Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition

Pan, Xiaoyan; Zhao, Wei; Wang, Chunyan; Lin, Jian; Zeng, Xiangbin; Ren, Ruxia; Wang, Keng; Xun, Tianrong; Shai, Yechiel; Liu, Shuwen

doi:10.1074/jbc.m116.743906

Cited by 31 publications

(26 citation statements)

References 35 publications

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“…Heat shock protein 90 (Hsp90) is a molecular chaperone that is required for the normal functioning of a number of client proteins, and recent studies have demonstrated that Hsp90 activity is required for reversal of HIV latency (29)(30)(31)(32)(33). Additional work has also shown that Hsp90 deacetylation by a class 2 HDAC, HDAC6, activates Hsp90 activity (34,35) and that vorinostat, which inhibits HDAC6, causes acetylation of Hsp90 and inhibits its function (36,37).…”

Section: Resultsmentioning

confidence: 99%

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Zaikos

Painter

Kettinger

et al. 2018

J Virol

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Combinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of protein kinase C (PKC) agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of proviral factors regulated by non-class 1 histone deacetylases. Here, we show that class 1-selective agents used alone or with the PKC agonist bryostatin-1 induced more HIV protein expression per infected cell. In addition, the combination of entinostat and bryostatin-1 induced viral outgrowth, whereas bryostatin-1 combinations with pan-HDIs did not. When class 1-selective HDIs were used in combination with pan-HDIs, the amount of viral protein expression and virus outgrowth resembled that of pan-HDIs alone, suggesting that pan-HDIs inhibit robust gene expression induced by class 1-selective HDIs. Consistent with this, pan-HDI-containing combinations reduced the activity of NF-κB and Hsp90, two cellular factors necessary for potent HIV protein expression, but did not significantly reduce overall cell viability. An assessment of viral clearance from cultures indicated that maximal protein expression induced by class 1-selective HDI treatment was crucial for reservoir clearance. These findings elucidate the limitations of current approaches and provide a path toward more effective strategies to eliminate the HIV reservoir. Despite effective antiretroviral therapy, HIV evades eradication in a latent form that is not affected by currently available drug regimens. Pharmacologic latency reversal that leads to death of cellular reservoirs has been proposed as a strategy for reservoir elimination. Because histone deacetylases (HDACs) promote HIV latency, HDAC inhibitors have been a focus of HIV cure research. However, many of these inhibitors broadly affect multiple classes of HDACs, including those that promote HIV gene expression (class 1 HDACs). Here, we demonstrate that targeted treatment with class 1-selective HDAC inhibitors induced more potent HIV latency reversal than broadly acting agents. Additionally, we provide evidence that broadly acting HDIs are limited by inhibitory effects on non-class 1 HDACs that support the activity of proviral factors. Thus, our work demonstrates that the use of targeted approaches to induce maximum latency reversal affords the greatest likelihood of reservoir elimination.

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Section: Resultsmentioning

confidence: 99%

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Zaikos

Painter

Kettinger

et al. 2018

J Virol

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“…While differences in HSP90 protein expression were not observed, it is still possible that a deficiency in HSP90 activity under hypothermic conditions is responsible for the observations we described. HSP90 has been shown to be a positive regulator of HIV gene expression in numerous studies (26)(27)(28)(29)(30)(31)(32)(33)(34), and the mechanism of this activity is likely pleiotropic. Our findings further implicate HSP90 as potentially playing an important role in regulating HIV-1 latency, drawing a novel connection between quiescence-induced latency and HSP90 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…A growing body of literature supports the role of HSP90 in regulating HIV-1 gene expression, and the mechanisms of this effect are likely pleiotropic. HSP90 has been implicated in the activation of the NF-B pathway (25), the formation of stable P-TEFb complexes (26,27), and the formation of RNA polymerase II (Pol II) complexes in the cytoplasm (28). Hyperthermia has been shown to increase HIV-1 gene expression in persistently infected cell lines, in an HSP90-dependent manner, increasing the colocalization of HSP90 with the HIV-1 promoter (29)(30)(31)(32).…”

mentioning

confidence: 99%

Quiescence Promotes Latent HIV Infection and Resistance to Reactivation from Latency with Histone Deacetylase Inhibitors

