Emory University researchers have provided the first proof-of-concept in a nonhuman primate model for eliminating HIV-infected cells with venetoclax, a clinically approved medication for cancer. Venetoclax effectively targets and blocks Bcl-2, a protein that not only regulates whether cells live or die but also promotes the survival of cancer cells. Similarly, Bcl-2 is a culprit in sustaining HIV cell reservoirs. The research team determined venetoclax is also effective at reducing simian immunodeficiency virus (SIV) reservoir levels in vivo when given as part of a combination treatment for HIV.<\/p>\n
The study results are reported in Nature Microbiology, and two clinical trials are under way to test venetoclax in people living with HIV.<\/p>\n
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Eliminating the viral reservoir is a priority in the pursuit of a cure for HIV. 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.”<\/p>\n
\n <\/p>\nMirko Paiardini, PhD, senior author<\/p>\n
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Paiardini is chief of the Microbiology and Immunology Division at the Emory National Biomedical Research Center (ENBRC) as well as a professor of Pathology and Laboratory Medicine at the Emory School of Medicine (SOM). He is also the contact principal investigator for ERASE HIV, a NIH-funded Martin Delaney Collaboratory for HIV Cure Research. This collaboratory is characterizing key immune system functions that control persistent HIV infection and designing immune-based therapies to eliminate or control the virus in the absence antiretroviral therapy (ART).<\/p>\n
Paiardini and his research team sought to determine if inhibiting Bcl-2 with venetoclax could kill infected cells in a nonhuman primate model once ART began. “To help people impacted by HIV, we need to find ways to eliminate the infected cells, prevent them from becoming part of the long-lived reservoir that persists despite treatment and stop the virus from rebounding if treatment is interrupted,” says Tomas Raul Wiche Salinas, MD, PhD, first author and an ENBRC researcher.<\/p>\n
The research team conducted the study with rhesus macaques. “The animals were vital to this work because they are the only preclinical model that fully represents human-based immune responses and harbors latently infected cells that persist during long-term ART,” says Paiardini.<\/p>\n
At 14 days post-infection, the researchers gave the animals ART alone or in combination with venetoclax.<\/p>\n
“We noted the combination of medications reduced the number of SIV-infected CD4+ T cells<\/a> more rapidly than ART alone,” says Wiche Salinas. “Importantly, the level of infected cells remained lower in the venetoclax-treated animals for months after we stopped administering it but were continuing ART.”<\/p>\n
The Paiardini lab is now assessing the effectiveness of a longer duration of venetoclax as well as determining what cellular mechanisms allow survival of infected cells despite blocking Bcl-2.<\/p>\n
\u00a0“For the proof-of-concept study, we only gave venetoclax to the rhesus macaques for 10 days,” says Paiardini. “Based on the encouraging results, our research team believes longer treatments will have a bigger impact on eliminating the reservoir.”<\/p>\n
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