Venetoclax shrank the SIV reservoir in macaques and the effect held for months
A team at Emory University added venetoclax, a cancer drug that blocks the Bcl-2 protein, to antiretroviral therapy in SIV-infected rhesus macaques, and the infected-cell reservoir fell faster and stayed lower for months after the ten-day course ended. The peer-reviewed Nature Microbiology study is the first proof-of-concept for the approach in a primate model, two human trials are already under way, and the researchers caution the short course may have limited the size of the effect.
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Emory team cuts the SIV reservoir in macaques with a cancer drug added to standard treatment
A team at Emory University added venetoclax, a Bcl-2 inhibitor already approved for certain blood cancers, to antiretroviral therapy in 24 rhesus macaques infected with simian immunodeficiency virus (SIV), the primate relative of HIV. The animals began antiretroviral therapy 14 days after infection, split across three arms of eight, and those that also received venetoclax got it as ten daily doses starting when antiretroviral treatment began. Infected CD4+ T cells fell faster in the venetoclax-treated animals than in those on antiretroviral therapy alone, and the reduction held for months after the ten-day venetoclax course ended while antiretroviral therapy continued. The peer-reviewed results, published in Nature Microbiology, describe the first proof-of-concept for eliminating HIV-related infected cells with venetoclax in a nonhuman primate model.[1], [2]
Blocking the protein that keeps infected cells alive targets a reservoir HIV cure research has struggled to clear
The reservoir of long-lived infected cells is what forces lifelong antiretroviral treatment, because it can refill the infection whenever the drugs stop, and eliminating it has been a stated priority in HIV cure research without a therapeutic strategy able to do so. Venetoclax works by blocking Bcl-2, a protein that governs whether a cell lives or dies and, in addition to helping cancer cells survive, also helps sustain the CD4+ T cells that make up the SIV and HIV reservoirs. Emory's Mirko Paiardini, who leads the university's ERASE HIV cure-research programme, and first author Tomas Raul Wiche Salinas said the approach could speed the path to an HIV cure by repurposing an already-approved medication rather than developing a new one. Two clinical trials are already testing venetoclax in people living with HIV, though no human reservoir measurement yet confirms the macaque result.[2]
A ten-day course and an animal model leave open how far the effect will reach
The result is a preclinical finding in an animal model of SIV, not a demonstration in people with HIV, and the researchers note that the short ten-day venetoclax course may have limited how large the effect could be. Rhesus macaques were used because they are described as the only preclinical model that fully represents human-based immune responses while also harbouring the kind of latently infected cells that persist through long-term antiretroviral therapy. The Emory team is now assessing whether a longer course of venetoclax produces a larger reduction in the reservoir and studying which cellular mechanisms let some infected cells survive despite the drug blocking Bcl-2. The two ongoing human trials will determine whether the reservoir reduction seen in macaques translates to people living with HIV.[1]
