Comprehensive analysis of HIV reservoirs in elite controllers.
Ontology highlight
ABSTRACT:
SUBMITTER: Kennedy BD
PROVIDER: S-EPMC9888367 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
Publications
Comprehensive analysis of HIV reservoirs in elite controllers.
Kennedy Brooke D BD Blazkova Jana J Justement Jesse S JS Shi Victoria V Rai M Ali MA Manning Maegan R MR Praiss Lauren L Gittens Kathleen K Wender Paul A PA Patro Sean S Wu Xiaolin X Moir Susan S Chun Tae-Wook TW
The Journal of clinical investigation 20230201 3
Similar Datasets
Project description:Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.
| S-EPMC3789563 | biostudies-literature
Project description:BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.
| S-EPMC11014653 | biostudies-literature
Project description:HIV elite controllers (EC) are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment. Adaptive immunity and host genetic factors, although implicated, do not entirely explain this phenomenon. On the other hand, plasmacytoid dendritic cells (pDCs) are the principal type I interferon (IFN) producers in response to viral infection, and it is unknown whether pDCs are involved in the control of HIV infection in EC. In our study, we analyzed peripheral pDC levels and IFN-? production by peripheral blood mononuclear cells (PBMCs) in EC compared to other groups of HIV-infected patients, the ability of pDCs to reduce HIV production in vitro, and the mechanisms potentially involved. We showed preserved pDC counts and IFN-? production in EC. We also observed a higher capacity of pDCs from EC to reduce HIV production and to induce T cell apoptosis, whereas pDCs from viremic patients barely responded without previous Toll-like receptor 9 (TLR-9) stimulus. The preserved functionality of pDCs from EC to reduce viral production may be one of the mechanisms involved in the control of HIV viremia in these subjects. These results demonstrate the importance of innate immunity in HIV pathogenesis, and an understanding of pDC mechanisms would be helpful for the design of new therapies.
| S-EPMC3318617 | biostudies-literature
Project description:Elite controllers spontaneously control HIV-1 replication, which in many cases is associated with preservation of normal CD4 T-cell counts. However, a subset of elite controllers has progressive CD4 T-cell losses despite undetectable viral loads, for reasons that remain undefined. Here, we assessed mechanisms of CD4 T-cell homeostasis in elite controllers with progressive vs. nonprogressive HIV-1 disease courses.Flow cytometry assays were used to determine the proliferation, activation and apoptosis levels of naive T cells in elite controllers with high or low CD4 T-cell counts and reference cohorts of HIV-1-negative and HAART-treated persons. Thymic output was measured by single-joint T-cell receptor excision circle (sjTREC)/? T-cell receptor excision circle (?TREC) ratios, and the frequency of circulating recent thymic emigrants was flow cytometrically determined by surface expression of protein tyrosine kinase 7.Proportions of naive T cells in elite controllers were severely reduced and closely resemble those of HIV-1 patients with progressive disease. Despite reductions in naive T cells, most elite controllers were able to maintain normal total CD4 T-cell counts by preservation of uncompromised thymic function in conjunction with extrathymic processes that led to elevated levels of circulating recent thymic emigrants. In contrast, elite controllers with low CD4 T-cell counts had reduced thymic output that mirrored thymic dysfunction during untreated progressive HIV-1 infection.These results indicate that both thymic and extrathymic mechanisms contribute to CD4 T-cell maintenance in elite controllers and support the idea that CD4 T-cell homeostasis and control of viral replication are distinct but frequently coinciding processes.
| S-EPMC3729591 | biostudies-literature
Project description:BackgroundData on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa.MethodsFor the Temprano trial, antiretroviral therapy (ART)-naive HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30 months. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral <2000 copies/ml and still off ART at month 30 were defined as HIV-1 controllers. Controllers with all viral loads <50 copies/ml were defined as elite controllers, the rest as viremic controllers.ResultsOf the 1023 HIV-1-infected adults randomized in the Temprano deferred-ART group, 18 (1.8%) met the criteria for classification as HIV controllers, of whom seven (0.7%) were elite controllers and 11 (1.1%) viremic controllers. The HIV-1 controllers had low peripheral blood mononuclear cell HIV-1 DNA and low inflammatory marker levels. They maintained high CD4+ cell count and percentages and had a low morbidity rate.DiscussionHIV controllers exist in Africa at a proportion close to that reported elsewhere. They represent a small fraction of all HIV-1-infected patients but raise important questions. Further studies should assess whether starting ART might represent more risk than benefit for some controllers, and where it does, how to identify these patients before they start ART.
| S-EPMC8654265 | biostudies-literature
Project description:Elite controllers maintain HIV-1 viral loads below the limit of detection. The mechanisms responsible for this phenomenon are poorly understood. As microRNAs (miRNAs) are regulators of gene expression and some of them modulate HIV infection, we have studied the miRNA profile in plasma from HIV elite controllers and chronically infected individuals and compared against healthy donors. Several miRNAs correlate with CD4+ T cell count or with the known time of infection. No significant differences were observed between elite controllers and healthy donors; however, 16 miRNAs were different in the plasma of chronic infected versus healthy donors. In addition, levels of hsa-miR-29b-3p, hsa-miR-33a-5p and hsa-miR-146a-5p were higher in plasma from elite controllers than chronic infected and hsa-miR-29b-3p and hsa-miR-33a-5p overexpression significantly reduced the viral production in MT2 cells. Therefore, levels of circulating miRNAs might be of diagnostic and/or prognostic value for HIV infection. Additionally, hsa-miR-29b-3p and miR-33a-5p may be used in therapeutic strategies.
