Epigenetic regulation of HIV latency

Hakre, Shweta; Chávez, Leonard; Shirakawa, Kotaro; Verdin, Eric

doi:10.1097/coh.0b013e3283412384

Cited by 93 publications

(84 citation statements)

References 51 publications

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“…These findings provided indirect and direct evidence that RNA polymerase II activity is paused on the FIV promoter, a finding also reported for cells latently infected with HIV [123,127,128]. These findings collectively reveal that circulating CD4+ T cells serve as a reservoir for latent FIV infections with latency characterized by at least one similar regulatory mechanism, repressive chromatin, that has also been described for HIV-1 latency in patients on ART [129].…”

Section: Fiv Latencysupporting

confidence: 72%

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Eckstrand

Sparger

Murphy

2017

Journal of General Virology

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Infection with feline immunodeficiency virus (FIV), a lentivirus similar to human immunodeficiency virus (HIV), results in lifelong viral persistence and progressive immunopathology in the cat. FIV has the ability to infect and produce infectious virus in a number of different cell types. FIV provirus can also be maintained in a replication-competent but transcriptionally quiescent state, facilitating viral persistence over time. Immediately after the initial infection, FIV infection quickly disseminates to many anatomical compartments within the host including lymphoid organs, gastrointestinal tract and brain. Collectively, the anatomic and cellular compartments that harbour FIV provirus constitute the viral reservoir and contain foci of both ongoing viral replication and transcriptionally restricted virus that may persist over time. The relative importance of the different phenotypes observed for infected cells, anatomic compartment, replication status and size of the reservoir represent crucial areas of investigation for developing effective viral suppression and eradication therapies. In this review, we discuss what is currently known about FIV reservoirs, and emphasize the utility of the FIV-infected cat as a model for the HIV-infected human.

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Section: Fiv Latencysupporting

confidence: 72%

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Eckstrand

Sparger

Murphy

2017

Journal of General Virology

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“…Cellular activation leads to virus production and, if treatment is interrupted, viremia rebounds within weeks (5). Several molecular mechanisms maintain latency, including epigenetic modifications, transcriptional interference from host genes, and the absence of activated transcription factors (6)(7)(8)(9).…”

mentioning

confidence: 99%

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Hill

Rosenbloom

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

248

313

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Significance HIV infection cannot be cured by current antiretroviral drugs, due to the presence of long-lived latently infected cells. New antilatency drugs are being tested in clinical trials, but major unknowns remain. It is unclear how much latent virus must be eliminated for a cure, which remains difficult to answer empirically due to few case studies and limited sensitivity of viral reservoir assays. In this paper, we introduce a mathematical model of HIV dynamics to calculate the likelihood and timing of viral rebound following antilatency treatment. We derive predictions for the required efficacy of antilatency drugs, and demonstrate that rebound times may be highly variable and occur after years of remission. These results will aid in designing and interpreting HIV cure studies.

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“…The chromatin environment is critical for the establishment and maintenance of latent HIV infection (8)(9)(10). Epigenetic modifications such as histone methylation and deacetylation appear to play a role in maintaining HIV latency.…”

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confidence: 99%

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Tripathy

McManamy

Burch

et al. 2015

J Virol

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Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV gag RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4 ؉ T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials. IMPORTANCEDemethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4 ؉ T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection. C urrent antiretroviral therapy (ART) potently suppresses human immunodeficiency virus type 1 (HIV-1) replication; however, HIV infection persists (1, 2). The primary reservoir of persistent infection is a small pool of latently infected resting central memory CD4 ϩ T cells (3-5). This reservoir must be targeted in any attempt to eradicate HIV-1 infection. Latent HIV infection is defined as dormant, nonreplicating virus that can be recovered following activation of the latently infected cell. However, a recent study found that a single exposure to latency-reversing agents, even a broad mitogenic signal, does not reverse latency universally throughout a population of infected cells,...

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Epigenetic regulation of HIV latency

Abstract: These new epigenetic regulators of HIV latency pose as potential interesting candidates for therapeutics against HIV latency.

Cited by 93 publications

References 51 publications

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

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Epigenetic regulation of HIV latency

Abstract: These new epigenetic regulators of HIV latency pose as potential interesting candidates for therapeutics against HIV latency.

Cited by 93 publications

References 51 publications

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 + T Cells

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H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells