Background: The expression of the inhibitory receptor programmed death-1 (PD-1) on anti-viral CD8 T cells and virally infected CD4 T cells provides an immunological signature for both T cell dysfunction and viral latency during chronic SIV/HIV infection. We hypothesized that PD-1 blockade administered during the initiation of anti-retroviral therapy (ART) and under fully suppressive ART would have direct effects on both dysfunctional CD8 T cells and latently infected CD4 T cells. To test our hypothesis we developed a primatized anti-human PD-1 Ab to allow for repeated infusions in rhesus macaques (RMs) and administered PD-1 blockade to chronically SIV infected RMs in combination with ART.
Methods: SIVmac251 infected RMs were administered 5 infusions (over 14 days) of a 3mg/kg dose of primatized anti-PD-1 Ab 10 days prior to the initiation of ART. About 8 months post ART, RMs received 3 monthly infusions of 10mg/kg anti-PD-1 or saline. ART was interrupted at 2 weeks after the final PD-1 Ab infusion.
Results: PD-1 blockade administered during the initiation of ART enhanced proliferation of anti-viral CD8 T cells (p=0.02), increased their cytotoxic potential (p=0.04) and polyfunctionality (p=0.01). Importantly, the PD-1 Ab treated animals showed more rapid viral suppression (42 days in the PD-1 group versus 140 days in saline group; p = 0.01) and greater reconstitution of Th17 cells in the rectal mucosa (p = 0.01) following initiation of ART. Moreover, PD-1 blockade administered under suppressive ART resulted in transient but significant increases in viremia, suggesting possible effects on destabilizing the latent viral reservoir. Following ART interruption, PD-1 Ab treated animals showed up to 80-fold reduction in set point viremia compared to set point levels prior to initiation of ART.
Conclusions: These results reveal for the first time the potential of PD-1 blockade both on restoring anti-viral CD8 T cell function and possibly destabilizing the viral reservoir under ART. They highlight the potential of PD-1 blockade to work synergistically with other therapeutic agents such as vaccines and latency reversing agents to effectively diminish HIV reservoir under ART as a means to establish a functional cure.