A unique viral reservoir landscape associated with durable natural control of HIV-1 infection
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ABSTRACT:
PROVIDER: PRJNA603379 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10972300_1.fastq.gz | Fastqsanger.gz | |||
| SRR10972300_2.fastq.gz | Fastqsanger.gz | |||
| SRR10972500_1.fastq.gz | Fastqsanger.gz | |||
| SRR10972500_2.fastq.gz | Fastqsanger.gz | |||
| SRR10972301_1.fastq.gz | Fastqsanger.gz |
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Project description:A unique viral reservoir landscape associated with durable natural control of HIV-1 infection [ATAC-seq]
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Project description:A unique viral reservoir landscape associated with durable natural control of HIV-1 infection [RNA-seq]
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Project description:Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected persons (“elite controllers”, ECs), despite the presence of a replication-competent viral reservoir. Such an ability to spontaneously maintain undetectable plasma viremia is a major objective of functional cure efforts, yet the characteristics of proviral reservoirs in ECs remain to be determined. Using single-genome, near full-length next-generation sequencing and chromosomal integration site analysis, we here show that proviral reservoirs of ECs frequently consist of oligoclonal to near monoclonal clusters of identical intact proviral sequences. In contrast to persons treated with long-term antiretroviral therapy, intact proviral species from ECs displayed highly distinct chromosomal integration sites in the human genome and were preferentially located in centromeric satellite DNA or in KRAB-ZNF genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, integration sites of intact proviruses from ECs showed increased distance to host transcriptional start sites and accessible chromatin and were enriched for repressive chromatin marks. These data suggest that a distinct proviral reservoir configuration represents a structural correlate of natural viral control, and that quality rather than quantity of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, failure to detect intact proviral sequences despite analyzing > 1.5 billion peripheral blood mononuclear cells in one EC raises the possibility that a sterilizing cure of HIV-1 infection, previously only observed following allogeneic hematopoietic stem cell transplantation, may be feasible in rare instances.
2020-06-15 | GSE144332 | GEO
Project description:Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected persons (“elite controllers”, ECs), despite the presence of a replication-competent viral reservoir. Such an ability to spontaneously maintain undetectable plasma viremia is a major objective of functional cure efforts, yet the characteristics of proviral reservoirs in ECs remain to be determined. Using single-genome, near full-length next-generation sequencing and chromosomal integration site analysis, we here show that proviral reservoirs of ECs frequently consist of oligoclonal to near monoclonal clusters of identical intact proviral sequences. In contrast to persons treated with long-term antiretroviral therapy, intact proviral species from ECs displayed highly distinct chromosomal integration sites in the human genome and were preferentially located in centromeric satellite DNA or in KRAB-ZNF genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, integration sites of intact proviruses from ECs showed increased distance to host transcriptional start sites and accessible chromatin and were enriched for repressive chromatin marks. These data suggest that a distinct proviral reservoir configuration represents a structural correlate of natural viral control, and that quality rather than quantity of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, failure to detect intact proviral sequences despite analyzing > 1.5 billion peripheral blood mononuclear cells in one EC raises the possibility that a sterilizing cure of HIV-1 infection, previously only observed following allogeneic hematopoietic stem cell transplantation, may be feasible in rare instances.
2020-06-15 | GSE144329 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-06-15 | GSE144334 | GEO
Project description:The latent reservoir of HIV persists for decades in people living with HIV (PWH) on antiretroviral therapy (ART). To determine if persistence arises from the natural dynamics of memory CD4+ T cells harboring HIV, we compared the clonal dynamics of HIV proviruses to that of memory CD4+ T cell receptors (TCRβ) from the same PWH and from HIV-seronegative people. We show that clonal dominance of HIV proviruses and antigen-specific CD4+ T cells are similar but that the field’s understanding of the persistence of the less clonally dominant reservoir is significantly limited by undersampling. We demonstrate that increasing reservoir clonality over time and differential decay of intact and defective proviruses cannot be explained by mCD4+ T cell kinetics alone. Finally, we develop a stochastic model of TCRβ and proviruses that recapitulates experimental observations and suggests that HIV-specific negative selection mediates approximately 6% of intact and 2% of defective proviral clearance. Thus, HIV persistence is mostly, but not entirely, driven by natural mCD4+ T cell kinetics.
