Cancer Drug Reduces SIV Reservoir in Macaques, May Inform HIV Cure Strategies

A cancer drug designed to push malignant cells toward death may also help researchers chip away at one of the toughest barriers to curing HIV: the long-lived viral reservoir that persists despite antiretroviral therapy.

In a study titled, “BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques,” and published in Nature Microbiology, researchers at Emory University reported that a short course of venetoclax, a BCL-2 inhibitor approved for certain blood cancers, reduced the intact simian immunodeficiency virus (SIV) reservoir in rhesus macaques when given at the start of antiretroviral therapy (ART). SIV infection in macaques is commonly used as a nonhuman primate model for studying HIV persistence and cure strategies.

The work builds on a biological idea with implications for both cancer and HIV: cells that overexpress the anti-apoptotic protein BCL-2 are better able to survive. In cancer, that survival advantage can help malignant cells resist death. In HIV infection, BCL-2 may similarly help infected CD4⁺ T cells persist as part of the latent or transcriptionally active reservoir, which can reignite viral replication if ART is interrupted.

“Eliminating the viral reservoir is a priority in the pursuit of a cure for HIV,” said Mirko Paiardini, PhD, senior author of the study and chief of the Microbiology and Immunology Division at the Emory National Biomedical Research Center (ENBRC). “Despite many attempts, there hasn’t been a therapeutic strategy able to do this. Our study, however, offers hope for accelerating the timeline to cure by using an approved medication.”

To test the approach, the investigators infected 24 rhesus macaques with SIV and initiated ART 14 days later. Animals were assigned to receive ART alone, ART plus 10 daily doses of venetoclax, or ART plus venetoclax and CD8α depletion. The animals were followed for nearly 10 months after infection, allowing the team to assess whether a brief period of BCL-2 inhibition had effects that lasted beyond the treatment window.

Venetoclax-treated macaques showed a rapid reduction in intact SIV DNA in CD4⁺ T cells in blood compared with ART-only controls, and the reduction was sustained through day 294 post-infection. The researchers also observed reduced reservoir levels in lymph nodes, an important tissue site for viral persistence. By accounting for both the frequency of infected CD4+ T cells and overall CD4+ T-cell counts, the team found that venetoclax also reduced the absolute number of circulating SIV-infected cells.

“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, MD, PhD, an ENBRC 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.”

The effect was not complete. CD4⁺ T cells that persisted after venetoclax treatment showed signs of partial resistance to apoptosis in ex vivo testing. Those cells had elevated expression of BCL-2 and BCL-xL and reduced expression of pro-apoptotic molecules such as PUMA, pointing to compensatory survival pathways that could limit reservoir clearance.

Still, the authors concluded that the findings support further testing of BCL-2 inhibition as part of HIV cure strategies, including longer venetoclax dosing and determining the cellular mechanisms that allow survival of infected cells despite BCL-3 blockage. The study did not include an analytical treatment interruption, so it remains unknown whether venetoclax would delay or prevent viral rebound after ART is stopped.