Public T cell receptors confer high-avidity CD4 responses to HIV controllers

Abstract

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.

DNA Vaccination by Electroporation Amplifies Broadly Cross-Restricted Public TCR Clonotypes Shared with HIV Controllers

“…2C, top panels) were compared to those previously reported for the HIC and HAART groups (Fig. 2C, middle and bottom panels) (22). …”

“…A minimum of 50 productive CDR3 sequences were analyzed per ADVAX sample, with the full list of sequences provided in Supplemental Table 1. This dataset, which consisted in 473 TRAV24 sequences and 723 TRBV2 sequences, was compared to those previously reported for 8 HIV controllers (HIC: 584 TRAV24 and 716 TRBV2 sequences) and 8 efficiently treated patients (HAART: 496 TRAV24 and 566 TRBV2 sequences) (22). …”

“…To further evaluate the degree of CDR3 motif sharing, we quantified the frequency of simpler motifs that were previously found to be highly prevalent in HIV controller Gag293-specific CDR3 sequences (22). The first TRAV24 motif, [AS]x[KR]AAGNKLT, was found in 33% of ADVAX TRAV24 sequences, compared to 37% of HIC and 22% of HAART sequences (Fig.…”

“…The treated patients had a median CD4+ T cell count of 570 (IQR: 270–1,534). The Gag293-specific repertoire of patients from the HIC and HAART groups was previously reported in (22). …”

“…The expression of high affinity TCRs helped explain how controllers maintained CD4+ T cell effector functions, as minimal amounts of viral antigens were sufficient to trigger full effector differentiation. We recently characterized the set of TCRs directed at Gag293, and uncovered a highly biased repertoire characterized by the preferential expression of the TCR variable genes TRAV24 and TRBV2, with the bias being more marked in controllers than in treated patients (22). Of note, the degree of TCR clonotype sharing was unusually high in the HIV controller group, with close to half of TCR sequences sharing common CDR3 motifs.…”