that results from chronic antigenic stimulation. T cell exhaustion is defined by decreased cytokine production upon TCR activation, decreased proliferation, increased expression of inhibitory cell surface receptors, and increased susceptibility to apoptosis. We characterized sarcoidosis CD4+ T cell immune function in systemic and local environments among subjects undergoing disease progression compared to those experiencing disease resolution. Spontaneous and TCR-stimulated Th1 cytokine expression and proliferation assays were performed in 53 sarcoidosis subjects and 30 healthy controls. PD-1 expression and apoptosis were assessed by flow cytometry. Compared to healthy controls, sarcoidosis CD4+ T cells demonstrated reductions in Th1 cytokine expression, proliferative capacity (p<0.05, enhanced apoptosis (p<0.01, and increased PD-1 expression (p<0.001. BAL-derived CD4+ T cells also demonstrated multiple facets of T cell exhaustion (p<0.05. Reversal of CD4+ T cell exhaustion was observed in subjects undergoing spontaneous resolution (p<0.05. Sarcoidosis CD4+ T cells exhibit loss of cellular function during progressive disease that follows the archetype of T cell exhaustion.

  16. CD4+ T cell effects on CD8+ T cell location defined using bioluminescence.

    Directory of Open Access Journals (Sweden)

    Mitra Azadniv

    2011-01-01

    Full Text Available T lymphocytes of the CD8+ class are critical in delivering cytotoxic function and in controlling viral and intracellular infections. These cells are "helped" by T lymphocytes of the CD4+ class, which facilitate their activation, clonal expansion, full differentiation and the persistence of memory. In this study we investigated the impact of CD4+ T cells on the location of CD8+ T cells, using antibody-mediated CD4+ T cell depletion and imaging the antigen-driven redistribution of bioluminescent CD8+ T cells in living mice. We documented that CD4+ T cells influence the biodistribution of CD8+ T cells, favoring their localization to abdominal lymph nodes. Flow cytometric analysis revealed that this was associated with an increase in the expression of specific integrins. The presence of CD4+ T cells at the time of initial CD8+ T cell activation also influences their biodistribution in the memory phase. Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells.

  17. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.

    Science.gov (United States)

    Kursar, Mischo; Bonhagen, Kerstin; Fensterle, Joachim; Köhler, Anne; Hurwitz, Robert; Kamradt, Thomas; Kaufmann, Stefan H E; Mittrücker, Hans-Willi

    2002-12-16

    CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

  18. Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Kim Julian A

    2004-11-01

    Full Text Available Abstract T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4+ and CD8+ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 108-fold numerical hyperexpansion of either the CD4+ or CD8+ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN cells were segregated to purify the CD62Llow subset, or the CD4+ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8+ subset, or IL-7 + IL-23 for the CD4+ subset. A broad repertoire of TCR Vβ families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8+ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4+ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8+ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4+ and CD8+ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.

  19. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing?

    Directory of Open Access Journals (Sweden)

    Kathrin Maly

    2015-01-01

    Full Text Available CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

  20. The effect of probiotics on CD4 counts among people living with HIV: a systematic review.

    Science.gov (United States)

    Miller, H; Ferris, R; Phelps, B R

    2016-06-01

    Probiotics are defined by the WHO as 'live microorganisms which when administered in adequate amounts confer a health benefit on the host'. Ongoing research has shown probiotics provide benefits to humans, including protection and restoration of the gastrointestinal and other mucosal tracts. As human immunodeficiency virus (HIV) activates gut-associated lymphoid tissue (GALT), several studies have investigated the effect of probiotics on CD4 cell count and related outcomes among those living with HIV. These studies are summarised here. Manuscripts were identified using the search terms 'probiotics', 'synbiotics', 'HIV', and 'CD4', and were reviewed for relevance and inclusion of CD4 count as an immunologic endpoint. Bibliographies of relevant manuscripts were also reviewed for additional studies matching inclusion and exclusion criteria. The search yielded 91 results; 13 included relevant outcomes. Seven of these studies produced beneficial CD4 outcomes, while the remaining 6 reported on insignificant beneficial or negative CD4 outcomes. The studies summarised here collectively suggest that daily consumption of probiotics over a prolonged period of time may improve CD4 count in people living with HIV.

  1. Scaffold protein JLP mediates TCR-initiated CD4+T cell activation and CD154 expression.

    Science.gov (United States)

    Yan, Qi; Yang, Cheng; Fu, Qiang; Chen, Zhaowei; Liu, Shan; Fu, Dou; Rahman, Rahmat N; Nakazato, Ryota; Yoshioka, Katsuji; Kung, Sam K P; Ding, Guohua; Wang, Huiming

    2017-07-01

    CD4 + T-cell activation and its subsequent induction of CD154 (CD40 ligand, CD40L) expression are pivotal in shaping both the humoral and cellular immune responses. Scaffold protein JLP regulates signal transduction pathways and molecular trafficking inside cells, thus represents a critical component in maintaining cellular functions. Its role in regulating CD4 + T-cell activation and CD154 expression, however, is unclear. Here, we demonstrated expression of JLP in mouse tissues of lymph nodes, thymus, spleen, and also CD4 + T cells. Using CD4+ T cells from jlp-deficient and jlp-wild-type mice, we demonstrated that JLP-deficiency impaired T-cell proliferation, IL-2 production, and CD154 induction upon TCR stimulations, but had no impacts on the expression of other surface molecules such as CD25, CD69, and TCR. These observed impaired T-cell functions in the jlp-/- CD4 + T cells were associated with defective NF-AT activation and Ca 2 + influx, but not the MAPK, NF-κB, as well as AP-1 signaling pathways. Our findings indicated that, for the first time, JLP plays a critical role in regulating CD4 + T cells response to TCR stimulation partly by mediating the activation of TCR-initiated Ca 2+ /NF-AT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Operational challenges in delivering CD4 diagnostics in sub-Saharan Africa.

    Science.gov (United States)

    Thairu, L; Katzenstein, D; Israelski, D

    2011-07-01

    Access to reliable and low cost CD4 T-cell enumeration to stage illness and monitor anti-retroviral therapy remains elusive in resource-limited settings. We report challenges in delivering CD4 testing using the microcapillary Fluorescence-Activated Cell Sorter (FACS) methodology (Guava EasyCD4 instrument Guava Technologies, Hayward) in Burkina Faso and Zimbabwe. Resources, instruments, reagents, and training were provided to local laboratories within the existing infrastructure and data on CD4 were collected from routine laboratory testing. Challenges encountered included frequent instrument breakdown; poor manufacturer maintenance; difficulties in managing reagent stocks; high technician turnover; reliance on antiquated data management systems; redundant service provision; and lack of repeat testing in male HIV+ patients and in patients with higher CD4 counts after initial staging. While adopting newer, less expensive technologies such as fluorescent platforms and point of care tests can facilitate access to lower cost CD4 testing, our experience suggests that supply chain, corporate commitment to implementation, and community factors also require consideration.

