SMAC Mimetics as Therapeutic Agents in HIV Infection

Abstract

Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4⁺ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.

Keywords: HIV; HIV latency; HIV therapeutics; SMAC mimetics; apoptosis.

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).