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Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4⁺ T cells.

ABSTRACT: Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4⁺ T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs. non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of 'shock and kill', and suggest the need to explore other strategies to control the latent HIV reservoir.

SUBMITTER: Battivelli E

PROVIDER: S-EPMC5973828 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4<sup>+</sup> T cells.

Battivelli Emilie E Dahabieh Matthew S MS Abdel-Mohsen Mohamed M Svensson J Peter JP Tojal Da Silva Israel I Cohn Lillian B LB Gramatica Andrea A Deeks Steven S Greene Warner C WC Pillai Satish K SK Verdin Eric E

eLife 20180501

Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4<sup>+</sup> T cells and determined which ...[more]

PMID: 29714165

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Project description:DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.

Dataset Information

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4⁺ T cells.

Publications

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4<sup>+</sup> T cells.

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Dataset Information

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T cells.

Publications

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4⁺ T cells.