Comparison of the antigen sensitivity of Gag-specific CD4+ T cell responses in controlled HIV infection and HIV vaccination

Spontaneous control of HIV infection is characterized by a highly efficient cellular immune response. We showed in particular that HIV Controllers from the ANRS CO21 CODEX cohort harbor a population of specific CD4+ T cells that detect the immunodominant CD4 epitope Gag293 with high antigen sensitivity. To determine whether candidate vaccines can induce the high sensitivity responses seen in Controllers, we analyzed Gag293-specific responses in healthy volunteers who received the ADVAX DNA vaccine administered by electroporation. Comparison of Gag293-specific responses in primary CD4+ T cell lines via IFN-γ ELISpot revealed that the median antigen sensitivity in vaccinees was similar to that observed for Controllers (5x10-8 M) but higher than that in treated patients (5x10-7 M). However, antigen sensitivity remained higher in a subset of Controllers compared to vaccinees. TCR repertoire analysis of Gag293-specific CD4+ T cells from vaccinees revealed a preferential amplification of TCRβ family chain TRBV2, which also predominates in Controllers. However, TRAV family gene usage appeared more diverse in vaccinees compared to Controllers. Sequence analysis of the TCR chains amplified in 4 vaccinees revealed a biased TCR repertoire with the presence of public clonotypes (3 TRAV24 and 2 TRBV2) shared with HIV Controllers. In conclusion, DNA vaccination administered by electroporation has the potential to induce Gag-specific CD4+ T cells responses with a high antigen sensitivity and partial TCR repertoire overlap with that of Controllers. Monitoring the amplification of public TCR clonotypes could provide a novel approach to evaluate the quality of HIV vaccine responses.