The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. Inhibitor of apoptosis protein antagonists (IAPa) reverse HIV latency and costimulate T-cells through modulation of NF-kB signaling in vitro.
We asked in this study whether a new IAPa would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice.
Four weeks of Anti-PD-1 mAb treatment decreased the PD-1+ CD8+ cell population among CD45+ in blood by 22% compared to vehicle, while IAPa co-treatment reduced it by 50%. Anti-PD-1 mAb administration reduced HIV load in blood by 94% with detectable levels in 8 of 8 mice, and addition of the IAPa further enhanced this reduction from 94 to 97% with undetectable levels in 5 of 8 mice. 2 weeks after drug treatment interruption, Anti-PD-1 mAb administration had reduced HIV loads in CD4+ cells also in all tissues analyzed compared to vehicle, including spleen (5.6 to 2 log in viral RNA copies), lymph nodes (5.6 to 1.1 log in viral RNA copies), liver (5.4 to 1.6 log in viral RNA copies), lung (5.6 to 2 log in viral RNA copies) and thymic organoid (5.5 to 1.2 log in viral RNA copies). IAPa further enhanced the anti-PD-1-mediated reduction of HIV tissue loads achieving a >5 log reduction in all tissues analyzed, notably with undetectable levels in some individual organs; spleen (5.6 to 0.2 log in viral RNA copies), lymph nodes (5.6 to 0.2 log in viral RNA copies), liver (5.4 to 0.3 log in viral RNA copies), lung (5.6 to 0.2 log in viral RNA copies) and thymic organoid (5.5 to 0.1 log in viral RNA copies). Following the 4 weeks of in vivo treatments, ex vivo anti-CD3/CD28 stimulation increased the ability to activate CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold in mice having received IAPa co-treatment (39.6 to 67.3%).
These findings demonstrate for the first time that an IAPa greatly enhances the effects of an immune checkpoint inhibitor on antiviral immunity resulting in undetectable HIV titers in blood and organs of humanized mice. This suggests that the combination of two distinct classes of immunomodulatory agents constitutes a promising immunotherapeutic approach to cure HIV.