2024-09-15 | GSE266695 | GEO
Project description:The size of lentiviral DNA reservoirs reflects effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding of innate mechanisms contributing to containment of HIV-DNA reservoir, however, are only partly clarified and are relevant to guide interventions for reservoir containment or eradication. We studied the contribution of Natural Killer (NK) cell functional features in HIV patients either controlling replication either spontaneously (HIC) or after progression and antiretroviral treatment (PP). An inverse correlation between HIV-DNA copy numbers (either total or integrated) in circulating CD4+ cells and NK cell function were observed. Induced IFN-gamma production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only when considering a homogeneous cohort of HIC patients, but also when PP patients were included in the analysis. Adaptive (NKG2C + CD57 + ) NK cell features were not associated with reservoir size. However a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV-DNA reservoir size. In proof-of-principle in vitro experiments of CD4+ cell infection with HIV-1, purified NK cells with the above functional/transcriptional features displayed a 10- and 30-fold higher ability to control HIV replication and DNA burden in vitro, respectively, compared to other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of HIV reservoir in CD4+ cells. Their selection, expansion and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment.
2018-08-01 | GSE102771 | GEO
Project description:Introduction: HIV infection causes pathologic changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long term viral control (5years) due to effective ART in a multicentre cross-sectional study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated. Methods: Peripheral Blood Mononuclear Cells (PBMCs) from 40 PHIV that started ART within two years of life (early treated patients, ET ≤ 6 months; late treated patients, LT > 6 months), with at least five years of HIV-1 suppression (< 40 HIV copies/ml), were collected between November 2017 and August 2018. NK phenotype and function were analysed by flow cytometry and transcriptional profile of PBMCs by RNA-Seq. HIV-1 DNA was measured by real-time PCR. Data were analysed by Spearman correlation plots and multivariable Poisson regression model (adjusted for baseline %CD4 and RNA HIV viral load and for age at ART start as interaction term, either ET or LT) to explore the association between NK cell parameters and HIV reservoir modulated by age at ART start. Results: A significantly higher frequency of CD56neg NK cells was found in LT compared with ET. We further found in LT a positive correlation of CD56neg NK with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, CD107a+ and IFN-γ+ frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally, RNA-Seq analysis showed in LT an upregulation of genes related to NK activating pathways and susceptibility to apoptosis compared with ET. Conclusions: We show that ET present a preserved NK compartment compared with LT, which is associated with lower HIV-1 reservoir and persist despite long-term viral control due to effective ART.
2021-07-14 | GSE168658 | GEO
Project description:Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a major impediment for HIV cure research. To address this, we developed single-cell viral ASAPseq to precisely define the unperturbed peripheral blood HIV-infected memory CD4+ T cell reservoir from antiretroviral treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by novel and known surface markers within total and individual memory CD4+ T cell subsets. We further uncovered novel epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.
2022-10-21 | GSE199727 | GEO
Project description:Despite antiretroviral therapy, HIV mainly persists in memory CD4+ T cells in people living with HIV. Most long-lived viral reservoir cells are infected near the time of therapy initiation. A better understanding of the early events in reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrated that CD4+ T cells expressing CCR5, permissive to HIV-1 infection, are effector or terminally differentiated cells. BACH2 is expressed by a small subset of CCR5+ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2 knockout human immune system has a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding of long-lived HIV-1 reservoir and demonstrates the potential of targeting BACH2 at the time of treatment initiation to eliminate HIV-1 reservoirs in T cells.
2024-11-01 | GSE275936 | GEO