Blockade of PD-1 (programmed death-1), a B7/CD28 family immune-receptor molecule that inhibits the immune response to chronic viral infections, is shown to improve anti-viral immune responses in SIV-infected macaques without adverse side effects. The treatment, which used an antibody specific to human PD-1, also prolonged survival. PD-1 blockade was effective without antiretroviral drugs, suggesting that a similar approach might also be effective in HIV/AIDS patients, combined perhaps with drugs or therapeutic vaccination. This study shows that blockade of PD-1 in SIV-infected macaques transiently increases the frequency, activation and functionality markers of virus-specific CD8 T cells without adverse side effects. Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses1,2,3. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1)4,5 during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (∼week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.

Enhancing SIV-specific immunity in vivo by PD-1 blockade