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

P>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 center dot 01). PD-1 on CD8+ HIV-specific subsets was higher than CMV-specific CD8+ cells (P < 0 center dot 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 center dot 50 to -0 center dot 77, P < 0 center dot 01) than the total number of Gag-specific CD8+ cells (r = 0 center dot 44-0 center dot 85, P < 0 center dot 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.