Combined Env- and Gag-specific T cell responses in relation to programmed death-1 receptor and CD4 T cell loss rates in human immunodeficiency virus-1 infection.

Additional progression markers for human immunodeficiency virus (HIV) infection are warranted. In this study we related antigen-specific responses in CD4(+) and CD8(+) T cells to CD38, reflecting chronic immune activation, and to CD4(+) T cell loss rates. Clones transiently expressing CD107a (CD8(+)) or CD154 (CD4(+)) in response to Gag, Env and Nef overlapping peptide pools were identified, along with their expression of the inhibitory programmed death-1 receptor (PD-1) in fresh peripheral blood mononuclear cells (PBMC) from 31 patients off antiretroviral treatment (ART). HIV-specific CD8(+) T cell responses dominated over CD4(+) T cell responses, and among CD8(+) responses, Gag and Nef responses were higher than Env-responses (P < 0.01). PD-1 on CD8(+) HIV-specific subsets was higher than CMV-specific CD8(+) cells (P < 0.01), whereas PD-1 on HIV-specific CD4(+) cells was similar to PD-1 on CMV-specific CD4(+) cells. Gag and Env CD8(+) responses correlated oppositely to the CD4 loss rate. Env/Gag CD8(+) response ratios, independently of PD-1 levels, correlated more strongly to CD4 change rates (r = -0.50 to -0.77, P < 0.01) than the total number of Gag-specific CD8(+) cells (r = 0.44-0.85, P < or = 0.02). The Env/Gag ratio performed better than CD38 and HIV-RNA in logistic regression analysis predicting CD4 change rate as a measure of progression. In conclusion, HIV-specific CD8(+)CD107a(+) Env/Gag response ratio was a stronger predictor for progression than CD38 and HIV-RNA. The Env/Gag ratio may reflect the balance between possibly beneficial (Gag) and detrimental (Env) CD8(+) T cell responses and should be explored further as a progression marker.