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 ≤ 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.