FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency

Huang, Huachao; Santoso, Netty; Power, Derek G.; Simpson, Sydney; Dieringer, Michael; Miao, Hongyu; Gurova, Katerina V.; Giam, Chou-Zen; Elledge, Stephen J.; Zhu, Jian

doi:10.1074/jbc.m115.652339

Cited by 45 publications

(57 citation statements)

References 73 publications

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“…VSV-G pseudotyped HIV-1 NL4–3 luciferase virus (HIV-1 Luc) or retroviruses expressing HIV-1 Tat (pQCXIP-Tat) were created as described previously (Huang et al, 2015; Power et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

“…After 24 hr, cells were collected and subjected to RNA extraction (RNeasy mini kit, QIAGEN), cDNA synthesis (iScript™ cDNA Synthesis Kit, Bio-Rad), and qPCR analysis using the iTaq™ Universal SYBR® Green Supermix (Bio-Rad) as described previously (Huang et al, 2015; Zhu et al, 2012). We used initiation primers (Ini) targeting bp 10–59 of HIV-1 transcript, proximal primers targeting bp 29–180 of HIV-1 transcript, intermediate primers targeting bp 836–1015 of HIV-1 transcript, distal primers targeting bp 2341–2433 of HIV-1 transcript, and GAPDH primers for normalization.…”

Section: Methodsmentioning

confidence: 99%

“…Co-immunoprecipitation and western blot analysis was performed as described previously (Huang et al, 2015; Power et al, 2015). Briefly, HeLa cells stably expressing Tat-Flag were treated with levosimendan (10 μM) for 24 hr.…”

Section: Methodsmentioning

confidence: 99%

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Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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“…However, Huang et al, using RNAi functional genomic screens, demonstrated that individual proteins from the FACT complex act as transcriptional repressors of HIV [138]. In this study, Tat was shown to recruit the FACT complex to the HIV-1 LTR promoter by interacting with SUPT16H [138].…”

Section: Host Factors Influencing Hiv-1 Latencymentioning

confidence: 91%

“…However, the exact mechanism of inhibition by FACT is not known and could be different from a simple block between Tat and CycT1. Indeed, depletion of FACT in the U1 latent cell line, which contains a Tat-defective H13L mutant impairing P-TEFb binding, also lead to the activation of both transcription initiation and elongation, suggesting another unknown mechanism [138, 139]. Lastly, FACT seems to have a general role on retrovirus silencing since HTLV-1 Tax-dependent transcription was also affected [138].…”

Section: Host Factors Influencing Hiv-1 Latencymentioning

confidence: 99%

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

Mousseau

Valente

2017

CPD

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Background The viral transactivator Tat protein is a key modulator of HIV-1 replication, as it regulates transcriptional elongation from the integrated proviral genome. Tat recruits the human transcription elongation factor b, and other host proteins, such as the super elongation complex, to activate the cellular RNA polymerase II, normally stalled shortly after transcription initiation at the HIV promoter. By means of a complex set of interactions with host cellular factors, Tat determines the fate of viral activity within the infected cell. The virus will either actively replicate to promote dissemination in blood and tissues, or become dormant mostly in memory CD4+ T cells, as part of a small but long-living latent reservoir, the main obstacle for HIV eradication. Objective In this review, we summarize recent advances in the understanding of the multi-step mechanism that regulates Tat-mediated HIV-1 transcription and RNA polymerase II release, to promote viral transcription elongation. Early events of the human transcription elongation factor b release from the inhibitory 7SK small nuclear ribonucleoprotein complex and its recruitment to the HIV promoter will be discussed. Specific roles of the super elongation complex subunits during transcription elongation, and insight on recently identified cellular factors and mechanisms regulating HIV latency will be detailed. Conclusion Understanding the complexity of HIV transcriptional regulation by host factors may open the door for development of novel strategies to eradicate the resilient latent reservoir.

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Curaxin CBL0137 has the potential to reverse HIV‐1 latency

Jean

Zhou

Fiches

et al. 2019

Journal of Medical Virology

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A cure for human immunodeficiency virus type-1 (HIV-1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV-1 patients. One strategy proposed to eradicate these reservoirs is the "shock and kill" approach, where latency-reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells.Here, we report that curaxin CBL0137, an antitumor compound, can potentiate tumor necrosis factor-α-mediated reactivation of latently infected HIV-1cell lines.Additionally, the single use of CBL0137 is sufficient to reactivate HIV-1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV-1 positive, cART-treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the "shock and kill" approach. K E Y W O R D S curaxins, facilitates chromatin transcription complex, HIV-1 latency, human immunodeficiency virus type 1, latency-reversing agents 1 | INTRODUCTION Since the implementation of combination antiretroviral therapy (cART), rates of human immunodeficiency virus type-1 (HIV-1)mortality, morbidity, and newly acquired infections have decrease drastically. 1 However, long-term therapy is still required because the virus established a reversible state of latency in memory CD4 + T cells. To address these reservoirs, two main strategies are being investigated. First, the "shock and kill" approach aims to purge the latent reservoirs by inducing renewed viral transcription/reactivation using latency-reversing agents (LRAs) to favor viral cytopathic cell death and immune clearance. Second, another strategy coined the "block and lock" approach focuses on the development of latencypromoting agents (LPAs) to instead induce a deep state of HIV-1 resulting in permanent silencing of latently infected cells and lead to their potential decay overtime. In that regard, we have previously implicated the facilitates chromatin transcription (FACT) complex as a negative regulator of HIV-1 latency. 2 Furthermore, we showed in an earlier publication that curaxin 100 (CBL0100), a compound first described as an antitumor drug that targets FACT, is a promising LPA by targeting HIV-1 transcriptional elongation. 3,4 Interestingly, another curaxin, CBL0137, has been implicated in promoting HIV integration. Its mechanism of action involves FACT-mediated destabilization of chromatin nucleosomes to favor viral genome J Med Virol. 2019;91:1571-1576.wileyonlinelibrary.com/journal/jmv

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FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency

Cited by 45 publications

References 73 publications

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

Curaxin CBL0137 has the potential to reverse HIV‐1 latency

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