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Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221687 | GEO
Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221686 | GEO
Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221685 | GEO
Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy 1. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells 2. However, the modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy 3,4. Aminobisphosphonates that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies 5. Here, we show the use of aminobisphosphonates as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that aminobisphosphonates induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin. RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further of alendronate-mediated latency reversal and activation of immune effector cells.Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of aminobisphosphonates to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
2023-09-13 | GSE224546 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-07-15 | E-GEOD-71065 | biostudies-arrayexpress
Project description:Antiretroviral therapy (ART) inhibits HIV replication but does not eradicate the latent reservoir. The previous research suggests that earlier ART initiation provides benefit on limiting reservoir size, but timing and extent of this effect remain unclear. Analytic treatment interruption (ATI) may be used to demonstrate HIV remission, but whether early ART also improves likelihood or duration of even temporary virologic remission is unclear. This review seeks to answer both questions. We performed a systematic review and analysis following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and included 21 interventional or observational studies with sufficient HIV reservoir outcomes. We also aggregated reservoir outcomes and transformed data into approximate measurements of total HIV DNA per million peripheral blood mononuclear cells and analyzed the correlation between timing of ART initiation and reservoir size. People living with HIV who initiate ART in primary infection maintain smaller reservoirs on suppressive ART than those who initiate treatment during chronic infection. The reduction of reservoir is most pronounced when ART is started within 2 weeks of HIV acquisition. Across studies, we found a moderately strong association between longer time to ART initiation and reservoir size, which was strongest when measured after 1 year on ART (Pearson's r = 0.69, p = 0.0003). After ATI, larger pre-ATI reservoir size predicts shorter time to viral rebound. Early ART may also facilitate long-term control of viremia. Although achieving sustained HIV remission will require further interventions, initiating ART very early in infection could limit the extent of the reservoir and also lead to post-ATI control in rare cases.
| S-EPMC7987773 | biostudies-literature
Project description:BackgroundPersistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men.MethodsART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells.ResultsWe did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes.ConclusionsDifferences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.
| S-EPMC7653086 | biostudies-literature
Project description:BackgroundA major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir"). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART).MethodsWe evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.ResultsAmong 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.ConclusionsOur findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.
| S-EPMC4970722 | biostudies-literature
Project description:BackgroundHIV-infection is known to aggravate the course of many infectious diseases, including COVID-19. International guidance recommends vaccination of HIV+ individuals against SARS-CoV-2. There is a paucity of data on epidemiological efficacy assessment of COVID-19 vaccines among HIV+. This paper provides a preliminary assessment of Sputnik V vaccine effectiveness in HIV+ patients on antiretroviral therapy (ART).MethodsWe performed a retrospective cohort study to assess the effectiveness of the standard Sputnik V vaccination regimen in 24,423 HIV+ Moscow residents during spring - summer 2021, that included dominance of delta variant, with estimation of hospitalization and severe illness rates in vaccinated and unvaccinated patients. Data were extracted from the Moscow anti-COVID-19 vaccination and COVID-19 incidence Registries.FindingsThe data obtained indicate that Sputnik V epidemiological efficiency in the entire cohort of HIV+ on ART was 76·33%; in HIV+ with CD4+ ≥ 350 cells/µl, vaccine efficiency was 79·42%, avoiding hospitalization in 90·12% cases and protecting from the development of moderate or severe disease in 97·06%. For delta variant in this group the efficiency was 65·35%, avoiding the need for hospitalization in 75·77% cases and protecting from the development of moderate or severe disease in 93·05% of patients. There was a trend, although not statistically significant, of declining vaccine efficiency in immune-compromised individuals (CD4+ < 350 cells/µl).InterpretationThe study suggested epidemiological efficiency of immunization with Sputnik V in HIV+ ART-treated patients for the original and delta SARS-CoV-2 variants.FundingMinistry of Health of Russia and Moscow Healthcare Department.
| S-EPMC8943473 | biostudies-literature
Project description:ObjectiveWe evaluated brain glucose metabolism in people living with HIV (PWH) with [18F]-Fluoro-Deoxyglucose (FDG) PET/computed tomography (CT) before and after antiretroviral therapy (ART) initiation.DesignWe conducted a longitudinal study wherein ART-naive late-presenting untreated PWH with CD4+ cell counts less than 100 cells/μl were prospectively assessed for FDG uptake at baseline and at 4-8 weeks (n = 22) and 19-26 months (n = 11) following ART initiation.MethodsRelative uptake in the subcortical regions (caudate, putamen and thalamus) and cortical regions (frontal, parietal, temporal and occipital cortices) were compared across time and correlated with biomarkers of disease activity and inflammation, in addition to being compared with a group of uninfected individuals (n = 10).ResultsBefore treatment initiation, putaminal and caudate relative FDG uptake values in PWH were significantly higher than in uninfected controls. Relative putaminal and thalamic uptake significantly decreased shortly following ART initiation, while frontal cortex values significantly increased. FDG uptake changes correlated with changes in CD4+ cell counts and viral load, and, in the thalamus, with IL-6R and sCD14. Approximately 2 years following ART initiation, there was further decrease in subcortical relative uptake values, reaching levels below those of uninfected controls.ConclusionOur findings support pretreatment basal ganglia and thalamic neuroinflammatory changes in PWH, which decrease after treatment with eventual unmasking of long-term irreversible neuronal damage. Meanwhile, increased frontal cortex metabolism following ART initiation suggests reversible cortical dysfunction which improves with virologic control and increased CD4+ cell counts. Early initiation of treatment after HIV diagnosis and secondary control of inflammation are thus necessary to halt neurological damage in PWH.
| S-EPMC8556661 | biostudies-literature