Figure 1.

Mechanism of action of SMAC mimetics in latency reversal and apoptosis. (A) SMAC mimetics can induce latency reversal in HIV infected cells. TRAF2 and TRAF3 recruit NIK to cIAP1, and cIAP1 ubiquitinates NIK, resulting in its proteosomal degradation, preventing non-canonical NFκB signalling. SMAC mimetics bind to the BIR3 domain of cIAP1, which results in cIAP1’s autoubiquitination and degradation, freeing NIK. NIK accumulates in the cytoplasm, and activates IKKα, which in turn phosphorylates p100. p100 undergoes proteosomal processing to form p52, and the RelB/p52 NFκB complex translocates into the nucleus. NFκB can then bind to the LTR to inducing HIV gene expression leading to latency reversal. (B) SMAC mimetics can lead to apoptosis of HIV infected cells. SMAC mimetics cause the degradation of cIAP1 and XIAP, resulting in autophagy induction in HIV infected T_CM. A ripoptosome-like DISC complex (Caspase 8, RIPK1, RIPK3, FADD), forms on unclosed phagophore membranes by using autophagy machinery (SQSTM1, ATG5, ATG2, LC3-II) as a scaffold, leading to selective killing of HIV infected CD4⁺ T_CM. (Adapted from 63). (Created with Biorender.com).