CLINICAL TRIALS AND OBSERVATIONS PD-1 up-regulation is correlated with HIV-specific memory CD8 T-cell exhaustion in typical progressors but not in long-term nonprogressors

The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8 T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8 T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8 T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8 T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFNproduction, as well as decreased HIV-specific effector memory CD8 T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8 T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8 T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs. (Blood. 2007;109:4671-4678)