Targeting Latent HIV Reservoirs: Effectiveness of Combination Therapy with HDAC and PARP Inhibitors

The "Kick and Kill" strategy, which aims to reactivate latent HIV reservoirs and facilitate the clearance of reactivated HIV-infected cells, has yet to achieve a functional cure due to the limited efficacy of current latency reversal agents. This study evaluates the combination efficacy of histone deacetylase (HDAC) inhibitor with poly(ADP-ribose) polymerase (PARP) inhibitor in latency reversal and immune-mediated clearance. Latently infected J-Lat cells and dual-fluorescent HIV-infected primary CD4 T cells were treated with the HDAC inhibitor (vorinostat) and one of four PARP inhibitors (olaparib, rucaparib, niraparib, or talazoparib). PARP inhibitors, when administered alone, showed no latency reversal activity. However, when combined with vorinostat, their efficacy increased threefold compared to vorinostat alone. This effect was mediated by the inhibition of tankyrase, a PARP superfamily member, which modulates the Hippo signaling pathway. In HIV_GR670-infected primary cells, the combination reduced the reservoir size by 67%. In addition, talazoparib alone significantly reduced actively infected cells by 50%. Talazoparib-treated peripheral blood mononuclear cells co-cultured with K562 cells demonstrated enhanced NK-cell-mediated cytotoxicity, with a 10% reduction in K562 cell viability. These findings demonstrate that combining HDAC and PARP inhibitors augments latency reversal and reservoir reduction. With both the HDAC inhibitors and PARP inhibitors used in this study approved by the FDA for cancer treatment, this combination therapy holds strong potential for rapid clinical integration, contingent upon the confirmation of efficacy and safety in ongoing in vivo studies.