Similar Datasets
Project description:Cellular composition and responsiveness of immune system evolve upon ageing and are influenced by biological sex. CD4+ T cells from women living with HIV exhibit decreased viral replication ex vivo compared to men. We thus hypothesized that these findings could be recapitulated in vitro, and infected primary CD4+ T cells with HIV-based vectors pseudotyped with VSV-G or HIV envelopes. We used cells isolated from twenty donors to interrogate the effect of sex and age on permissiveness over a six-day activation kinetics. Our data identified an increased permissiveness to HIV between 24 and 72h post-stimulation. Sex- and age-based analysis at these time points showed increased susceptibility to HIV of cells isolated from males and from donors over 50 years old, respectively. Parallel assessment of surface marker expression revealed higher frequencies of activation markers (CD69, CD25, HLA-DR) and immune check point inhibitors (PD-1 and CTLA-4 in cells from highly permissive donors. Furthermore, positive correlations were identified between CD69, PD-1 and CTLA-4 expression kinetics and HIV expression kinetics. Cell population heterogeneity was assessed by single-cell RNA-Seq analysis and no cell subtype enrichment was identified according to sex. Finally, transcriptomic analyses further highlighted the role of activation in those differences with enriched activation and cell cycle gene sets in men and in older women cells. Altogether, this study brought further evidence about individual features affecting HIV replication at the cellular level and should be considered in latency reactivation studies for HIV cure.
2023-12-13 | GSE247484 | GEO
Project description:Cellular composition and responsiveness of immune system evolve upon ageing and are influenced by biological sex. CD4+ T cells from women living with HIV exhibit decreased viral replication ex vivo compared to men. We thus hypothesized that these findings could be recapitulated in vitro, and infected primary CD4+ T cells with HIV-based vectors pseudotyped with VSV-G or HIV envelopes. We used cells isolated from twenty donors to interrogate the effect of sex and age on permissiveness over a six-day activation kinetics. Our data identified an increased permissiveness to HIV between 24 and 72h post-stimulation. Sex- and age-based analysis at these time points showed increased susceptibility to HIV of cells isolated from males and from donors over 50 years old, respectively. Parallel assessment of surface marker expression revealed higher frequencies of activation markers (CD69, CD25, HLA-DR) and immune check point inhibitors (PD-1 and CTLA-4 in cells from highly permissive donors. Furthermore, positive correlations were identified between CD69, PD-1 and CTLA-4 expression kinetics and HIV expression kinetics. Cell population heterogeneity was assessed by single-cell RNA-Seq analysis and no cell subtype enrichment was identified according to sex. Finally, transcriptomic analyses further highlighted the role of activation in those differences with enriched activation and cell cycle gene sets in men and in older women cells. Altogether, this study brought further evidence about individual features affecting HIV replication at the cellular level and should be considered in latency reactivation studies for HIV cure.
2023-12-13 | GSE247485 | GEO
Project description:Sex and Age Impact CD4+ T Cell Susceptibility to HIV In Vitro Through Cell Activation Dynamics
| PRJNA1038762 | ENA
Project description:Sex and Age Impact CD4+ T Cell Susceptibility to HIV In Vitro Through Cell Activation Dynamics [scRNA-Seq]
| PRJNA1038764 | ENA
Project description:Sex and Age Impact CD4+ T Cell Susceptibility to HIV In Vitro Through Cell Activation Dynamics [bulk RNA-Seq]
| PRJNA1038768 | ENA
Project description:BackgroundCD4 cell count is a key measure of HIV disease progression, and the basis of successive international guidelines for treatment initiation. CD4 cell dynamics are used in mathematical and econometric models for evaluating public health need and interventions. Here, we estimate rates of CD4 decline, stratified by relevant covariates, in a form that is clinically transparent and can be directly used in such models.MethodsWe analyse the AIDS Therapy Evaluation in the Netherlands cohort, including individuals with date of seroconversion estimated to be within 1 year and with intensive clinical follow-up prior to treatment initiation. Owing to the fact that CD4 cell counts are intrinsically noisy, we separate the analysis into long-term trends of smoothed CD4 cell counts and an observation model relating actual CD4 measurements to the underlying smoothed counts. We use a monotonic spline smoothing model to describe the decline of smoothed CD4 cell counts through categories CD4 above 500, 350-500, 200-350 and 200 cells/μl or less. We estimate the proportion of individuals starting in each category after seroconversion and the average time spent in each category. We examine individual-level cofactors which influence these parameters.ResultsAmong untreated individuals, the time spent in each compartment was 3.32, 2.70, 5.50 and 5.06 years. Only 76% started in the CD4 cell count above 500 cells/μl compartment after seroconversion. Set-point viral load (SPVL) was an important factor: individuals with at least 5 log10 copies/ml took 5.37 years to reach CD4 cell count less than 200 cells/μl compared with 15.76 years for SPVL less than 4 log10 copies/ml.ConclusionMany individuals already have CD4 cell count below 500 cells/μl after seroconversion. SPVL strongly influences the rate of CD4 decline. Treatment guidelines should consider measuring SPVL, whereas mathematical models should incorporate SPVL stratification.
