Targeting HIV latency: pharmacologic strategies toward eradication

Xing, Sifei; Siliciano, Robert F.

doi:10.1016/j.drudis.2012.12.008

Cited by 129 publications

(128 citation statements)

References 85 publications

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“…This has fueled the search for small molecule latency-reversing agents (LRAs) that do not induce T cell activation and cytokine release (reviewed in ref. 12).…”

Section: Introductionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

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“…This has fueled the search for small molecule latency-reversing agents (LRAs) that do not induce T cell activation and cytokine release (reviewed in ref. 12).…”

Section: Introductionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

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“…The removal of acetyl groups from histones by HDACs leads to transcriptional repression; inhibition of these enzymes is therefore thought to favour gene expression [34]. Vorinostat and panobinostat are hydroxamic acids that bind to zinc, preventing its use by the zinc-dependent HDACs [29], while romidepsin is activated in vivo to produce a zinc-binding thiol [35].…”

Section: Introductionmentioning

confidence: 99%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results:In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions:We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.

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“…It is generally accepted that eradication of the virus will require elimination of this latent reservoir (8,9). The absence of specific markers to distinguish latently infected cells from uninfected cells has led to the proposition that substances able to reverse the latent viral state should be used to "purge" the latent reservoir (10).…”

mentioning

confidence: 99%

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

Spivak

Bosque

Balch

et al. 2015

Antimicrob Agents Chemother

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The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4؉ T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4 ؉ T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4 ؉ T cells from aviremic HIV-1 ؉ patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1 ؉ antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4 ؉ T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation. Durable blockade of viral replication by combinations of antiretroviral drugs has transformed human immunodeficiency virus type 1 (HIV-1) infection from an untreatable, lethal condition characterized by progressive immune deficiency into a chronic, manageable medical problem for the vast majority of patients with access to therapy (1). Despite the ability of antiretroviral therapy (ART) to block ongoing HIV-1 replication and allow for restoration of the circulating CD4ϩ T cell population, HIV-1 eradication does not occur with these drugs due to the presence of long-lived viral reservoirs in resting memory CD4 ϩ T cells(2-4). ART can continuously suppress viral replication for years or even decades; however, patients who stop therapy will develop viremia within a matter of weeks and progress to overt immunodeficiency if ART is not resumed (5). This rebound viremia arises from a minority of cells among the resting memory CD4 ϩ T cell population harboring unexpressed HIV-1 proviral DNA that is stably integrated into the cellular genome (6).The HIV-1 latent reservoir in patients on ART is stable over a period of many years and does not decay significantly during the life span of an infected patient (7). It is generally accepted that eradication of the virus will require elimination of this latent reservoir (8, 9). The absence of specific markers to dist...

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Targeting HIV latency: pharmacologic strategies toward eradication

Cited by 129 publications

References 85 publications

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients

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Targeting HIV latency: pharmacologic strategies toward eradication

Cited by 129 publications

References 85 publications

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4+T Cells from Aviremic Patients

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Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4⁺T Cells from Aviremic Patients