A clearer understanding of HIV-specific immune responses in highly-exposed, persistently seronegative (HEPS) subjects is important in developing models of HIV-l protective immunity, and ultimately for vaccine development. Various HIV-specific immune responses have been described in HEPS cohorts, including cytotoxic T lymphocyte (CTL) responses, T helper (Th) responses, and IgA specific for HIV-1 envelope proteins. The presence and correlates of these responses were examined in a Kenyan cohort of HEPS sex workers, and the frequency, specificity, and clinical significance of HTV-specific CD8+ responses were studied. Systemic HIV-1 Env-specific CTL and CD8+ lymphocyte responses against predefined CTL epitopes were present in most HEPS sex workers, as were HIV-1 Env-specific IgA and Th responses. The proportion of HEPS women with HIV-specific CTL or CD8+ responses increased with the duration of uninfected sex work, suggesting that responses were acquired over time. CD8+ responses were also found in the genital tract of HEPS sex workers, where they were enhanced in comparison to seropositive women. Overall, while systemic CD8+ responses in HEPS women were approximately tenfold weaker than those in infected women, they also targeted different epitopes. This suggests that qualitative rather than quantitative differences may explain HIV-1 protection. Several HIV-1 ‘resistant’ sex workers became infected by HTV-1 despite pre-existing HIV-specific immune responses (CTL, CD8+ responses, and/or IgA), possibly related to the waning of HIV-specific immunity after a temporary break from sex work. These findings imply that vaccine-induced protective HIV immunity may be possible, but that vaccine strategies of boosting or persistent antigen may be necessary for long-lived protection