  3. Increased Aqueous Humor CD4+/CD8+ Lymphocyte Ratio in Sarcoid Uveitis.

    Science.gov (United States)

    Dave, Namita; Chevour, Priyanka; Mahendradas, Padmamalini; Venkatesh, Anitha; Kawali, Ankush; Shetty, Rohit; Ghosh, Arkasubhra; Sethu, Swaminathan

    2018-02-08

    To determine aqueous humor CD4+/CD8+ T-lymphocyte ratio changes in sarcoid and non-sarcoid uveitis with anterior chamber involvement. The case-control study includes 61 patients with either anterior uveitis, intermediate uveitis with anterior spill, or panuveitis. A total of 21 of them were categorized as sarcoid uveitis and 40 as non-sarcoid uveitis according to diagnostic criteria. CD4+/CD8+ ratio in the aqueous humor was determined using flow cytometry. Significantly higher CD4+/CD8+ ratio in the aqueous humor was observed in patients with sarcoid uveitis (6.3 ± 1.4; mean ± SEM) compared to non-sarcoid uveitis (1.6 ± 0.1; mean ± SEM). Whole blood CD4+/CD8+ ratio was not elevated in subjects with sarcoid and non-sarcoid uveitis. Aqueous humor CD4+/CD8+ ratio >3.5 was observed to be associated with sarcoid uveitis (OR 38, 95% CI 7.0-205.2). Increased aqueous humor CD4+/CD8+ ratio in sarcoid uveitis. Immunophenotyping of localized lymphocytosis in aqueous humor could be utilized as an additional confirmatory marker for ocular sarcoidosis.

  4. A dominant EV71-specific CD4+ T cell epitope is highly conserved among human enteroviruses.

    Directory of Open Access Journals (Sweden)

    Ruicheng Wei

    Full Text Available CD4+ T cell-mediated immunity plays a central role in determining the immunopathogenesis of viral infections. However, the role of CD4+ T cells in EV71 infection, which causes hand, foot and mouth disease (HFMD, has yet to be elucidated. We applied a sophisticated method to identify promiscuous CD4+ T cell epitopes contained within the sequence of the EV71 polyprotein. Fifteen epitopes were identified, and three of them are dominant ones. The most dominant epitope is highly conserved among enterovirus species, including HFMD-related coxsackieviruses, HFMD-unrelated echoviruses and polioviruses. Furthermore, the CD4+ T cells specific to the epitope indeed cross-reacted with the homolog of poliovirus 3 Sabin. Our findings imply that CD4+ T cell responses to poliovirus following vaccination, or to other enteroviruses to which individuals may be exposed in early childhood, may have a modulating effect on subsequent CD4+ T cell response to EV71 infection or vaccine.

  5. Reliable and accurate CD4+ T cell count and percent by the portable flow cytometer CyFlow MiniPOC and "CD4 Easy Count Kit-Dry", as revealed by the comparison with the gold standard dual platform technology.

    Directory of Open Access Journals (Sweden)

    Milena Nasi

    Full Text Available An accurate and affordable CD4+ T cells count is an essential tool in the fight against HIV/AIDS. Flow cytometry (FCM is the "gold standard" for counting such cells, but this technique is expensive and requires sophisticated equipment, temperature-sensitive monoclonal antibodies (mAbs and trained personnel. The lack of access to technical support and quality assurance programs thus limits the use of FCM in resource-constrained countries. We have tested the accuracy, the precision and the carry-over contamination of Partec CyFlow MiniPOC, a portable and economically affordable flow cytometer designed for CD4+ count and percentage, used along with the "CD4% Count Kit-Dry".Venous blood from 59 adult HIV+ patients (age: 25-58 years; 43 males and 16 females was collected and stained with the "MiniPOC CD4% Count Kit-Dry". CD4+ count and percentage were then determined in triplicate by the CyFlow MiniPOC. In parallel, CD4 count was performed using mAbs and a CyFlow Counter, or by a dual platform system (from Beckman Coulter based upon Cytomic FC500 ("Cytostat tetrachrome kit" for mAbs and Coulter HmX Hematology Analyzer (for absolute cell count.The accuracy of CyFlow MiniPOC against Cytomic FC500 showed a correlation coefficient (CC of 0.98 and 0.97 for CD4+ count and percentage, respectively. The accuracy of CyFlow MiniPOC against CyFlow Counter showed a CC of 0.99 and 0.99 for CD4 T cell count and percentage, respectively. CyFlow MiniPOC showed an excellent repeatability: CD4+ cell count and percentage were analyzed on two instruments, with an intra-assay precision below ± 5% deviation. Finally, there was no carry-over contamination for samples at all CD4 values, regardless of their position in the sequence of analysis.The cost-effective CyFlow MiniPOC produces rapid, reliable and accurate results that are fully comparable with those from highly expensive dual platform systems.

  6. Role of the frequency of blood CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells in autoimmunity in patients with Sjoegren's syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xue-yi; Wu, Zhen-biao; Ding, Jin; Zheng, Zhao-hui [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China); Li, Xiao-yan [Department of Endocrine and Metabolic Diseases, Shaanxi Provincial People' s Hospital, Xi' an, Shaanxi Province (China); Chen, Li-na [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China); Zhu, Ping, E-mail: zhuping@fmmu.edu.cn [Department of Clinical Immunology, State key Discipline of Cell Biology, Xi-jing Hospital, Fourth Military Medical University, Shaanxi Province (China)

    2012-06-01

    Highlights: Black-Right-Pointing-Pointer The frequency of CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells increased in pSS patients and positively correlated with autoantibodies in the blood. Black-Right-Pointing-Pointer CD4{sup +} CXCR5{sup +} CCR6{sup +} T cells in blood invariably coexpressed PD-1, ICOS, CD40L, Bcl-6 and secreted IL-21 after stimulated by PHA. Black-Right-Pointing-Pointer CD4{sup +} CXCR5{sup +} CCR6{sup +} Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. -- Abstract: The blood CD4{sup +} CXCR5{sup +} T cells, known as 'circulating' Tfh, have been shown to efficiently induce naieve B cells to produce immunoglobulin. They play an important role in certain autoimmune diseases. In the present study, we show for the first time that the frequency of CD4{sup +} CXCR5{sup +} T cells is increased in pSS patients and positively correlated with autoantibodies in the blood. The concentration of Th17-like subsets (CD4{sup +} CXCR5{sup +} CCR6{sup +}) in pSS patients was found to be significantly higher than in healthy controls. Functional assays showed that activated Th17-like subtypes in the blood display the key features of Tfh cells, including invariably coexpressed PD-1, ICOS, CD40L and IL-21. Th17 subsets were found to highly express Bcl-6 protein and Th1 and Th2 were not. Bcl-6 is believed to be a master transforming factor for Tfh cell differentiation and facilitate B cell proliferation and somatic hypermutation within the germinal center. These data indicate that Th17 subsets of CD4{sup +} CXCR5{sup +} T cells in the blood may participate in the antibody-related immune responses and that high frequency of CD4{sup +} CXCR5{sup +} CCR6{sup +} Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. It might provide insights into the pathogenesis and perhaps help researchers identify novel therapeutic targets for pSS.

