Researchers at Emory University have demonstrated the first proof-of-concept in a nonhuman primate model that the clinically approved cancer medication venetoclax can help reduce the viral reservoir associated with HIV. Published in Nature Microbiology and detailed by Genetic Engineering & Biotechnology News, the findings point toward potential new strategies for accelerating the timeline toward an HIV cure.
Cancer Drug Venetoclax Reduces SIV Reservoir in Breakthrough Primate Study
Venetoclax, marketed under the brand name Venclexta, is designed to target and block BCL-2. This protein regulates cell survival and death while promoting the persistence of cancer cells. In the context of HIV, BCL-2 helps sustain viral reservoirs by allowing infected cells to survive despite antiretroviral therapy (ART).
Study Design and Key Findings in Macaques
To evaluate the treatment approach, investigators infected 24 rhesus macaques with the simian immunodeficiency virus (SIV), which serves as a preclinical model for studying HIV persistence. ART was initiated 14 days post-infection. The study assigned animals to receive ART alone, ART combined with 10 daily doses of venetoclax, or ART combined with venetoclax and CD8α depletion.
The research team followed the animals for nearly 10 months following infection. Macaques receiving venetoclax exhibited a rapid reduction in intact SIV DNA within CD4+ T cells in the blood compared to ART-only controls, with reductions sustained through day 294 post-infection. Reservoir levels also decreased in lymph nodes, a critical tissue site for viral persistence.
We noted the combination of medications reduced the number of SIV-infected CD4+ T cells more rapidly than ART alone,
said first author Tomas Raul Wiche Salinas, an Emory National Biomedical Research Center researcher. Importantly, the level of infected cells remained lower in the venetoclax-treated animals for months after we stopped administering it but were continuing ART.
Implications for HIV Cure Strategies and Future Research
Eliminating the viral reservoir remains a major hurdle in achieving an HIV cure because latent reservoirs can reignite viral replication if ART is interrupted. Senior author Mirko Paiardini noted that while many therapeutic strategies have attempted to target the reservoir, this study offers hope by utilizing an already approved medication.
Paiardini serves as chief of the Microbiology and Immunology Division at the Emory National Biomedical Research Center, a professor of Pathology and Laboratory Medicine at the Emory School of Medicine, and the contact principal investigator for ERASE HIV, an NIH-funded Martin Delaney Collaboratory for HIV Cure Research. Additional Emory researchers involved in the work include Deanna Kulpa and Guido Silvestri.
Current Limitations and Next Steps
Despite the promising results, the treatment effect was not complete. Ex vivo testing revealed that CD4+ T cells surviving venetoclax treatment displayed partial resistance to apoptosis. These surviving cells showed elevated expression of BCL-2 and BCL-xL alongside reduced expression of pro-apoptotic molecules like PUMA, pointing toward compensatory survival pathways.
Furthermore, the study did not include an analytical treatment interruption, leaving it unknown whether venetoclax would successfully delay or prevent viral rebound once ART is stopped. Researchers emphasize that the findings support further investigation, including longer venetoclax dosing regimens and deeper analysis of the cellular mechanisms allowing infected cells to survive BCL-2 blockage. Two clinical trials are already underway to test venetoclax in humans living with HIV.
