Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

Zhou, Chenliang; Li, Ting; Xia, Muye; Wu, Ziyao; Zhong, Xuelin; Li, Axing; Rashid, Huba Khamis; Ma, Chengnuo; Zhou, Ruijing; Duan, Heng; Zhang, Xuanxuan; Peng, Jie; Li, Lin

doi:10.1021/acsinfecdis.3c00218

Cited by 3 publications

(1 citation statement)

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“…In two studies published during the last few months, venetoclax monotherapy decreased plasma viremia and intact HIV DNA in a humanized mouse model of acute HIV infection [ 49 ], reduced total and intact HIV DNA in CD4 + T cells ex vivo [ 50 ], and delayed viral rebound in humanized mice [ 50 ]. Finally, obatoclax was recently shown to activate caspase 8 and preferentially induced apoptosis in latently infected cell lines [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules

Kadiyala,

Telwatte,

Wedrychowski

et al. 2024

Aids

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Objectives: Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or SIV, but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses. Design: To investigate this hypothesis, drugs were tested ex vivo on Peripheral Blood Mononuclear Cells (PBMC) from nine ART-suppressed individuals. Methods: We tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant (IAP inhibitor), bortezomib (proteasome inhibitor), and INK128/sapanisertib (mTOR[c]1/2 inhibitor). After six days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay). Results: Obatoclax reduced intact HIV DNA (median = 27–30% of DMSO) but not defective or total HIV DNA. Other drugs showed no statistically significant effects. Conclusions: Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

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Section: Discussionmentioning

confidence: 99%

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules

Kadiyala,

Telwatte,

Wedrychowski

et al. 2024

Aids

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A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs

Chang,

Yin,

Laird

et al. 2024

Preprint

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The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. The "shock and kill" strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir. We repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and selective apoptosis of infected cells. Treatment of ex vivo CD4+ T cells from ART-suppressed HIV-1 patients achieved a ~50% reduction in the replication-competent reservoir. Our study provides proof-of-concept for using protein degraders to reverse HIV latency and induce cell death, highlighting PZ703b's potential in HIV cure strategies. This approach may pave the way for novel therapeutic interventions aimed at eliminating the HIV-inducible reservoir.

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Interventions during Early Infection: Opening a Window for an HIV Cure?

Hiner,

Mueller,

et al. 2024

Viruses

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Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection.

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Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

Cited by 3 publications

References 60 publications

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules

A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs

Interventions during Early Infection: Opening a Window for an HIV Cure?

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