DIABLO/SMAC mimetics selectively kill HIV-1-infected resting memory CD4+ T cells: a potential role in a cure strategy for HIV-1 infection.

Despite advances in HIV therapy, there is no cure, and lifelong antiretroviral treatment is required to suppress viral replication. We hypothesized that HIV maintains the survival of latently infected CD4+ T cells through increased expression of cell survival factors including XIAP, BIRC2 and BECN1. We found that DIABLO/SMAC mimetics promote the degradation of XIAP and BIRC2 in latent HIV-infected resting memory CD4+ T cells (HIV-TCM) without activating viral transcription. Also in HIV-TCM, but not in uninfected cells, the degradation of XIAP and BIRC2 leads to the induction of macroautophagy/autophagy, and the formation of a cell death complex on phagophore membranes that consist of autophagy (ATG5, ATG7 and SQSTM1) and pro-apoptotic (FADD, RIPK1, RIPK3, CASP8) proteins. This results in autophagy-dependent apoptosis of HIV-TCM while sparing uninfected cells. These findings support the potential use of DIABLO/SMAC mimetics as part of an HIV cure strategy. Abbreviations: ART: antiretroviral therapy; ATG2A: autophagy related 2A; ATG2B: autophagy related 2B; ATG5: autophagy related 5; ATG7: autophagy related 7; BCL2: BCL2, apoptosis regulator; BECN1: beclin 1; BIRC2: baculoviral IAP repeat containing 2; CASP8: caspase 8; CFLAR: CASP8 and FADD like apoptosis regulator; DIABLO/SMAC: diablo IAP-binding mitochondrial protein; SM: DIABLO/SMAC mimetics; DISC: death-inducing signaling complex; FADD: Fas associated via death domain; FAS: Fas cell surface death receptor; HIV: human immunodeficiency virus type 1; HIV-TCM: HIV latent resting central memory CD4+ T cells; IAP: inhibitor of apoptosis protein; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; RNAi: RNA interference; SQSTM1: sequestosome 1; TCM: resting central memory CD4+ T cells; TNF: tumor necrosis factor; TNFSF10: TNF superfamily member 10; XIAP: X-linked inhibitor of apoptosis.