2014-08-04 | GSE58868 | GEO
Project description:Elite controllers maintain HIV-1 viral loads below the limit of detection. The mechanisms responsible for this phenomenon are poorly understood. As microRNAs (miRNAs) are regulators of gene expression and some of them modulate HIV infection, we have studied the miRNA profile in plasma from HIV elite controllers and chronically infected individuals and compared against healthy donors. Several miRNAs correlate with CD4+ T cell count or with the known time of infection. No significant differences were observed between elite controllers and healthy donors; however, 16 miRNAs were different in the plasma of chronic infected versus healthy donors. In addition, levels of hsa-miR-29b-3p, hsa-miR-33a-5p and hsa-miR-146a-5p were higher in plasma from elite controllers than chronic infected and hsa-miR-29b-3p and hsa-miR-33a-5p overexpression significantly reduced the viral production in MT2 cells. Therefore, levels of circulating miRNAs might be of diagnostic and/or prognostic value for HIV infection. Additionally, hsa-miR-29b-3p and miR-33a-5p may be used in therapeutic strategies. An exploratory cross-sectional study of microRNA levels in EDTA plasma samples. Plasma samples were obtained from 24 subjects and were classified in 3 groups, 9 Elite Controllers (defined as individuals with plasma viral load (PVL) < 50 copies/ml, CD4 count >350/ml), 9 chronic HIV patients (CH) under anti-retroviral treatment and 6 healthy HIV negative donors (HD). This study was approved by the HuM-CM-)sped Foundation Ethics Committee and informed consent was obtained from all subjects.
2014-08-04 | E-GEOD-58868 | biostudies-arrayexpress
Project description:Impaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; however, activity of the accessory protein Nef remains incompletely characterized. We examined the ability of 91 Nef clones, isolated from plasma of 45 EC and 46 chronic progressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariant chain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC.In general, EC Nef clones were functional; however, all five activities were significantly lower in EC compared to CP. Nef clones from HLA-B*57-expressing EC exhibited poorer CD4 down-regulation function compared to those from non-B*57 EC, and the number of EC-specific B*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in these individuals.Results indicate that decreased HIV-1 Nef function, due in part to host immune selection pressures, may be a hallmark of the EC phenotype.
| S-EPMC3564836 | biostudies-literature
Project description:Less than 0.5% of people living with HIV-1 are elite controllers (ECs) - individuals who have a replication-competent viral reservoir in their CD4+ T cells but maintain undetectable plasma viremia without the help of antiretroviral therapy. While the EC CD4+ T cell transcriptome has been investigated for gene expression signatures associated with disease progression (or, in this case, a lack thereof), the expression and regulatory activity of transposable elements (TEs) in ECs has not been explored. Yet previous studies have established that TEs can directly impact the immune response to pathogens, including HIV-1. Thus, we hypothesize that the regulatory activities of TEs could contribute to the natural resistance of ECs against HIV-1. We perform a TE-centric analysis of previously published multi-omics data derived from EC individuals and other populations. We find that the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, treated patients, and viremic progressors. However, there is a substantial level of transcriptomic heterogeneity among ECs. We categorize individuals with distinct chromatin accessibility and expression profiles into four clusters within the EC group, each possessing unique repertoires of TEs and antiviral factors. Notably, several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their transcript levels in ECs positively correlate with their chromatin accessibility and negatively correlate with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated variation is seen at the level of individual TE loci likely acting or, in some cases, known to act as cis-regulatory elements for nearby genes involved in the immune response and HIV-1 restriction. Based on these results, we propose that the EC phenotype is driven in part by the reduced availability of specific KZNF proteins to repress TE-derived cis-regulatory elements for antiviral genes, thereby heightening their basal level of resistance to HIV-1 infection. Our study reveals considerable heterogeneity in the CD4+ T cell transcriptome of ECs, including variable expression of TEs and their KZNF controllers, that must be taken into consideration to decipher the mechanisms enabling HIV-1 control.
| S-EPMC10760019 | biostudies-literature
Project description:BackgroundLess than 0.5% of people living with HIV-1 are elite controllers (ECs)-individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated with HIV-1 resistance, the expression and regulatory activity of transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute to HIV-1 elite control. To begin testing this hypothesis, we conduct a TE-centric analysis of public multi-omics data from ECs and other populations.ResultsWe find the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, from people living with HIV-1 on antiretroviral therapy, and from viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. We categorize ECs into four clusters with distinct expression and chromatin accessibility profiles of TEs and antiviral factors. Several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their expression positively correlates with their chromatin accessibility in ECs and negatively correlates with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms a network of putative cis-regulatory elements for genes involved in HIV-1 restriction.ConclusionsWe propose that the EC phenotype is driven in part by reduced KZNF-mediated repression of specific TE-derived cis-regulatory elements for antiviral genes, heightening their resistance against HIV-1. Our study reveals heterogeneity in the EC CD4+ T cell transcriptome, including variable expression of TEs and their KZNF controllers, that must be considered when deciphering HIV-1 control mechanisms.
| S-EPMC11849351 | biostudies-literature