Work

OA2-5 LB No evidence of ongoing replication in tissue compartments during combination antiretroviral therapy

Year: 2016

Type: article

Abstract: following were analyzed over time: cell death by flow cytometry; HIV replication by supernatant p24 levels; cell associated HIV DNA by qPCR.Results: Venetoclax did not significantly reduce survival of mockinfected, activated primary CD4 T cells at a dose consistent with achievable plasma concentrations in vivo (1 μM), consistent with the favorable safety profile of venetoclax in clinical trials.In contrast, when primary activated CD4 T cells from 7 donors were infected with HIV and analyzed for survival over 9 days, venetoclax reduced survival of the infected cells compared to vehicle control (P=0.039).These results suggest that HIV infected cells might be dying preferentially in response to venetoclax.Consistent with this possibility, HIV infected cultures treated with venetoclax had decreased cell associated HIV-1 DNA compared to vehicle control treated cells (mean difference -35%, P=0.021), and reduced p24 production in cultures treated with venetoclax compared to vehicle control (mean difference -24.4%, P=0.032).Similar results were seen with navitoclax, an inhibitor of BCL-2, BCL-XL, and BCL-W, although there was increased non specific toxicity.Conclusions: The latent reservoir for HIV represents the main barrier for HIV cure, as it is unaffected by current ART, and is not reduced following HIV reactivation from latency.Clinically available BCL-2 inhibitors result in reduced HIV DNA levels following acute HIV infection in vitro, and reduce cell associated HIV DNA levels following reactivation of primary CD4 T cells from latency when studied ex vivo, and therefore warrant further study.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)31012-8