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

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-T_CM) without activating viral transcription. Also in HIV-T_CM, 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-T_CM 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-T_CM: 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; T_CM: resting central memory CD4⁺ T cells; TNF: tumor necrosis factor; TNFSF10: TNF superfamily member 10; XIAP: X-linked inhibitor of apoptosis.