BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques.

The anti-apoptotic molecule BCL-2 favours the maintenance of the CD4+ T-cell reservoir during HIV infection. Whether inhibition of BCL-2 can lead to long-term reduction of the HIV reservoir is unclear. Here we initiated antiretroviral therapy (ART) in 24 simian immunodeficiency virus (SIV)-infected rhesus macaques at 14 days post infection (p.i.), alone or combined with a 10-day treatment of venetoclax or venetoclax and CD8α depletion, with a follow-up to day 294 p.i. We report a rapid and sustained reduction of the intact SIV reservoir in venetoclax-treated rhesus macaques in blood and lymph nodes. CD4+ T cells that persisted after venetoclax treatment showed partial reduction in apoptotic sensitivity in ex vivo assays. These exhibited elevated expression of anti-apoptotic BCL-2 and BCL-xL, and showed reduced expression of pro-apoptotic molecules such as PUMA. These findings support the rationale for extended venetoclax dosing and suggest that combining BCL-2 inhibition with agents targeting additional anti-apoptotic molecules could enhance clearance of the viral reservoir in HIV cure strategies.