The flexibility of the TCR allows recognition of a large set of naturally occurring epitope variants by HIV-specific cytotoxic T lymphocytes

Pathogens attempt to evade immune recognition by expressing mutated antigen s. The present study shows that two mechanisms happen in vivo during the co urse of HIV infection to limit the escape of antigenic variants from cytoto xic T lymphocyte (CTL) recognition: recognition of several epitope variants by the same TCR and generation of several CTL populations specific for a s ingle epitope but recognizing different variant sequences. We have studied two CTL populations directed towards the HIV-p24(gag) amino acids 176-184 Q ASQEVKNW epitope, presented by HLA-B5301. Both CTL populations were derived from a long-term asymptomatic HIV-infected child and they express differen t TCR. Each of the two CTL recognizes five of the 10 naturally occurring va riants. These variants are distinct for both CTL and thus a total of eight variants are recognized. Thus, polyclonality of CTL specific for the same e pitope but differing in variant sequences recognized may improve the contro l of variant viruses' replication in vivo. In addition to cross-recognition of several variant epitopes, promiscuous recognition of exogenous peptides complexed to allogeneic HLA-B molecules occurs, showing that the TCR can t olerate amino acid changes on both the peptide and the MHC molecule. This f lexibility of the TCR is probably of great importance for control of viruse s with high genetic variability, such as HIV.