Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection

To address the issue of clonal exhaustion in humans, we monitored HLA class I-restricted, epitope-specific CTL responses in an in utero HIV-I-infected infant from 3 mo through 5 years of age. Serial functional CTL precursor a ssays demonstrated persistent, vigorous, and broadly directed HIV-1 specifi c CTL activity with a dominant response against an epitope in HIV-1 Gag-p17 (SLYNTVATL, aa 77-85). A clonal CTL response directed against the immunodo minant, HLA-A*0201-restricted epitope was found to persist over the entire observation period, as shown by TCR analysis of cDNA libraries generated fr om PBMC. The analysis of autologous viral sequences did not reveal any esca pe mutations within the targeted epitope, and viral load measurement indica ted ongoing viral replication, Furthermore, inhibition of viral replication assays indicated that the epitope was properly processed from autologous v iral protein. These data demonstrate that persistent exposure to high level s of viral Ag does not necessarily lead to clonal exhaustion and that epito pe-specific clonal CTL responses induced within the first weeks of life can persist for years without inducing detectable viral escape variants.