  7. Glycosylphosphatidylinositol-Anchored Anti-HIV scFv Efficiently Protects CD4 T Cells from HIV-1 Infection and Deletion in hu-PBL Mice.

    Science.gov (United States)

    Ye, Chaobaihui; Wang, Weiming; Cheng, Liang; Li, Guangming; Wen, Michael; Wang, Qi; Zhang, Qing; Li, Dan; Zhou, Paul; Su, Lishan

    2017-02-01

    Despite success in viral inhibition and CD4 T cell recovery by highly active antiretroviral treatment (HAART), HIV-1 is still not curable due to the persistence of the HIV-1 reservoir during treatment. One patient with acute myeloid leukemia who received allogeneic hematopoietic stem cell transplantation from a homozygous CCR5 Δ32 donor has had no detectable viremia for 9 years after HAART cessation. This case has inspired a field of HIV-1 cure research focusing on engineering HIV-1 resistance in permissive cells. Here, we employed a glycosylphosphatidylinositol (GPI)-scFv X5 approach to confer resistance of human primary CD4 T cells to HIV-1. We showed that primary CD4 T cells expressing GPI-scFv X5 were resistant to CCR5 (R5)-, CXCR4 (X4)-, and dual-tropic HIV-1 and had a survival advantage compared to control cells ex vivo In a hu-PBL mouse study, GPI-scFv X5-transduced CD4 T cells were selected in peripheral blood and lymphoid tissues upon HIV-1 infection. Finally, GPI-scFv X5-transduced CD4 T cells, after being cotransfused with HIV-infected cells, showed significantly reduced viral loads and viral RNA copy numbers relative to CD4 cells in hu-PBL mice compared to mice with GPI-scFv AB65-transduced CD4 T cells. We conclude that GPI-scFv X5-modified CD4 T cells could potentially be used as a genetic intervention against both R5- and X4-tropic HIV-1 infections. Blocking of HIV-1 entry is one of most promising approaches for therapy. Genetic disruption of the HIV-1 coreceptor CCR5 by nucleases in T cells is under 2 clinical trials and leads to reduced viremia in patients. However, the emergence of viruses using the CXCR4 coreceptor is a concern for therapies applying single-coreceptor disruption. Here, we report that HIV-1-permissive CD4 T cells engineered with GPI-scFv X5 are resistant to R5-, X4-, or dual-tropic virus infection ex vivo In a preclinical study using hu-PBL mice, we show that CD4 T cells were protected and that GPI-scFv X5-transduced cells were

  8. Normal telomere lengths in naive and memory CD4+ T cells in HIV type 1 infection: a mathematical interpretation

    NARCIS (Netherlands)

    Wolthers, K. C.; Noest, A. J.; Otto, S. A.; Miedema, F.; de Boer, R. J.

    1999-01-01

    To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal

  9. Normal telomere lengths in naive and memory CD4 T cells in HIV type 1 infection : a mathematical interpretation

    NARCIS (Netherlands)

    Wolthers, K.C.; Noest, A.J.; Otto, S.A.; Miedema, F.; Boer, R.J. de

    1999-01-01

    To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal

  10. Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection

    NARCIS (Netherlands)

    Geldmacher, Christof; Ngwenyama, Njabulo; Schuetz, Alexandra; Petrovas, Constantinos; Reither, Klaus; Heeregrave, Edwin J.; Casazza, Joseph P.; Ambrozak, David R.; Louder, Mark; Ampofo, William; Pollakis, Georgios; Hill, Brenna; Sanga, Erica; Saathoff, Elmar; Maboko, Leonard; Roederer, Mario; Paxton, William A.; Hoelscher, Michael; Koup, Richard A.

    2010-01-01

    HIV-1 infection results in the progressive loss of CD4 T cells. In this study, we address how different pathogen-specific CD4 T cells are affected by HIV infection and the cellular parameters involved. We found striking differences in the depletion rates between CD4 T cells to two common

  11. Cytotoxic reactivity of gut lamina propria CD4+ alpha beta T cells in SCID mice with colitis

    DEFF Research Database (Denmark)

    Bonhagen, K; Thoma, S; Bland, P

    1996-01-01

    Polyclonal, mucosa-seeking memory/effector CD4+ T cells containing a large fraction of blasts activated in situ accumulate in the gut lamina propria of severe-combined immunodeficient (SCID) mice developing colitis after CD4+ T cell transplantation. CD4+ T cells isolated from different repopulated...

  12. Pulmonary candidiasis and CD4 count in HIV positive patients seen ...

    African Journals Online (AJOL)

    Background: Accurate and reliable diagnosis of HIV opportunistic infections plays a central role in effective HIV intervention programmes. Pulmonary infections are the leading cause of morbidity and mortality in HIV infected individuals. Objectives: We set out to determine the prevalence of Pulmonary candidiasis by isolating ...

  13. cd4 changes in haart-naïve hiv positive pregnant women on haart

    African Journals Online (AJOL)

    boaz

    cells/ L (224.90), C.I = 355.98, 732.02, and Mean2= 626.63 cells/ L (247.27), C.I = 419.90, 833.00. The counts in the 2nd trimester group are, *Mean0= 367.07 cells/ L (202.67), C.I = 202.67, 328.95, *Mean1. = 489.41 cells/ L (173.23), C.I = 456.82 – 521.99,. *Mean2= 560.43 cells/ L (154.56), C.I = 531.36,. 589.51. The 3rd ...

  14. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

    International Nuclear Information System (INIS)

    Wirsdörfer, Florian; Cappuccini, Federica; Niazman, Muska; Leve, Simone de; Westendorf, Astrid M; Lüdemann, Lutz; Stuschke, Martin; Jendrossek, Verena

    2014-01-01

    Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease

  15. Quorum sensing in CD4+ T cell homeostasis: a hypothesis and a model.

    Directory of Open Access Journals (Sweden)

    Afonso R.M. Almeida

    2012-05-01

    Full Text Available Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to count the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4+ T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4+ T cells and sensed by a population of CD4+ Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4+ T cells and the total CD4+T cell population. In other words, CD4+ T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the role of IL-2 and quorum-sensing mechanisms in CD4+ T cell homeostasis during an immune response.

