Latency reversal and restoring T cell function are the two major barriers to HIV cure and there is a need for the development of therapeutic strategies that both reverse latency and restore T and B cell function to facilitate immune mediated clearance of the reactivated latent CD4 T cells. PD-1 blockade has not only been shown to potentiate HIV/SIV latency reversal but also to reverse immune exhaustion, improve antiviral immunity and reduce viral reservoirs. Therefore, the objective of this study was to combine PD-1 blockade with AZD5582 (a potent latency reversal agent, LRA) as a ‘shock and kill’ approach and study safety, virological and immunological effects in SIV infected and ART suppressed rhesus macaques (RMs).
A total of 9 RMs were chronically infected with SIVmac239 for 2 years and were on a second cycle of daily ART for 14 weeks with complete viral suppression. Both the groups received five weekly infusions of AZD5582 (0.1mg/kg), one without (LRA only, n=5) and the other with two primatized anti-PD-1 antibody (10mg/kg) infusions at 1st and 4th cycle of AZD5582 infusion (LRA+PD-1, n=4) under ART. Plasma viral load and immunophenotypic analyses on PBMCs, lymph nodes and gut were performed throughout the study. RNASeq analyses were performed at days 0, 3 and 7 post 1st infusion. Cell Associated DNA and RNA were measured pre- and post-treatment in PBMCs.
Strong latency reversal as well as instances of sustained viremia were observed in both the groups with no significant difference in events of viral rebound between the groups. Interestingly, flow cytometry data revealed that combination of PD-1 blockade and AZD5582 but not AZD5582 alone, showed a robust increase in proliferating total and memory CD4 and CD8 T cells with each AZD5582 administration in PBMCs. Total CD8 T cells co-expressing granzyme B and perforin (cytolytic potential) also significantly increased following the 2nd infusion of anti-PD-1 antibody. The combination group also showed an increase for T regs. Similar immune changes were observed in LN and Gut. Treatment with AZD5582 decreased cell associated RNA copies in PBMCs and addition of PD-1 blockade didn’t reduce it further.
In summary, combined treatment of PD-1 blockade and AZD5582 is safe and effective in inducing latency reversal. Despite no additive advantage on reservoir size, the combined treatment changed the landscape of T cell responses in blood and tissues.