Public TCRs confer high-avidity CD4 responses to HIV controllers

Rare patients termed HIV Controllers are able to spontaneously control HIV replication to undetectable levels and maintain normal CD4+ T cell counts in the absence of anti-retroviral therapy. Accumulating evidence suggests that control of viral replication in these patients is mediated by a particularly efficient cellular immune response. To identify the molecular determinants underlying this response, we characterized the TCR repertoire directed at the most immunoprevalent CD4 epitope in HIV-1 capsid, Gag293. HIV Controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire characterized by a predominance of TRAV24 and TRBV2 variable gene families, the presence of conserved motifs in both CDR3 regions, and a high frequency of public clonotypes (n=18 for each TCR chain). The most prevalent public clonotypes generated TCRs with affinities in the micromolar range, at the higher end of values reported for naturally occurring TCRs. These highaffinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for their expression in HIV Controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctional cytokine responses, thus recapitulating key features of the Controller CD4 response. Transfer 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. Amplifying or transferring such clonotypes may contribute to immunotherapeutic approaches that aim at a functional HIV cure.