Background:  Functional impairment of HIV-specific CD4⁺ T cells during chronic HIV infection is closely linked to HIV replication and thought to be due to T-cell exhaustion. Programmed death-1 (PD-1), an inhibitory receptor in the CD28 family has been linked to CD8⁺ T-cell dysfunction in chronic HIV and lymphocytic choriomeningitis virus (LCMV) infection. Blockade of the PD-1 pathway has been shown to restore in vitro HIV-specific CD8⁺ T-cell function in HIV infection and reduce viral load in LCMV infection.

Methods:  To investigate the role of PD-1 in HIV-associated CD4⁺ T-cell dysfunction, we used intracellular cytokine staining and multi-parameter flow cytometry to identify HIV-specific CD4⁺ T cells and measured PD-1 expression on the surface of peripheral blood mononuclear cell (PBMC) (n = 38) and lymph node (n = 7) T cells from HIV-infected subjects with chronic disease.

Results:  PD-1 expression was more than 3-fold higher on interferon-gamma (IFN-γ)- producing HIV Gag-specific CD4⁺ T cells than on total or cytomegalovirus (CMV)-specific CD4⁺ T cells in untreated HIV-infected subjects (p <0.0001). Suppression of HIV replication with HAART reduced the levels of PD-1 expression on HIV-specific CD4⁺ T cells by more than 2-fold (p = 0.007). There was a direct correlation between PD-1 expression on HIV-specific CD4⁺ T cells and plasma viral load (r = 0.71, p = 0.005), suggesting that increased expression was driven by HIV replication. PD-1 expression was 2-fold higher on HIV-specific CD4⁺ and CD8⁺ T cells in the lymph node, the main site of HIV replication, in comparison with those T cells circulating in the peripheral blood (p = 0.01 and 0.03, respectively). Interestingly, PD-L1, the ligand for PD-1 was also expressed at a 5-fold higher level on CD14⁺ cells and a 3-fold higher level on mDC in the lymph node than in the peripheral blood (p = 0.007 and 0.015, respectively). HIV-specific CD4⁺ T-cell proliferation was enhanced in 5 of 7 subjects by blocking PD-1 binding to its ligand PD-L1.

Conclusions:  These data indicate that PD-1 expression on HIV-specific CD4⁺ T cells is driven by HIV replication. These findings also demonstrate that the PD-1 pathway is active in both the peripheral blood and especially the lymph node during chronic HIV infection, and that it provides a potential target for enhancing the ability of HIV-specific CD4⁺ T cells to control disease.