The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation

Mediouni, Sonia; Kessing, Cari F.; Jablonski, Joseph; Thenin-Houssier, Suzie; Clementz, Mark A.; Kovach, Melia D.; Mousseau, Guillaume; Vera, Ian Mitchelle S. de; Li, Chuan; Kojetin, D.J.; Evans, David T.; Valente, Susana T.

doi:10.1096/fj.201801165r

Cited by 19 publications

(17 citation statements)

References 54 publications

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“…dCA also induces rapid repressive chromatin remodeling of the HIV promoter that is maintained even when treatment is removed (159). Similar results have been obtained using dCA against SIV in vitro and ex vivo, which suggests that this drug is appropriate for studies in nonhuman primates (161). One of the major challenges in HIV therapy is residual low-level viremia or transient reactivation events ("blips") that can be detected only by highly sensitive assays and persist despite ART (6,8,162,163).…”

Section: Novel Directions In Hiv Cure Strategiessupporting

confidence: 59%

Advances toward Curing HIV-1 Infection in Tissue Reservoirs

Henderson

Reoma

Kovacs

et al. 2020

J Virol

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A disease of more than 39.6 million people worldwide, HIV-1 infection has no curative therapy. To date, one man has achieved a sterile cure, with millions more hoping to avoid the potential pitfalls of lifelong antiretroviral therapy and other HIV-related disorders, including neurocognitive decline. Recent developments in immunotherapies and gene therapies provide renewed hope in advancing efforts toward a sterilizing or functional cure. On the horizon is research concentrated in multiple separate but potentially complementary domains: vaccine research, viral transcript editing, T-cell effector response targeting including checkpoint inhibitors, and gene editing. Here, we review the concept of targeting the HIV-1 tissue reservoirs, with an emphasis on the central nervous system, and describe relevant new work in functional cure research and strategies for HIV-1 eradication.

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Section: Novel Directions In Hiv Cure Strategiessupporting

confidence: 59%

Advances toward Curing HIV-1 Infection in Tissue Reservoirs

Henderson

Reoma

Kovacs

et al. 2020

J Virol

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“…dCA potently inhibited Tat transactivation by specifically binding to Tat via the basic domain [73], but did not bind to CDK9 in the P-TEFb complex. dCA also specifically bound to the basic domain of HIV-2 Tat [73] and SIV Tat [76]. The binding of dCA to the basic domain of Tat occurred across HIV subtypes A to E in the main group M [104], but dCA did not bind to the basic domain of Rev and HEXIM1 [74].…”

Section: Two Compounds That Inhibit Tat Activitymentioning

confidence: 96%

“…dCA caused a redistribution of Tat in the nucleus from the nucleolus to the nucleoplasm and periphery of the nucleolus in a dose-dependent manner [73]. In vitro cell based experiments have demonstrated that dCA inhibited virus transactivation by Tat in different HIV subtypes [104] and SIV [76]. dCA did not inhibit the initiation of transcription but inhibited the interaction of RNAP II with the LTR promoter [46].…”

Section: Two Compounds That Inhibit Tat Activitymentioning

confidence: 99%

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Jin

Lin

et al. 2020

Viruses

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The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable in the blood, with the aim of allowing patients to live without cART. Tat, the viral transactivator of transcription protein, plays a critical role in controlling HIV transcription, latency, and viral rebound following the interruption of cART treatment. Therefore, a logical approach for controlling HIV would be to block Tat. Tackling Tat with inhibitors has been a difficult task, but some recent discoveries hold promise. Two anti-HIV proteins, Nullbasic (a mutant of Tat) and HT1 (a fusion of HEXIM1 and Tat functional domains) inhibit viral transcription by interfering with the interaction of Tat and cellular factors. Two small molecules, didehydro-cortistatin A (dCA) and triptolide, inhibit Tat by different mechanisms: dCA through direct binding and triptolide through enhanced proteasomal degradation. Finally, two Tat-based vaccines under development elicit Tat-neutralizing antibodies. These vaccines have increased the levels of CD4+ cells and reduced viral loads in HIV-infected people, suggesting that the new vaccines are therapeutic. This review summarizes recent developments of anti-Tat agents and how they could contribute to a functional cure for HIV.

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“…dCA is the only block and lock therapeutic, thus far, to progress to ex vivo non-human primate studies. A study in 2019 reported the dCA treatment inhibits reactivation of SIV in latently infected Hut78 cells, as well as ex vivo isolated primary CD4+ T cell isolated from SIV mac 239-infected rhesus macaques (Mediouni et al, 2019b ). This is encouraging data and, similar to NullBasic, dCA warrants further investigation in order to enhance the permanency of silencing.…”

Section: Block and Lock Strategiesmentioning

confidence: 99%

“…This is encouraging data and, similar to NullBasic, dCA warrants further investigation in order to enhance the permanency of silencing. Another important avenue of investigation is whether the dCA resistant strains isolated in vitro (Mediouni et al, 2019b ) are also present in PLWA globally (Rice, 2019 ).…”

Section: Block and Lock Strategiesmentioning

confidence: 99%

Block and Lock HIV Cure Strategies to Control the Latent Reservoir

Ahlenstiel

Symonds

Kent

et al. 2020

Front. Cell. Infect. Microbiol.

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The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid cells at multiple locations in the body, including sanctuary sites such as the brain, the latent reservoir is not eliminated by ART and has the ability to reactivate virus replication to pre-therapy levels when ART is ceased. There are four broad areas of HIV cure research. The only successful cure strategy, thus far, is stem cell transplantation using naturally HIV resistant CCR5 32 stem cells. A second potential cure approach uses gene editing technology, such as zinc-finger nucleases and CRISPR/Cas9. Another two cure strategies aim to control the HIV reservoir, with polar opposite concepts; The "shock and kill" approach, which aims to "shock" or reactivate the latent virus and then "kill" infected cells via targeted immune responses. Lastly, the "block and lock" approach, which aims to enhance the latent virus state by "blocking" HIV transcription and "locking" the HIV promoter in a deep latent state via epigenetic modifications. "Shock and kill" approaches are a major focus of cure studies, however we predict that the increased specificity of "block and lock" approaches will be required for the successful development of a sustained HIV clinical remission in the absence of ART. This review focuses on the current research of novel "block and lock" approaches being explored to generate an HIV cure via induction of epigenetic silencing. We will also discuss potential future therapeutic delivery and the challenges associated with progressing "block and lock" cure approaches as these move toward clinical trials.

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The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation

Cited by 19 publications

References 54 publications

Advances toward Curing HIV-1 Infection in Tissue Reservoirs

Advances toward Curing HIV-1 Infection in Tissue Reservoirs

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Block and Lock HIV Cure Strategies to Control the Latent Reservoir

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