Abstract
Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure HIV infection. In separate studies, we have previously shown that CD8+ T cells may contribute to the maintenance of viral latency and identified a novel SMAC mimetic/IAP inhibitor (AZD5582) capable of reversing HIV/SIV latency in vivo by activating the non-canonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody-mediated depletion of CD8α+ cells to further evaluate the role of CD8+ T cells in viral latency maintenance. Six rhesus macaques (RM) were infected with SIVmac239 and treated with ART starting at week 8 post-infection. After 84-85 weeks of ART, all animals received a single dose of the anti-CD8α depleting antibody (Ab), MT807R1 (50mg/kg, s.c.), followed by 5 weekly doses of AZD5582 (0.1 mg/kg, i.v.). Following CD8α depletion + AZD5582 combined treatment, 100% of RMs experienced on-ART viremia above 60 copies per ml of plasma. In comparator groups of ART-suppressed SIV-infected RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals respectively. Furthermore, the frequency of increased viremic episodes during the treatment period was greater in the CD8α depletion + AZD5582 group as compared to other groups. Mathematical modeling of virus reactivation suggested that, in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α+ cell depletion.
Highlights
Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure human immunodeficiency virus (HIV) infection
Using a small molecule that induces the degradation of inhibitor of apoptosis protein (IAP; known as the second mitochondrial activator of caspases [SMAC]), AZD5582, in rhesus macaques (RMs) infected with simian immunodeficiency virus (SIV) and in humanized mice infected with HIV, we demonstrated latency reversal on antiretroviral therapy (ART), as defined by increased viral RNA levels [12]
In three independent in vivo studies, two performed on SIV-infected, ART-suppressed RMs and one on HIV-infected bone marrowliver-thymus (BLT) humanized mice treated with ART, we demonstrated that experimental CD8a1 cell depletion was consistently followed by increases in plasma viral loads [13, 14]
Summary
Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure human immunodeficiency virus (HIV) infection. We tested a combination of two recently identified LRAs, the SMAC mimetic/IAP inhibitor AZD5582, which activates the noncanonical NF-κB pathway, and the antibody (Ab) MT807R1, which depletes CD8a1 cells, in SIV-infected rhesus. Using a small molecule that induces the degradation of inhibitor of apoptosis protein (IAP; known as the second mitochondrial activator of caspases [SMAC]), AZD5582, in rhesus macaques (RMs) infected with simian immunodeficiency virus (SIV) and in humanized mice infected with HIV, we demonstrated latency reversal on ART, as defined by increased viral RNA levels [12]. In three independent in vivo studies, two performed on SIV-infected, ART-suppressed RMs and one on HIV-infected bone marrowliver-thymus (BLT) humanized mice treated with ART, we demonstrated that experimental CD8a1 cell depletion was consistently followed by increases in plasma viral loads [13, 14]. This study suggested that CD81 T cells might inhibit latency reversal during an HIV cure approach [14]
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