Immune Exhaustion Occurs Concomitantly With Immune Activation and Decrease in Regulatory T Cells in Viremic Chronically HIV-1-Infected Patients

Background: Chronic HIV-1 infection is associated with excessive immune activation and immune exhaustion. We investigated the relationship of these 2 phenotypes and frequency of regulatory T cells (Tregs) in controlled and uncontrolled chronic HIV-1 infection. Methods: Immune exhaustion marker PD-1, its ligand PD-L1, CD4(+) CD25(bright) FoxP3(+) Tregs, HLA-DR, and CD38 coexpression as activation markers were investigated in peripheral blood lymphocytes of 44 HIV-1-infected patients and 11 HIV-1-uninfected controls by multicolor flow cytometry. Results: Activated and PD-1 expressing T cells were increased, and Tregs were decreased in HIV-1-infected patients as compared with controls, and alterations were greatest in viremic patients. The proportion of activated CD8(+) T cells exceeded activated CD4(+) T cells. Tregs had an inverse correlation with activated T cells and PD-1 expressing T cells. PD-L1 was highly expressed on monocytes and to a lesser extent on T lymphocytes of patients. These abnormalities partially reversed with virologic control after potent antiretroviral therapy. Conclusions: Immune exhaustion is a component of aberrant immune activation in chronic HIV-1 infection and is associated with loss of Tregs and ongoing virus replication. These defects are corrected partially with effective virologic control by potent antiretroviral therapy.