| S-EPMC4645962 | biostudies-literature
Project description:ObjectiveNew guidelines recommend that all HIV-infected individuals initiate antiretroviral treatment (ART) immediately following diagnosis. This study describes how immune reconstitution varies by gender and age to help identify poorly reconstituting subgroups and inform targeted testing initiatives.DesignLongitudinal data from the outpatient monitoring system of the National AIDS Control Program in Tanzania.MethodsAn asymptotic nonlinear mixed effects model was fit to post-treatment CD4+ cell count trajectories, allowing for fixed effects of age and sex, and an age by sex interaction.ResultsAcross 220,544 clinic visits from 32,069 HIV-infected patients, age- and sex-specific average CD4+ cell count at ART initiation ranged from 83-136 cells/mm3, long term asymptotic CD4+ cell count ranged from 301-389 cells/mm3, and time to half of maximal CD4+ reconstitution ranged from 3.57-5.68 months. CD4+ cell count at ART initiation and asymptotic CD4+ cell count were 1.28 (95% CI: 1.18-1.40) and 1.25 (95% CI: 1.20-1.31) times higher, respectively, for females compared to males in the youngest age group (19-29 years). Older patients started treatment at higher CD4+ counts but experienced slower CD4+ recovery than younger adults. Treatment initiation at greater CD4+ cell counts was correlated with greater asymptotic CD4+ cell counts within all sex and age groups.ConclusionOlder adults should initiate care early in disease progression because total immune reconstitution potential and rate of reconstitution appears to decrease with age. Targeted HIV testing and care linkage remains crucial for patient populations who tend to initiate treatment at lower CD4+ cell counts, including males and younger adults.
| S-EPMC5055355 | biostudies-literature
Project description:BackgroundHIV infection induces chronic immune activation which is associated with accelerated disease progression; the causes of this activation, however, are incompletely understood. We investigated the activation status of CD4+ T cells specific for chronic herpes viruses and the non-persistent antigen tetanus toxoid (TT) in HIV positive and HIV negative donors to assess whether persistent infections contribute to chronic CD4+ T cell activation.MethodsUntreated HIV+ patients and healthy, aged matched controls were recruited and activation levels assessed and compared between cells specific for persistent and non-persistent antigens. Activation levels on antigen-specific CD4+ T cells were measured by intracellular cytokine staining following in vitro stimulation with various recall antigens (CMV, EBV, HSV, VZV and TT) in conjunction with cell surface phenotyping.ResultsActivation levels of herpes virus-specific CD4+ T cell populations, assessed by co-expression of CD38 and HLA-DR, were significantly elevated in HIV+ individuals compared to normal controls and compared to TT-specific responses. In contrast, we found similar levels of activation of TT-specific CD4+ T cells in HIV+ and HIV- donors.ConclusionsThese results show a disparate distribution of immune activation within CD4+ T cell populations depending on their specificity and suggest that the elevated level of immune activation that characterizes chronic HIV infection may be influenced by the persistence of other antigens.
| S-EPMC3598342 | biostudies-literature
Project description: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.
| S-EPMC5648138 | biostudies-literature
Project description:The increasing prevalence of human immunodeficiency virus (HIV) drug resistance mutations (HIVDRM) in untreated seropositive persons has consequences for future treatment options. This is extremely important in key populations such as female sex workers (FSWs), where the prevalence of pretreatment drug resistance (PDR) and associated risk factors are unknown. In this study, we analyzed PDR and associated risk factors in recently diagnosed and treatment-naive FSWs in Nairobi, Kenya. In this cross-sectional study, we used 64 HIV-seropositive plasma samples collected from FSWs between November 2020 and April 2021. To identify HIVDRM, the pol gene was amplified and genotyped using sanger sequencing. The effects of age, tropism, CD4+ T cell count, subtype, and location on HIVDRM counts were examined using Poisson regression. Overall, the prevalence of PDR was 35.9% (95% CI: 24.3-48.9), which was strongly influenced by K103N and M184V mutations, which confer resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTI), respectively. Subtype A1 was predominant followed by subtype D with a notable increase in inter-subtype recombinants. We found statistically significant evidence that age was inversely related to HIVDRM. A FSW who is 1 year older had 12% less HIVDRM (incidence rate ratios [IRR]: 0.88; 95% CI: 0.82-0.95; P < .001), after adjusting for CD4+ T cell count, subtype, location, and tropism. Similarly, an increase in CD4+ T cell count by 1 unit, was associated with 0.4% fewer HIVDRM (IRR: 0.996; 95% CI: 0.994-0.998; P = .001), while controlling for the other variables. HIV-1 tropism was not associated with HIVDRM counts. In conclusion, our findings show a high prevalence of NNRTIs. Lower CD4+ T cell counts and younger age were significant risk factors that influenced HIVDRM loads. This finding underscores the relevance of targeted interventions and the importance of continuing to focus on FSWs as a way of addressing the HIV epidemic.
| S-EPMC10270489 | biostudies-literature