Frequent sharing of high-affinity TCRs in naturally controlled HIV infection: implications for vaccination

The rare patients who spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants underlying this response, we characterized the TCR repertoire directed at the most immunodominant CD4 epitope in HIV-1 capsid, Gag293. HIV Controllers from the ANRS CO21 CODEX cohort showed a highly skewed TCR repertoire characterized by a predominance of the TRAV24 and TRBV2 variable gene families. Controllers shared public clonotypes at higher frequencies than treated patients, suggesting the implication of particular TCRs in HIV control. The most prevalent public clonotypes generated TCRs with affinities in the micromolar range, at the higher end of values reported for naturally occurring TCRs. Transfer of the high-affinity Gag293-specific TCRs via lentivector conferred broad HLA II cross-restriction to healthy donor T cells, with up to 5 HLA-DR alleles recognized. In addition, transfer of a high-affinity Gag293-specific TCR was sufficient to confer a series of properties characteristic of HIV Controller CD4+ T cells, including high antigen sensitivity, polyfunctionality, and cytotoxicity. Of note, transduction of a high-affinity Gag293-specific TCR could also redirect CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. These findings indicate that TCR clonotypes with superior functions are associated with HIV control. Due to their broad HLA II cross-restriction, Gag293-specific public clonotypes can be amplified in individuals of different genetic backgrounds. This opens the possibility to test for the induction of these clonotypes in the diverse populations involved in HIV vaccination trials, and rapidly assess the quality of the vaccine responses at the clonotypic level. Analysis of the Gag293-specific repertoire induced by a candidate HIV vaccine reveals significant amplification of public clonotypes found in HIV Controllers, indicating the feasibility and potential of this approach for vaccine evaluation.