  16. Role of ROCK2 in CD4+cells in allergic airways responses in mice.

    Science.gov (United States)

    Kasahara, D I; Mathews, J A; Ninin, F M C; Wurmbrand, A P; Liao, J K; Shore, S A

    2017-02-01

    Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration. To determine the role of ROCK2 acting within CD4 + cells in allergic airways responses. ROCK2-haploinsufficient (ROCK2 +/- ) and wild-type mice were sensitized with ovalbumin (OVA). ROCK2 +/- mice then received either CD4 + cells from ROCK2-sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 h before challenge with aerosolized OVA. Wild-type mice received saline before challenge. Allergic airways responses were measured 48 h after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4 + cells (ROCK2 CD 4Cre mice) vs. control (CD4-Cre and ROCK2 flox/flox ) mice. OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2 +/- vs. wild-type mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2 +/- mice, adoptive transfer with CD4 + cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wild-type levels, whereas eotaxin and airway hyperresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2-insufficient mice, allergic inflammation was not different in ROCK2 CD 4Cre vs. control mice. ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non-lymphocyte cells involved in lymphocyte activation and migration into the airways. © 2016 John Wiley & Sons Ltd.

  17. Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses.

    Science.gov (United States)

    Bizzell, Erica; Sia, Jonathan Kevin; Quezada, Melanie; Enriquez, Ana; Georgieva, Maria; Rengarajan, Jyothi

    2017-12-28

    Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-γ and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge. ©2017 Society for Leukocyte Biology.

  18. Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bingfen Yang

    Full Text Available CD244 (2B4 is a member of the signaling lymphocyte activation molecule (SLAM family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+ T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+ T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+ T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4(+ T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+ T cells, CD244/2B4-bright CD4(+ T cell subset had significantly reduced expression of IFN-γ, suggesting that CD244/2B4 expression may modulate IFN-γ production in M. tuberculosis antigen-responsive CD4(+ T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-γ. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-γ, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+ T cell function.

  19. Role of certain trace minerals in oxidative stress, inflammation, CD4/CD8 lymphocyte ratios and lung function in asthmatic patients.

    Science.gov (United States)

    Guo, Chih-Hung; Liu, Po-Jen; Hsia, Simon; Chuang, Chia-Ju; Chen, Pei-Chung

    2011-07-01

    Asthma is associated with increased inflammation, oxidative stress and abnormal immune system function. We determined the distributions of several essential trace minerals and assessed their relationships to factors that are associated with the pathophysiological status of patients with mild/moderate asthma. We enrolled 25 asthmatic patients and 25 healthy subjects. We measured: blood trace minerals, zinc (Zn), copper (Cu) and selenium (Se); oxidative stress markers thiobarbituric acid reactive substances (TBARS); antioxidant enzyme activities; percentages of CD4 and CD8 lymphocyte subsets; high-sensitivity C-reactive protein (hs-CRP); and a lung function index (FEV1/FVC%). Compared with healthy subjects, asthmatics had lower concentrations of Zn and Se; higher Cu concentrations, and Cu/Zn and Cu/Se ratios; and lower antioxidant enzyme glutathione peroxidase (GPx), glutathione reductase (GR) and catalase activities. Significantly increased concentrations of hs-CRP, TBARS and CD4/CD8 lymphocyte ratios were also observed. Furthermore, plasma TBARS or hs-CRP concentrations were negatively associated with Se concentrations, but were positively associated with Cu/Se ratios. CD4/CD8 lymphocyte ratios were inversely correlated with Se, while it was positively correlated with Cu/Se ratio. FEV1/FVC% was also significantly correlated with Se concentrations, and Cu/Se and Cu/Zn ratios. Abnormal distributions of these trace minerals may aggravate oxidative damage and inflammation, increased CD4/CD8 lymphocyte ratios and decreased lung function in asthma.

  20. Comparative analysis of CD8 expressed on mature CD4+ CD8+ T cell clones cultured with IL-4 and that on CD8+ T cell clones: implication for functional significance of CD8 beta

    NARCIS (Netherlands)

    Hori, T.; Paliard, X.; de Waal Malefijt, R.; Ranes, M.; Spits, H.

    1991-01-01

    Interleukin (IL-4) can induce CD8 expression on mature CD4+ T cells. To study this phenomenon in more detail, we characterized CD8 expressed on IL-4-induced CD4+ CD8+ (double positive) T cell clones in comparison with that on CD8+ T cell clones. Using 2ST8-5H7 mAb that detects CD8 beta expression,

  1. CLINICAL AND LABORATORY PROFILE OF PATIENTS WITH IDIOPATHIC CD4 LYMPHOCYTOPENIA- A RARE CLINICAL ENTITY

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    Vijayashree Thyagaraj

    2017-01-01

    Full Text Available BACKGROUND Since 1989, several investigators have reported unusual cases of severe opportunistic infections associated with CD4 lymphocytopenia in the absence of human immunodeficiency virus infection. The cause of this condition is unknown. The Centres for Disease Control and Prevention (CDC defines Idiopathic CD4 T Lymphocytopenia (ICL as a clinical condition in which patients with depressed numbers of circulating CD4+ T-cell lymphocytes (<300 cells/μL or <20% of total T cells at a minimum of two separate time points at least 6 weeks apart, have no laboratory evidence of infection with human HIV-1 or HIV-2, or any defined immunodeficiency or therapy associated with depressed levels of CD4 T cells. The aim of the study is to analyse the clinical profile, opportunistic infections, laboratory parameters and outcome in terms of survival of patients diagnosed with ICL. MATERIALS AND METHODS Eight HIV negative patients who presented with opportunistic infections and who were diagnosed with ICL from 2007 to 2015 were included in the study. A detailed history was taken; physical examination was performed and the nature of illness with which they presented was documented. Then, CD4 and CD8 counts were done and CD4 count was repeated after a 6-week interval. The patients were followed up until discharge or death. RESULTS The mean age was 37.50±9.55 years. There were six males (75% and two females (25%. Fever was a presenting symptom among six (75% of them. Two were diagnosed to have cutaneous cryptococcosis (25%, two with invasive aspergillosis (25% and four with tuberculosis (50%. Absolute lymphocyte count was less than 1200 in seven patients (87.5%, which roughly correlates with a CD4 count of less than 200 cells/μL, among PLWHIV. The mean CD4 count was 183.63±63.74 cells/μL during the first measurement and 214.43±103.98 cells/μL during the second one. Two patients died (37.5%. None of the patients were recorded to have any form of malignancy

