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

ABSTRACT: Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4⁺ T cell reservoir from ART-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 new and known surface markers within total and individual memory CD4⁺ T cell subsets. We further uncovered new 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.

SUBMITTER: Wu VH

PROVIDER: S-EPMC9892009 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4<sup>+</sup> T cell reservoir.

Wu Vincent H VH Nordin Jayme M L JML Nguyen Son S Joy Jaimy J Mampe Felicity F Del Rio Estrada Perla M PM Torres-Ruiz Fernanda F González-Navarro Mauricio M Luna-Villalobos Yara Andrea YA Ávila-Ríos Santiago S Reyes-Terán Gustavo G Tebas Pablo P Montaner Luis J LJ Bar Katharine J KJ Vella Laura A LA Betts Michael R MR

Nature immunology 20221219 2

Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4<sup>+</sup> T cell reservoir from ART-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 id ...[more]

PMID: 36536105

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Project description:Despite significant advances in the treatment of human immunodeficiency virus type-1 (HIV) infection, antiretroviral therapy only suppresses viral replication but is unable to eliminate infection. Thus, discontinuation of antiretrovirals results in viral reactivation and disease progression. A major reservoir of HIV latent infection resides in resting central memory CD4+ T cells (TCM) that escape clearance by current therapeutic regimens and will require novel strategies for elimination. Here, we evaluated the therapeutic potential of autophagy-inducing peptides, Tat-Beclin 1 and Tat-vFLIP-α2, which can induce a novel Na+/K+-ATPase dependent form of cell death (autosis), to kill latently HIV-infected TCM while preventing virologic rebound. In this study, we encapsulated autophagy inducing peptides into biodegradable lipid-coated hybrid PLGA (poly lactic-co-glycolic acid) nanoparticles for controlled intracellular delivery. A single dose of nanopeptides was found to eliminate latent HIV infection in an in vitro primary model of HIV latency and ex vivo using resting CD4+ T cells obtained from peripheral blood mononuclear cells of HIV-infected patients on antiretroviral with fully suppressed virus for greater than 12 months. Notably, increased LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase activity characteristic of autosis, were detected in nanopeptide treated latently HIV-infected cells compared to untreated uninfected or infected cells. Nanopeptide-induced cell death could be reversed by knockdown of autophagy proteins, ATG5 and ATG7, and inhibition or knockdown of Na+/K+-ATPase. Importantly, viral rebound was not detected following the induction of the Na+/K+-ATPase dependent form of cell death induced by the Tat-Beclin 1 and Tat-vFLIP-α2 nanopeptides. These findings provide a novel strategy to eradicate HIV latently infected resting memory CD4+ T cells, the major reservoir of HIV latency, through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells.

Dataset Information

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

Publications

Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4<sup>+</sup> T cell reservoir.

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Dataset Information

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

Publications

Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4<sup>+</sup> T cell reservoir.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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