Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BACH2 Controls Seeding and Establishment of Long-Lived HIV-1 Reservoir in CD4+ T cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275936 | GEO | 2024/11/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

Project description:During HIV infection, a latent viral reservoir is formed that persists during antiretroviral therapy (ART) and is maintained by a heritable state of transcriptional repression. Recent findings indicate that much of the reservoir originates from infections occurring in the weeks near the time of ART initiation, raising the important possibility that interventions during this period might prevent reservoir seeding and substantially reduce reservoir size. Based on this concept, we tested the ability of compounds that target epigenetic machinery to prevent the establishment of latent HIV infection in primary CD4 T cells. We identified class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention, an activity distinct from latency reversal. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression, even after HDACi withdrawal, and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to a striking change in the memory subset distribution indicating reprogramming of cell identity. Through knockout of individual HDACs and use of HDAC-selective inhibitors, we determined that HDAC1 and HDAC3 play crucial and distinct roles in proviral silencing initiation. Overall, this work indicates that a network of HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus. Epigenetic reprogramming by clinical targeting of HDACs during ART initiation may represent a novel way to prevent seeding of the HIV reservoir in vivo

2023-08-08 | GSE199946 | GEO

Long-term Antiretroviral Treatment Initiated in Primary HIV-1 Infection Affects the Size, Composition and Decay Kinetics of the Reservoir of HIV-1 Infected CD4 T Cells

Project description:Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy in primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of therapy in chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed exclusively during the initial 3-4 years of treatment; however, in patients who started antiretroviral therapy in acute infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. Moreover, gene transcripts in CD4 T cells associated with the total viral CD4 T cell reservoir size frequently correlated with the relative proportion of these long-lived CD4 T cell subsets, suggesting shared gene expression signatures for maintaining HIV-1 persistence and preservation of long-lasting CD4 T cell subsets. Despite effective suppression of viral antigens for >10 years, HIV-1-specific T cell responses remained continuously detectable in both study groups. Together, these data suggest that although early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients attractive candidates for future interventional studies aiming at HIV-1 eradication and cure.

2017-01-01 | GSE53527 | GEO

BACH2 Controls Seeding and Establishment of Long-Lived HIV-1 Reservoir in CD4+ T cells

Project description:BACH2 Controls Seeding and Establishment of Long-Lived HIV-1 Reservoir in CD4+ T cells

| PRJNA1153621 | ENA

Infusion of CCR5-edited T cells Allows Immune Reconstitution and HIV Reservoir Decay

Project description:Hematopoietic stem cell transplantation from a donor whose T cells did not express CCR5—a co-receptor for HIV—resulted in an apparent cure of an HIV-infected adult1. Herein, we have exploited this strategy by adoptive transfer of autologous CCR5 gene disrupted CD4+ T cells (SB-728-T) in 9 HIV+ participants. A single infusion of SB-728-T, a minimally invasive intervention, led to sustained increases in CD4+ T cell counts through 3.5 years (33-44 months) compared to baseline (median increase of +193 cells/µl, P = 0.02). The degree of long-term immune reconstitution was associated with expansion of a polyclonal stem cell-like CCR5-depleted CD4+ T cell population. SB-728-T therapy was also associated with expansion of polyfunctional HIV-specific CD8+ T cells (P = 0.03) and decline in size of the HIV reservoir (-0.23 to -3.6 log decrease). Collectively, these data suggest that generation and protection of CD4 memory cells will improve T cell homeostasis, enhance HIV-specific immunity, and accelerate the decline of the host HIV reservoir.

2016-02-01 | GSE66214 | GEO

Profound phenotypic and epigenetic heterogeneity of the HIV-1 infected CD4+ T cell reservoir

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

Transcriptional reprogramming of human CD4 T cells transitioning from active to memory state

Project description:The latent reservoir for HIV-1 in resting memory CD4+ T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4+ T cells undergoing effector-to-memory transition including temporary up-regulation of CCR5 expression and rapid down-regulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration, but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4+ T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4+ T cells. Establishment of latent HIV-1 infection in CD4+ T could be inhibited by viral-specific CD8+ T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines.

2017-09-27 | GSE104275 | GEO

People with HIV have higher percentages of circulating CCR5+ CD8+ T cells and lower percentages of CCR5+ regulatory T cells

Project description:CCR5 is the main HIV co-receptor. We aimed to (1) compare CCR5 expression on immune cells between people living with HIV (PLHIV) using combination antiretroviral therapy (cART) and HIV-uninfected controls, (2) relate CCR5 expression to viral reservoir size and (3) assess detereminants of CCR5 expression. Percentages of CCR5 positive cells (%) and CCR5 mean fluorescence intensity (MFI) assessed by flow cytometry in monocytes and lymphocyte subsets were correlated to host factors, HIV-1 cell-associated (CA)-RNA and CA-DNA, plasma inflammation markers and metabolites.

2022-08-12 | PXD031628 | Pride

IL-15 Enhances HIV-1 infection by Promoting Differentiation and Survival of CCR5+CD4+ T cells

Project description:HIV-1 usually utilize CCR5 as the co-receptor and rarely switches to CXCR4-tropic until late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in patients as well as SIV-infected non-human primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4+ T cells exhibiting effector or effector memory phenotype with high expression levels of the IL-2/IL-15 receptor common beta and gamma chains. IL-15 but not IL-7 improves the survival of CCR5+CD4+ T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15-based boosting of anti-HIV-1 immunity should carefully exam the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.

2022-04-03 | GSE199729 | GEO

Pharmacological modulation of the Wnt/β-catenin pathway inhibits the proliferation of long-lived latently-infected memory CD4+ T-cells in ART-suppressed SIV-infected macaques

Project description:The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently-infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4+ T-cells with high self-renewal capacity such as central memory T-cells (CM) and T memory stem cells (SCM) are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T-cells and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently-infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4+ T-cells in the rhesus macaque (RM) model of SIV infection. We used an inhibitor of the Wnt/β-catenin pathway, PRI-724, that blocks the interaction between the co-activator CREB binding protein (CBP) and β-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIVmac251-infected RMs: (i) was well tolerated, with blood counts, liver enzymes, and renal function within normal limits and no alteration of tri-lineage hematopoiesis observed in bone marrow, (ii) resulted in decreased proliferation of SCM and CM T-cells, (iii) modified the SCM and CM CD4+ T-cell transcriptome towards a profile of more differentiated memory T-cells, and (iv) reduced SIV-DNA levels in CM and TFH CD4+ T-cells in the lymph nodes, but did not decrease the overall viral reservoir size. This work is the first demonstration in vivo that pharmacological modulation can effectively target T cell stemness in long-lived memory CD4+ T-cells, and represents a potential strategy to reduce HIV persistence.

2022-02-24 | GSE127330 | GEO

Transcriptional profiling of VIH ALT patients

Project description:Elite Long-Term Nonprogressors are asymptomatic HIV-infected individuals who display long-term virtually undetectable viremia, stable CD4 T cell counts and extremeley low levels of HIV reservoir, in the absence of antiretroviral therapy. We conducted a whole-genome transcriptional profiling study of sorted resting CD4 T cell subsets (naive, central memory, transitional memory and effector memory) in 7 Elite Long-Term Nonprogressors, 7 HIV-infected viremic and 7 uninfected individuals. HIV-1 cellular DNA levels were quantified in each sorted CD4 T cell subset

2015-01-10 | E-MTAB-1480 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data