  2. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Kim, Kyung-Chang; Kim, Hyeon Guk; Roh, Tae-Young; Park, Jihwan; Jung, Kyung-Min; Lee, Joo-Shil; Choi, Sang-Yun; Kim, Sung Soon; Choi, Byeong-Sun

    2011-01-01

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56 Lck , ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56 Lck , ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  3. Dynamic Changes in Fetal Microchimerism in Maternal Peripheral Blood Mononuclear Cells, CD4+ and CD8+ Cells in Normal Pregnancy

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    Adams Waldorf, Kristina M.; Gammill, Hilary S.; Lucas, Joëlle; Aydelotte, Tessa M.; Leisenring, Wendy M.; Lambert, Nathalie C.; Nelson, J. Lee

    2010-01-01

    Objective Cell trafficking during pregnancy results in persistence of small populations of fetal cells in the mother, known as fetal microchimerism (FMc). Changes in cell-free fetal DNA during gestation have been well-described, however, less is known about dynamic changes in fetal immune cells in maternal blood. We investigated FMc in maternal peripheral blood mononuclear cells (PBMC) longitudinally across gestation. Study Design Thirty-five women with normal pregnancies were studied. FMc was identified in PBMC, CD4+ and CD8+ subsets employing quantitative PCR assays targeting fetal-specific genetic polymorphisms. FMc quantities were reported as fetal genome equivalents (gEq) per 1,000,000 gEq mother’s cells. Poisson regression modeled the rate of FMc detection. Main Outcome Measure FMc in PBMC Results The probability of detecting one fetal cell equivalent increased 6.2-fold each trimester [Incidence Rate Ratio (IRR) 95% CI: 1.73, 21.91; p=0.005]. Although FMC in PBMC was not detected for the majority of time points, 7 of 35 women had detectable FMc during pregnancy at one or more time points, with the majority of positive samples being from the third trimester. There was a suggestion of greater HLA-sharing in families where women had FMc in PBMC. FMc was detected in 9% of CD4+ (2/23) and 18% of CD8+ (3/25) subsets. Conclusions FMc in PBMC increased as gestation progressed and was found within CD4+ and CD8+ subsets in some women in the latter half of gestation. A number of factors could influence cellular FMc levels including subclinical fetal-maternal interface changes and events related to parturition. Whether FMc during pregnancy predicts persistent FMc and/or correlates with fetal-maternal HLA-relationships also merits further study. PMID:20569981

  4. Casp8p41: The Protean Mediator of Death in CD4 T-cells that Replicate HIV

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    Rahul Sampath

    2016-01-01

    Full Text Available HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound–-that occurs within weeks of combination anti retroviral therapy (cART interruption. Modalities to engineer transcriptional stimulation (reactivation of this dormant integrated HIV provirus, leading to expression of cytotoxic viral proteins, are thought to be a specific way to eradicate the latently infected CD4 pool and are becoming increasingly relevant in the era of HIV cure. HIV protease is one such protein produced after HIV reactivation that cleaves procaspase-8 to generate a novel protein Casp8p41. Casp8p41 then binds to the BH3 domain of BAK, leading to BAK oligomerization, mitochondrial depolarization, and apoptosis. In central memory T cells (TCMs from HIV-infected patients, an elevated Bcl-2/procaspase-8 ratio was observed, and Casp8p41 binding to Bcl-2 was associated with a lack of reactivation-induced cell death. This was reversed by priming cells with a specific Bcl-2 antagonist prior to reactivation, resulting in increased cell death and decreased HIV DNA in a Casp8p41-dependent pathway. This review describes the biology, clinical relevance, and implications of Casp8p41 for a potential cure.

  5. Intestinal Parasitosis in Relation to Anti-Retroviral Therapy, CD4(+) T-cell Count and Diarrhea in HIV Patients.

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    Khalil, Shehla; Mirdha, Bijay Ranjan; Sinha, Sanjeev; Panda, Ashutosh; Singh, Yogita; Joseph, Anju; Deb, Manorama

    2015-12-01

    Intestinal parasitic infections are one of the major causes of diarrhea in human immunodeficiency virus (HIV) seropositive individuals. Antiretroviral therapy has markedly reduced the incidence of many opportunistic infections, but parasite-related diarrhea still remains frequent and often underestimated especially in developing countries. The present hospital-based study was conducted to determine the spectrum of intestinal parasitosis in adult HIV/AIDS (acquired immunodeficiency syndrome) patients with or without diarrhea with the levels of CD4(+) T-cell counts. A total of 400 individuals were enrolled and were screened for intestinal parasitosis. Of these study population, 200 were HIV seropositives, and the remaining 200 were HIV uninfected individuals with or without diarrhea. Intestinal parasites were identified by using microscopy as well as PCR assay. A total of 130 (32.5%) out of 400 patients were positive for any kinds of intestinal parasites. The cumulative number of parasite positive patients was 152 due to multiple infections. A significant association of Cryptosporidium (P<0.001) was detected among individuals with CD4(+) T-cell counts less than 200 cells/μl.

  6. Target organ localization of memory CD4(+) T cells in patients with chronic beryllium disease.

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    Fontenot, Andrew P; Canavera, Scott J; Gharavi, Laia; Newman, Lee S; Kotzin, Brian L

    2002-11-01

    Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4(+) T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4(+) T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO(4)). Few, if any, beryllium-specific CD8(+) T cells were identified. In contrast, the frequency of beryllium-responsive CD4(+) T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO(4) exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4(+) cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.

  7. Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection.

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    Hua, Laiqing; Yao, Shuyu; Pham, Duy; Jiang, Li; Wright, Jeffrey; Sawant, Deepali; Dent, Alexander L; Braciale, Thomas J; Kaplan, Mark H; Sun, Jie

    2013-11-01

    Recent evidence has identified the role of granzyme B- and perforin-expressing CD4(+) T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4(+) T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4(+) T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4(+) T cells and was required for the cytolytic function of the in vitro- and in vivo-generated CD4(+) T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed.

  8. Computational modeling of heterogeneity and function of CD4+ T cells

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    Adria eCarbo

    2014-07-01

    Full Text Available The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation.

  9. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow.

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    Tokoyoda, Koji; Zehentmeier, Sandra; Hegazy, Ahmed N; Albrecht, Inka; Grün, Joachim R; Löhning, Max; Radbruch, Andreas

    2009-05-01

    CD4(+) T lymphocytes are key to immunological memory. Here we show that in the memory phase of specific immune responses, most of the memory CD4(+) T lymphocytes had relocated into the bone marrow (BM) within 3-8 weeks after their generation-a process involving integrin alpha2. Antigen-specific memory CD4(+) T lymphocytes highly expressed Ly-6C, unlike most splenic CD44(hi)CD62L(-) CD4(+) T lymphocytes. In adult mice, more than 80% of Ly-6C(hi)CD44(hi)CD62L(-) memory CD4(+) T lymphocytes were in the BM. In the BM, they associated to IL-7-expressing VCAM-1(+) stroma cells. Gene expression and proliferation were downregulated, indicating a resting state. Upon challenge with antigen, they rapidly expressed cytokines and CD154 and efficiently induced the production of high-affinity antibodies by B lymphocytes. Thus, in the memory phase of immunity, memory helper T cells are maintained in BM as resting but highly reactive cells in survival niches defined by IL-7-expressing stroma cells.

