Background
HIV-1 persists primarily in memory CD4+ T cells. The CARD8 inflammasome is an innate immune sensor which can be activated by viral protease activity to induce pyroptosis in HIV-1-infected cells. Our recent studies demonstrate that some NNRTIs including Efavirenz (EFV) drive intracellular Gag-Pol dimerization, which then forces premature viral protease activation. Induction of this pathway in people living with HIV-1 (PLWH) offers an attractive solution for targeted HIV-1 reservoir reduction.
Methods
To assess the feasibility of this approach, we conducted a prospective open-label single arm trial of EFV intensification of a baseline HIV antiretroviral therapy regimen for HIV-1 reservoir reduction. Participants with no documented EFV resistance were enrolled and maintained on their baseline antiretroviral regimen with the addition of EFV for 4-5months. No latency reversal agents were used in this study. Primary safety end points included unsolicited systemic adverse events, lab abnormalities and mood as measured by PHQ9 measurements. Blood samples were analyzed pre and post intensification by orthogonal measures of HIV reservoir including the quantitative viral outgrowth assay (QVOA), the intact proviral DNA assay (IPDA), and cell associated RNA (ca-RNA).
Results
EFV intensification did not drive immune activation or perturbation of T cell homeostasis. When analyzing blood CD4+ T cells before and after EFV intensification, we observed a unified reduction in IUPM quantified by QVOA, in unspliced cell-associated viral RNA by qPCR, and in intact proviral DNA by IPDA. Observed decay rates of intact proviruses during EFV intensification were compared to those reported from longitudinal observational studies, and accelerated viral reservoir decay was observed with EFV intensification.
Conclusions
Over the course of four months of EFV intensification, we observed a rapid reduction in the size of HIV-1 latent reservoir in all study participants. The impact on the viral reservoir in this study is dependent on intermittent and spontaneous production of HIV-1 proteins from a fraction of viral reservoirs and could be further improved when co-administered with viral latency reversal agents. This work underscores the importance of developing more potent, tolerable therapeutics that harness the CARD8 inflammasome for HIV reservoir reduction.