CD8 Lymphocyte Depletion Enhances the Latency Reversal Activity of the SMAC Mimetic AZD5582 in ART-Suppressed Simian Immunodeficiency Virus-Infected Rhesus Macaques

Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure human immunodeficiency virus (HIV) infection. In separate studies, we have shown previously that CD8(+)T cells may contribute to the maintenance of viral latency and have identified a novel SMAC (second mitochondrial activator of caspases) mimetic/IAP (inhibitor of apoptosis protein) inhibitor (AZD5582) capable of reversing HIV/simian immunodeficiency virus (SIV) latency in vivo by activating the noncanonical (nc) NF-kappa B pathway. Here, we use AZD5582 in combination with antibody (Ab)-mediated depletion of CD8 alpha(+) cells to further evaluate the role of CD8(+) T cells in the maintenance of viral latency. Six rhesus macaques (RMs) were infected with SIVmac239 and treated with antiretroviral therapy (ART) starting at week 8 postinfection. After 84 to 85 weeks of ART, all animals received a single dose of the anti-CD8 alpha depleting Ab MT807R1 (50 mg/kg of body weight, administered subcutaneously [s.c.]), followed by five weekly doses of AZD5582 (0.1mg/kg, administered intravenously [i.v.]). Following combined treatment with CD8 alpha depletion and AZD5582, 100% of RMs experienced on-ART viremia levels above 60 copies per ml of plasma. In comparator groups of SIV-infected, ART-suppressed RMs treated with AZD5582 only or CD8 alpha depletion only, on-ART viremia was experienced by 56% and 57% of the animals, respectively. Furthermore, the increased frequency of viremic episodes during the treatment period was greater in the group treated with CD8 alpha depletion plus AZD5582 than in the other groups. Mathematical modeling of virus reactivation suggested that in addition to viral dynamics during acute infection, CD8 alpha depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-kappa B signaling pathway with AZD5582 can be enhanced by CD8 alpha(+) cell depletion.

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