  10. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.

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    Swaims, Alison Y; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I; Devadas, Satish; Shi, Yufang; Rabson, Arnold B

    2010-10-21

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals.

  11. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

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    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  12. CD4-induced activation in a soluble HIV-1 Env trimer.

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    Guttman, Miklos; Garcia, Natalie K; Cupo, Albert; Matsui, Tsutomu; Julien, Jean-Philippe; Sanders, Rogier W; Wilson, Ian A; Moore, John P; Lee, Kelly K

    2014-07-08

    The HIV envelope glycoprotein (Env) trimer undergoes receptor-induced conformational changes that drive fusion of the viral and cellular membranes. Env conformational changes have been observed using low-resolution electron microscopy, but only large-scale rearrangements have been visible. Here, we use hydrogen-deuterium exchange and oxidative labeling to gain a more precise understanding of the unliganded and CD4-bound forms of soluble Env trimers (SOSIP.664), including their glycan composition. CD4 activation induces the reorganization of bridging sheet elements, V1/V2 and V3, much of the gp120 inner domain, and the gp41 fusion subunit. Two CD4 binding site-targeted inhibitors have substantially different effects: NBD-556 partially mimics CD4-induced destabilization of the V1/V2 and V3 crown, whereas BMS-806 only affects regions around the gp120/gp41 interface. The structural information presented here increases our knowledge of CD4- and small molecule-induced conformational changes in Env and the allosteric pathways that lead to membrane fusion. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Interleukin-27-Producing CD4(+) T Cells Regulate Protective Immunity during Malaria Parasite Infection.

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    Kimura, Daisuke; Miyakoda, Mana; Kimura, Kazumi; Honma, Kiri; Hara, Hiromitsu; Yoshida, Hiroki; Yui, Katsuyuki

    2016-03-15

    Interleukin-27 (IL-27) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4(+) T cells that produce IL-27 in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4(+) T cells were Foxp3(-)CD11a(+)CD49d(+) malaria antigen-specific CD4(+) T cells and were distinct from interferon-γ (IFN-γ) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4(+) T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4(+) T cells and their critical role in the regulation of the protective immune response against malaria parasites. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Specific interaction of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell receptor

    International Nuclear Information System (INIS)

    Schols, D.; Baba, M.; Pauwels, R.; Desmyter, J.; De Clercq, E.

    1989-01-01

    The triphenylmethane derivative aurintricarboxylic acid (ATA), but not aurin, selectively prevented the binding of OKT4A/Leu-3a monoclonal antibody (mAb) and, to a lesser extent, OKT4 mAb to the CD4 cell receptor for human immunodeficiency virus type 1 (HIV-1). The effect was seen within 1 min at an ATA concentration of 10 μM in various T4 + cells (MT-4, U-937, peripheral blood lymphocytes, and monocytes). It was dose-dependent and reversible. ATA prevented the attachment of radiolabeled HIV-1 particles to MT-4 cells, which could be expected as the result of its specific binding to the HIV/CD4 receptor. Other HIV inhibitors such as suramin, fuchsin acid, azidothymidine, dextran sulfate, heparin, and pentosan polysulfate did not affect OKT4A/Leu-3a mAb binding to the CD4 receptor, although the sulfated polysaccharides suppressed HIV-1 adsorption to the cells at concentrations required for complete protection against HIV-1 cytopathogenicity. Thus, ATA is a selective marker molecule for the CD4 receptor. ATA also interfered with the staining of membrane-associated HIV-1 glycoprotein gp120 by a mAb against it. These unusual properties of a small molecule of nonimmunological origin may have important implications for the study of CD4/HIV/AIDS pathogenesis and possibly treatment

  15. Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load.

    Science.gov (United States)

    Poon, Art F Y; Aldous, Jeannette L; Mathews, W Christopher; Kitahata, Mari; Kahn, James S; Saag, Michael S; Rodríguez, Benigno; Boswell, Stephen L; Frost, Simon D W; Haubrich, Richard H

    2011-01-01

    Human immunodeficiency virus type 1 (HIV-1) genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR) in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL) and CD4+ cell count (CD4) at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT) were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184) were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log₁₀pVL) and D67N/G (-2.1[³√CD4] and 0.4 log₁₀pVL) were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1 infections and

  16. Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load.

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    Art F Y Poon

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL and CD4+ cell count (CD4 at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184 were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log₁₀pVL and D67N/G (-2.1[³√CD4] and 0.4 log₁₀pVL were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1

  17. Identification of amino acids involved in recognition by dengue virus NS3-specific, HLA-DR15-restricted cytotoxic CD4+ T-cell clones.

    Science.gov (United States)

    Zeng, L; Kurane, I; Okamoto, Y; Ennis, F A; Brinton, M A

    1996-05-01

    The majority of T-cell clones derived from a donor who experienced dengue illness following receipt of a live experimental dengue virus type 3 (DEN3) vaccine cross-reacted with all four serotypes of dengue virus, but some were serotype specific or only partially cross-reactive. The nonstructural protein, NS3, was immuno-dominant in the CD4+ T-cell response of this donor. The epitopes of four NS3-specific T-cell clones were analyzed. JK15 and JK13 recognized only DEN3 NS3, while JK44 recognized DEN1, DEN2, and DEN3 NS3 and JK5 recognized DEN1, DEN3, and West Nile virus NS3. The epitopes recognized by these clones on the DEN3 NS3 protein were localized with recombinant vaccinia viruses expressing truncated regions of the NS3 gene, and then the minimal recognition sequence was mapped with synthetic peptides. Amino acids critical for T-cell recognition were assessed by using peptides with amino acid substitutions. One of the serotype-specific clones (JK13) and the subcomplex- and flavivirus-cross-reactive clone (JK5) recognized the same core epitope, WITDFVGKTVW. The amino acid at the sixth position of this epitope is critical for recognition by both clones. Sequence analysis of the T-cell receptors of these two clones showed that they utilize different VP chains. The core epitopes for the four HLA-DR15-restricted CD4+ CTL clones studied do not contain motifs similar to those proposed by previous studies on endogenous peptides eluted from HLA-DR15 molecules. However, the majority of these dengue virus NS3 core epitopes have a positive amino acid (K or R) at position 8 or 9. Our results indicate that a single epitope can induce T cells with different virus specificities despite the restriction of these T cells by the same HLA-DR15 allele. This finding suggests a previously unappreciated level of complexity for interactions between human T-cell receptors and viral epitopes with very similar sequences on infected cells.

