The combination of venetoclax and ixazomib selectively and efficiently kills HIV infected cell lines, but has unacceptable toxicity in primary cell models

The anti-apoptotic protein BCL2 inhibits death of HIV-infected cells. Previously, we have shown that the BCL2 inhibitor venetoclax selectively kills acutely HIV-infected cells and reduces HIV DNA in latently infected CD4 T cells after reactivation with αCD3/αCD28. However, there is a need to identify a combination therapy with venetoclax and a clinically relevant latency reversal agent. Ixazomib is an oral proteasome inhibitor which we have shown reactivates latent HIV and predisposes reactivated cells to cell death. Here, we determined that the combination of venetoclax and ixazomib kills more latently HIV-infected cells and leads to greater reduction in HIV replication compared to either treatment alone in a T cell model. However, combination treatment of CD4 T cells from ART-suppressed, HIV-positive participants resulted in unanticipated and unacceptable non-specific toxicity in primary cells. Therefore, while we show proof of concept that multiple agents can enhance selective killing of HIV infected cells, the combination of venetoclax and ixazomib has unacceptable toxicity in primary cells, and so further investigation is needed to identify a clinically relevant latency reversal agent to combine with venetoclax as a novel strategy to reduce the size of the HIV reservoir. A cure for HIV would require eliminating cells that contain the virus in a latent form from the body. Current antiretroviral medications are unable to rid the body of latently infected cells. Here we show that a combination of investigational agents - ixazomib plus venetoclax- which reactivate latent virus, and predispose infected cells to apoptosis, may reduce latent virus in a T cell model, but at the expense of non-specific toxicity in primary cells.