Prostratin Antagonizes HIV Latency by Activating NF-κB

Williams, Samuel A.; Chen, Linfeng; Kwon, Hakju; Fenard, David; Bisgrove, Dwayne A.; Verdin, Eric; Greene, Warner C.

doi:10.1074/jbc.m402124200

Cited by 291 publications

(302 citation statements)

References 41 publications

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“…Collectively called latencyreversing agents (LRAs), these drugs include histone deacetylase inhibitors (12)(13)(14), PKC activators (15)(16)(17)(18), and the bromodomain inhibitor JQ1 (19)(20)(21). Although LRAs are the subject of intense research, it is unclear how much the LR must be reduced to enable patients to safely discontinue ART.…”

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.

253

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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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.

253

313

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“…The HDAC inhibitors are currently one of the most promising HIV-1 latency-reversing agents, such as vorinostat (suberoylanilide hydroxamic acid (SAHA)) (14,15). The NF-B pathway is turned on by activating protein kinase C. Several drugs, such as TNF-␣ (16), prostratin (17), and bryostatin (18), are currently under investigation for treating HIV-1 latency through this mechanism. P-TEFb is activated by some small compounds to trigger its release from the inhibitory form in the 7SK small nuclear ribonucleoprotein complex, which allows more accessibility to HIV-1 Tat protein, such as hexamethylene bisacetamide (19) and disulfiram (20).…”

mentioning

confidence: 99%

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

Huang

Santoso

Power

et al. 2015

Journal of Biological Chemistry

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Background: FACT proteins SUPT16H and SSRP1 are identified as host factors that restrict HIV-1 replication. Results: Biochemical and genetic evidences that SUPT16H and SSRP1 affect HIV-1/HTLV-1 transcription and latency are provided. Conclusion: SUPT16H and SSRP1 suppress transcription of HIV-1/HTLV-1, and their presence may promote HIV-1 latency. Significance: Identification of host factors necessary for HIV-1 latency is critical, which may benefit the development of novel HIV-1 latency-reversing agents.

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“…Other small molecules, such as suberoylanilide hydroxamic acid (SAHA) (14 -16), resveratrol (17), and prostratin (18,19), have been proposed as potential agents for the disruption of HIV latent infection. Prostratin induces the NF-B activation pathway (20,21), which puts into question its use in clinical studies because abnormal NF-B signaling has been related to the pathophysiology of cancer, inflammatory diseases, and neurodegenerative disorders (22)(23)(24)(25).…”

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confidence: 99%

High-throughput Screening Uncovers a Compound That Activates Latent HIV-1 and Acts Cooperatively with a Histone Deacetylase (HDAC) Inhibitor

Micheva-Viteva

Kobayashi

Edelstein

et al. 2011

Journal of Biological Chemistry

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Current antiretroviral therapy (ART) provides potent suppression of HIV-1 replication. However, ART does not target latent viral reservoirs, so persistent infection remains a challenge. Small molecules with pharmacological properties that allow them to reach and activate viral reservoirs could potentially be utilized to eliminate the latent arm of the infection when used in combination with ART. Here we describe a cellbased system modeling HIV-1 latency that was utilized in a high-throughput screen to identify small molecule antagonists of HIV-1 latency. A more detailed analysis is provided for one of the hit compounds, antiviral 6 (AV6), which required nuclear factor of activated T cells for early mRNA expression while exhibiting RNA-stabilizing activity. It was found that AV6 reproducibly activated latent provirus from different lymphocyte-based clonal cell lines as well as from latently infected primary resting CD4 ؉ T cells without causing general T cell proliferation or activation. Moreover, AV6 complemented the latency antagonist activity of a previously described histone deacetylase (HDAC) inhibitor. This is a proof of concept showing that a high-throughput screen employing a cell-based model of HIV-1 latency can be utilized to identify new classes of compounds that can be used in concert with other persistent antagonists with the aim of viral clearance.The ability of human immunodeficiency virus type 1 (HIV-1) to establish a latent infection results in life-long virus persistence even after long-term antiretroviral therapy (ART). 4 The role that latency plays in preventing sustained clearance of the virus infection has become evident in recent years. Patients that have been successfully treated with ART, having undetectable levels of viral RNA (below 50 copies/ml) in the plasma for years, experienced rapid virus rebound upon withdrawal of therapy (1, 2). Moreover, it was found that after T cell activation, virus could be isolated from CD4 ϩ T cells taken from these patients, underscoring the need to eliminate the latently infected cells to eradicate the virus (3-5).Activation of latent proviruses from infected cells in combination with ART is part of a therapeutic strategy that may lead to the complete elimination of HIV infection. Prior attempts to "flush out" the virus by activation of latently infected resting CD4 ϩ T cells with the administration of IL-2 and/or anti-CD3 monoclonal antibodies were ultimately unsuccessful, probably because of its inability to reach all of the latent viral reservoirs and the toxicity of the regimen (6 -10). A more promising approach to complete viral clearance is the use of small molecules with pharmacological properties that allow them to access the viral reservoirs and to specifically reactivate the latent proviruses. The concept of small molecule activation of latent HIV-1 has been tested in a clinical study using the histone deacetylase (HDAC) inhibitor valproic acid (VA) (11). However, it is questionable whether VA alone can be used as a supplement to ART for succe...

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Prostratin Antagonizes HIV Latency by Activating NF-κB

Cited by 291 publications

References 41 publications

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

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

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

High-throughput Screening Uncovers a Compound That Activates Latent HIV-1 and Acts Cooperatively with a Histone Deacetylase (HDAC) Inhibitor

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