TY - JOUR AU - Benati, Daniela AU - Galperin, Moran AU - Lambotte, Olivier AU - Gras, Stéphanie AU - Lim, Annick AU - Mukhopadhyay, Madhura AU - Nouël, Alexandre AU - Campbell, Kristy-Anne AU - Lemercier, Brigitte AU - Claireaux, Mathieu AU - Hendou, Samia AU - Lechat, Pierre AU - de Truchis, Pierre AU - Boufassa, Faroudy AU - Rossjohn, Jamie AU - Delfraissy, Jean-François AU - Arenzana-Seisdedos, Fernando AU - Chakrabarti, Lisa A. T1 - Public T cell receptors confer high-avidity CD4 responses to HIV controllers PY - 2016/06/01/ AB - The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI83792 VL - 126 IS - 6 UR - https://doi.org/10.1172/JCI83792 SP - 2093 EP - 2108 PB - The American Society for Clinical Investigation ER -