Painter

Zaikos

Collins

2017

J Virol

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Human immunodeficiency virus type 1 (HIV-1) establishes transcriptionally silent latent infections in resting memory T cells and hematopoietic stem and progenitor cells (HSPCs), which allows the virus to persist in infected individuals despite antiretroviral therapy. Developing models of HIV-1 latency that recapitulate the characteristics of latently infected cells is crucial to identifying and developing effective latency-reversing therapies. HSPCs exist in a quiescent state , and quiescence is correlated with latent infections in T cells. However, current models for culturing HSPCs and for infecting T cells require that the cells be maintained in an actively proliferating state. Here we describe a novel culture system in which primary human HSPCs cultured under hypothermic conditions are maintained in a quiescent state. We show that these quiescent HSPCs are susceptible to predominantly latent infection with HIV-1, while actively proliferating and differentiating HSPCs obtain predominantly active infections. Furthermore, we demonstrate that the most primitive quiescent HSPCs are more resistant to spontaneous reactivation from latency than more differentiated HSPCs and that quiescent HSPCs are resistant to reactivation by histone deacetylase inhibitors or P-TEFb activation but are susceptible to reactivation by protein kinase C (PKC) agonists. We also demonstrate that inhibition of HSP90, a known regulator of HIV transcription, recapitulates the quiescence and latency phenotypes of hypothermia, suggesting that hypothermia and HSP90 inhibition may regulate these processes by similar mechanisms. In summary, these studies describe a novel model for studying HIV-1 latency in human primary cells maintained in a quiescent state. Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection for which there remains no feasible cure. Current approaches are unable to clear the virus despite decades of therapy due to the existence of latent reservoirs of integrated HIV-1, which can reactivate and contribute to viral rebound following treatment interruption. Previous clinical attempts to reactivate the latent reservoirs in an individual so that they can be eliminated by the immune response or viral cytopathic effect have failed, indicating the need for a better understanding of the processes regulating HIV-1 latency. Here we characterize a novel model of HIV-1 latency in primary hematopoietic stem and progenitor cells isolated from human cord blood that may better recapitulate the behavior of latently infected cells This model can be used to study mechanisms regulating latency and potential therapeutic approaches to reactivate latent infections in quiescent cells.

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“…Moreover, when added to cells together with entinostat, SAHA and RMD reduced GFP reporter expression (19). A specific inhibitory mechanism was proposed for the case of SAHA, which may interfere with HIV expression via inhibition of HDAC6, thus causing changes in the acetylation state of its nonhistone targets, such as chaperone protein HSP90 (19), which is required for reversal of HIV latency (35)(36)(37). This mechanism of inhibition, however, would not be an expected mechanism for RMD, because it does not inhibit HDAC6.…”

Section: Secondary Mechanisms Of Action Of Hdaci and Hiv Latencymentioning

confidence: 99%

Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

Beliakova-Bethell

Mukim

White

et al. 2019

Journal of Biological Chemistry

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Edited by Joel M. GottesfeldHistone deacetylase (HDAC) inhibitors (HDACis) have been widely tested in clinical trials for their ability to reverse HIV latency but have yielded only limited success. One HDACi, suberoylanilide hydroxamic acid (SAHA), exhibits off-target effects on host gene expression predicted to interfere with induction of HIV transcription. Romidepsin (RMD) has higher potency and specificity for class I HDACs implicated in maintaining HIV provirus in the latent state. More robust HIV reactivation has indeed been achieved with RMD use ex vivo than with SAHA; however, reduction of viral reservoir size has not been observed in clinical trials. Therefore, using RNA-Seq, we sought to compare the effects of SAHA and RMD on gene expression in primary CD4 ؉ T cells. Among the genes whose expression was modulated by both HDACi agents, we identified genes previously implicated in HIV latency. Two genes, SMARCB1 and PARP1, whose modulation by SAHA and RMD is predicted to inhibit HIV reactivation, were evaluated in the major maturation subsets of CD4 ؉ T cells and were consistently either up-or down-regulated by both HDACi compounds. Our results indicate that despite having different potencies and HDAC specific-

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Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition

Abstract: Edited by George DeMartinoThe persistence of HIV in resting memory CD4؉ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (

Cited by 31 publications

References 35 publications

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Quiescence Promotes Latent HIV Infection and Resistance to Reactivation from Latency with Histone Deacetylase Inhibitors

Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

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