CD8(+) lymphocytes respond to different HIV epitopes in seronegative and infected subjects

HIV-1-specific cyotoxic T-lymphocyte (CTL) responses have been detected at a low frequency in many HIV-1-exposed, persistently seronegative (HEPS) sub jects. However, it is unclear how CTLs could protect against HIV acquisitio n in HEPS subjects, when high levels of circulating CTL fail to prevent dis ease progression in most seropositive subjects. To address this issue we st udied CD8(+) lymphocyte responses to a panel of HIV-1 CTL epitopes in 91 HE PS and 87 HIV-1-infected Nairobi sex workers. HIV-specific responses in ser opositive women focused strongly on epitopes rarely or never recognized in HEPS subjects, who targeted epitopes that were subdominant or unrecognized in infected women. These differences in epitope specificity were restricted by only those HLA class I alleles that are associated with a reduced risk of HIV-1 infection in this cohort. Late seroconversion in HEPS donors was a ssociated with a switch in epitope specificity and/or immunodominance to th ose epitopes preferentially recognized by HIV-1-infected women. The Likelih ood of detecting HIV-1-specific responses in HEPS women increased with the duration of viral exposure, suggesting that HIV-1-specific CD8(+) responses are acquired over time. The association between differential recognition o f distinct CTL epitopes and protection from HIV-1 infection may have signif icant implications for vaccine design.