  18. Cell-to-Cell Transfer of M. tuberculosis Antigens Optimizes CD4 T Cell Priming

    Science.gov (United States)

    Srivastava, Smita; Ernst, Joel D.

    2014-01-01

    SUMMARY During Mycobacterium tuberculosis and other respiratory infections, optimal T cell activation requires pathogen transport from the lung to a local draining lymph node (LN). However, the infected inflammatory monocyte-derived dendritic cells (DCs) that transport M. tuberculosis to the local lymph node are relatively inefficient at activating CD4 T cells, possibly due to bacterial inhibition of antigen presentation. We found that infected migratory DCs release M. tuberculosis antigens as soluble, unprocessed proteins for uptake and presentation by uninfected resident lymph node DCs. This transfer of bacterial proteins from migratory to local DCs results in optimal priming of antigen-specific CD4 T cells, which are essential in controlling tuberculosis. Additionally, this mechanism does not involve transfer of the whole bacterium and is distinct from apoptosis or exosome shedding. These findings reveal a mechanism that bypasses pathogen inhibition of antigen presentation by infected cells and generates CD4 T cell responses that control the infection. PMID:24922576

  19. Dynamic transcription of long non-coding RNA genes during CD4+ T cell development and activation.

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    Fei Xia

    Full Text Available BACKGROUND: Recent evidence shows that long non-coding RNA (LncRNA play important regulatory roles in many biology process, including cell development, activation and oncogenesis. However, the roles of these LncRNAs in the development and activation of CD4+ T cells, which is an important component of immune response, remain unknown. RESULTS: To predict the function of LncRNA in the development and activation of CD4+ T cells, first, we examined the expression profiles of LncRNAs and mRNAs in CD4-CD8- (DN, CD4+CD8+ (DP, CD4+CD8-, and activated CD4+CD8- T cells in a microarray analysis and verified these results by real time PCRs (qPCR. We found that the expression of hundreds of LncRNAs significantly changed in each process of developmental transition, including DN into DP, DP into CD4+CD8-, and CD4+CD8- into activated CD4+ T cells. A Kendall distance analysis suggested that the expression of LncRNAs in DN, DP, CD4+CD8- T cells and activated CD4+ T cells were correlated with the expression of mRNAs in these T cells. The Blat algorithm and GO analysis suggested that LncRNAs may exert important roles in the development and activation of CD4+ T cells. These roles included proliferation, homeostasis, maturation, activation, migration, apoptosis and calcium ion transportation. CONCLUSION: The present study found that the expression profiles of LncRNAs in different stages of CD4+ T cells are distinguishable. LncRNAs are involved in the key biological process in CD4+ T cell development and activation.

  20. The effect of a 12-week combinational exercise program on CD4 count and mental health among HIV infected women: A randomized control trial

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    Mostafa Dianatinasab

    2018-04-01

    Full Text Available Background/objective: There are conflicting results regarding the effects of exercise on immune function of HIV positive patients. Exercise can also be beneficial to psychological functioning of the patients. The purpose of this study was to determine the impact of a 12-week aerobic and resistance exercise training program on mental health and CD4 counts among female HIV+ patients. Methods: This clinical trial was conducted between September and December 2013. Forty participants (women age range 20–40 were carefully selected from 240 HIV-positive women referred to Voluntary Counseling and Treatment Center (VCT and randomly assigned to either exercise (80 min of aerobic and strength training while receiving the VCT's routine services group (n = 20 or control (received the VCT's routine services only group (n = 20. To assess their mental health status, all participants completed GHQ28 questionnaire. Blood samples were collected to measure CD4 and T-cell counts at baseline and at the end of the 12-week intervention. Results: From a sample of 40 women with HIV infection, the data of 30 participants [experimental group (14 and control group (16] were analyzed (participation rate 75%. The results indicated that after the intervention program, a significant difference in CD4 cell counts was found between the two groups (P = 0.01. With regard to mental health, after performing intervention, significant improvement in all subscales including anxiety disorder, social function, depression and mental health's total score was observed in the exercise compared to the control groups (P < 0.001. Conclusion: Exercise training can be included in health care services in order to improve the mental health status of women with HIV infection. No effect on CD4 count was detected. Keywords: Exercises training, Mental health, CD4 count, HIV infected women

  1. Short communication: SAHA (vorinostat) induces CDK9 Thr-186 (T-loop) phosphorylation in resting CD4+ T cells: implications for reactivation of latent HIV.

    Science.gov (United States)

    Ramakrishnan, Rajesh; Liu, Hongbing; Rice, Andrew P

    2015-01-01

    The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxyamic acid (SAHA), also known as vorinostat, has recently been reported to activate latent HIV-1 in patients undergoing antiretroviral therapy. It is possible that SAHA reactivation of latent viruses may involve effects on cellular transcription factors such as positive transcription elongation factor b (P-TEFb), a protein kinase whose core is composed of CDK9 and Cyclin T1. P-TEFb is recruited by the HIV-1 Tat protein to activate productive RNA polymerase II elongation of the integrated provirus. We found that SAHA treatment of isolated resting CD4(+) T cells induced CDK9 Thr-186 (T-loop) phosphorylation in six of eight healthy donors and increased Cyclin T1 expression in one donor; Thr-186 phosphorylation is required for P-TEFb function. Disulfiram, another small molecule currently under evaluation in clinical trials for reactivation of latent HIV-1, was also found capable of inducing CDK9 Thr-186 phosphorylation and Cyclin T1 levels in resting CD4(+) T cells from healthy donors. In a Jurkat CD4(+) T cells HIV-1 latency system, disulfiram reactivated the latent provirus and induced CDK9 Thr-186 phosphorylation. Our findings suggest that small molecules capable of reactivating latent HIV-1 in resting CD4(+) T cells may function in part by increasing CDK9 Thr-186 phosphorylation and perhaps Cyclin T1 expression, thereby up-regulating P-TEFb function.

  2. Loss of correlation between HIV viral load and CD4+ T-cell counts in HIV/HTLV-1 co-infection in treatment naive Mozambican patients.

