SMAC (Second Mitochondrial-derived Activator of Caspases) mimetics are a class of compounds that have recently entered clinical trials as potential cancer treatments. The drugs antagonize anti-apoptotic proteins, thereby promoting the apoptotic death of cancer cells. Earlier this year at CROI, a poster presentation offered evidence that SMAC mimetics may also selectively promote the apoptosis of CD4 T cells latently infected by HIV. In a new open access paper published by Cell Host & Microbe, Lars Pache and colleagues add another string to SMAC mimetics bow, reporting that the drugs can work synergistically with HDAC inhibitors to reverse HIV latency. In an experiment using resting CD4 T cells sampled from individuals on suppressive ART, the combination of the SMAC mimetic SBI-0637142 and the HDAC inhibitor panobinostat activated latent HIV as efficiently as T cell activation. Preliminary results from a phase I cancer trial suggest that the SMAC mimetic birinapant has an acceptable toxicity profile for testing in humans, potentially opening the door for studies of these compounds in HIV.
Cell Host Microbe. 2015 Sep 9;18(3):345-53. doi: 10.1016/j.chom.2015.08.009.
Pache L, Dutra MS, Spivak AM, Marlett JM, Murry JP, Hwang Y, Maestre AM, Manganaro L, Vamos M, Teriete P, Martins LJ, König R, Simon V, Bosque A, Fernandez-Sesma A, Cosford ND, Bushman FD, Young JA, Planelles V, Chanda SK.
Combination antiretroviral therapy (ART) is able to suppress HIV-1 replication to undetectable levels. However, the persistence of latent viral reservoirs allows for a rebound of viral load upon cessation of therapy. Thus, therapeutic strategies to eradicate the viral latent reservoir are critically needed. Employing a targeted RNAi screen, we identified the ubiquitin ligase BIRC2 (cIAP1), a repressor of the noncanonical NF-κB pathway, as a potent negative regulator of LTR-dependent HIV-1 transcription. Depletion of BIRC2 through treatment with small molecule antagonists known as Smac mimetics enhanced HIV-1 transcription, leading to a reversal of latency in a JLat latency model system. Critically, treatment of resting CD4+ T cells isolated from ART-suppressed patients with the histone deacetylase inhibitor (HDACi) panobinostat together with Smac mimetics resulted in synergistic activation of the latent reservoir. These data implicate Smac mimetics as useful agents for shock-and-kill strategies to eliminate the latent HIV reservoir.