PD-1 Upregulation Is Associated with Exhaustion of Regulatory T Cells and Reflects Immune Activation in HIV-1-Infected Individuals

We hypothesized that PD-1expressed by regulatory T cells (Tregs) would be functional and their expression levels may associate with activation status of CD4+ T and CD8+ T cells and the disease progression of HIV-1-infected patients. To prove it, we dynamically examined PD-1 expression levels by Tregs in peripheral blood of HIV-1-infected individuals not receiving antiretroviral therapy. Eighty-one HIV-1-infected individuals not undergoing antiretroviral therapy and 22 HIV-1-seronegative donors were enrolled in our study. Tregs were defined as CD4+CD25+CD127lo/- by flow cytometry. Expression of PD-1 and the activation markers CD38, HLA-DR, and Ki67 by Tregs and CD4+ T and CD8+ T cells was also determined by flow cytometry. TGF-β and IL-10 were measured to evaluate the suppressive function of Tregs. In all Tregs, the proportion of PD-1+ Tregs observed in HIV-1-infected persons was significantly greater than that seen in HIV-1-seronegative donors, and correlated with the activation of Tregs and CD4+ T and CD8+ T cells. This increased proportion of Tregs was also statistically associated with the disease progression. Blockade of PD-1/PD-L1 pathway with anti-PD-L1 mAb profoundly increased the level of intracellular TGF-β and IL-10 in CD4+CD25+CD127lo/- Tregs. Our data not only support that PD-1 plays a critical role to predict the activation status of cellular immunity and disease progression during HIV-1 infection but also indicate that blockade of PD-1/PD-L1 pathway represents a novel therapeutic approach to AIDS.