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    Bhatt, N B; Gudo, E S; Semá, C; Bila, D; Di Mattei, P; Augusto, O; Garsia, R; Jani, I V

    2009-12-01

    Seven hundred and four HIV-1/2-positive, antiretroviral therapy (ART) naïve patients were screened for HTLV-1 infection. Antibodies to HTLV-1 were found in 32/704 (4.5%) of the patients. Each co-infected individual was matched with two HIV mono-infected patients according to World Health Organization clinical stage, age +/-5 years and gender. Key clinical and laboratory characteristics were compared between the two groups. Mono-infected and co-infected patients displayed similar clinical characteristics. However, co-infected patients had higher absolute CD4+ T-cell counts (P = 0.001), higher percentage CD4+ T-cell counts (P loads were inversely correlated with CD4+ T-cell-counts in mono-infected patients (P load parameters. These guidelines are not appropriate for co-infected individuals in whom high CD4+ T-cell counts persist despite high HIV viral load states. Thus, for co-infected patients, even in resource-poor settings, HIV viral loads are likely to contribute information crucial for the appropriate timing of ART introduction.

  3. Inflammation in disseminated lesions: an analysis of CD4+, CD20+, CD68+, CD31+ and vW+ cells in non-ulcerated lesions of disseminated leishmaniasis

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    Dayana Santos Mendes

    2013-02-01

    Full Text Available Disseminated leishmaniasis (DL differs from other clinical forms of the disease due to the presence of many non-ulcerated lesions (papules and nodules in non-contiguous areas of the body. We describe the histopathology of DL non-ulcerated lesions and the presence of CD4-, CD20-, CD68-, CD31- and von Willebrand factor (vW-positive cells in the inflamed area. We analysed eighteen biopsies from non-ulcerated lesions and quantified the inflamed areas and the expression of CD4, CD20, CD68, CD31 and vW using Image-Pro software (Media Cybernetics. Diffuse lymphoplasmacytic perivascular infiltrates were found in dermal skin. Inflammation was observed in 3-73% of the total biopsy area and showed a significant linear correlation with the number of vW+ vessels. The most common cells were CD68+ macrophages, CD20+ B-cells and CD4+ T-cells. A significant linear correlation between CD4+ and CD20+ cells and the size of the inflamed area was also found. Our findings show chronic inflammation in all DL non-ulcerated lesions predominantly formed by macrophages, plasmacytes and T and B-cells. As the inflamed area expanded, the number of granulomas and extent of the vascular framework increased. Thus, we demonstrate that vessels may have an important role in the clinical evolution of DL lesions.

  4. Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection

    International Nuclear Information System (INIS)

    Wade, Jessica; Sterjovski, Jasminka; Gray, Lachlan; Roche, Michael; Chiavaroli, Lisa; Ellett, Anne; Jakobsen, Martin R.; Cowley, Daniel; Fonseca Pereira, Candida da; Saksena, Nitin; Wang, Bin; Purcell, Damian F.J.; Karlsson, Ingrid; Fenyoe, Eva-Maria; Churchill, Melissa; Gorry, Paul R.

    2010-01-01

    CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains cause CD4+ T-cell loss in most infected individuals, but mechanisms underlying cytopathicity of R5 viruses are poorly understood. We investigated mechanisms contributing to R5 envelope glycoprotein (Env)-mediated cellular apoptosis by constructing a panel of retroviral vectors engineered to co-express GFP and R5 Envs derived from two HIV-1-infected subjects spanning asymptomatic (Early, E-R5 Envs) to late stages of infection (Late, L-R5 Envs). The L-R5 Envs induced significantly more cellular apoptosis than E-R5 Envs, but only in Env-expressing (GFP-positive) cells, and only in cells where CD4 and CCR5 levels were limiting. Studies with fusion-defective Env mutants showed induction of apoptosis required membrane-fusing events. Our results provide evidence for an intracellular mechanism of R5 Env-induced apoptosis of CD4+ cells that requires membrane fusion. Furthermore, they contribute to a better understanding of mechanisms involved in CD4+ T-cell loss in subjects experiencing progressive R5 HIV-1 infection.

  5. Evaluating total lymphocyte count as a surrogate marker for CD4 cell count in the management of HIV-infected patients in resource-limited settings: a study from China.

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    Jieqing Chen

    Full Text Available OBJECTIVE: To evaluate the correlation of total lymphocyte count (TLC and CD4 cell count and the suitability of TLC as a surrogate marker for CD4 cell count of HIV-infected patients in China. METHODS: Usefulness of TLC as a surrogate marker for a CD4 cell count <350 cells/mm(3 for HIV-positive patients in China was evaluated by 977 pairs of TLC and CD4 cell count from 977 outpatients. The result was then validated by a literature review which was conducted on 9 relevant articles. Further investigation using the 977 pairs of TLC and CD4 cell count data was done to determine a TLC threshold for predicting a CD4 cell count <500 cells/mm(3. Correlation and receiver operating characteristic (ROC analysis were performed for both CD4 cell counts, and the sensitivity and specificity were computed. RESULTS: Good correlation was noted between TLC and CD4 count (r = 0.60, 95% CI, 0.56-0.64. TLC obtained a relatively high diagnostic performance (area under ROC curve, 0.80 for predicting a CD4 cell count <350 cells/mm(3, with a sensitivity of 0.65 (95% CI, 0.61-0.68 and a specificity of 0.80 (95% CI, 0.75-0.85 at the TLC threshold of 1570 cells/mm(3. The literature review suggested that for a CD4 cell count <350 cells/mm(3, the optimal TLC threshold was 1500 cells/mm(3, which was similar to the figure presented in this observational study. As for predicting a CD4 cell count <500 cells/mm(3, TLC obtained a high diagnostic performance (area under ROC curve, 0.82 as well with a sensitivity of 0.70 (95% CI, 0.67-0.73 and a specificity of 0.80 (95% CI, 0.73-0.87. CONCLUSIONS: When considering the antiretroviral therapy for HIV-infected Chinese individuals, total lymphocyte count can be considered as an inexpensive and easily available surrogate marker for predicting two clinically important thresholds of CD4 count of 350 cells/mm(3 and 500 cells/mm(3.

  6. Homeostatically maintained resting naïve CD4+ T cells resist latent HIV reactivation

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    Yasuko Tsunetsugu-Yokota

    2016-12-01

    Full Text Available Homeostatic proliferation (HSP is a major mechanism by which long-lived naïve and memory CD4+ T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4+ T cells that were initially differentiated via T-cell receptor stimulation (TCR into memory/effector cells, latent infection of naïve resting CD4+ T cells maintained under HSP conditions has not been fully addressed. Here we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4+ T cells. CD4+ T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naïve cells are in part maintained in the non-dividing (= resting state. Although a few HIV-1 provirus+ cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naïve CD4+ T cells that may be distinct from that in TCR-stimulated memory/effector T cells.

  7. Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.

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    Chen, Li; Liu, Dan; Zhang, Yang; Zhang, Huan; Cheng, Hua

    2015-10-23

    The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T ce