It is not clear if HIV-1 variants lose the ability to prime naïve CD8+ cytotoxic T lymphocytes (CTL) during progressive, untreated infection. Answering this question is important for developing immunotherapeutic approaches for enhanced control of residual HIV-1 infection in persons on combination antiretroviral therapy (cART). We therefore conducted a comprehensive longitudinal analysis of viral evolution and its impact on primary and memory CD8+ T cell responses pre-seroconversion (SC), post-SC, and during cART. We report the emergence of variant sequences in Gag, Env, and Nef at early (0-3 yr) and late (3.3-7.8 yr) times following SC, and after ART (>8 yr). Memory T cell responses targeting autologous virus variants reached a nadir by 8 yr post-SC along with the development of AIDS. This was followed by a transient enhancement of anti-HIV-1 CTL responses upon initiation of cART. The frequency of epitope variants was clearly associated with the breadth but not the magnitude of memory T cell responses. Our study reveals that the immune system retained its capacity to induce broad and high magnitude, primary T cell responses to late variants in pre-SC T cells, comparable to primary anti-HIV-1 responses induced in T cells from HIV-1 uninfected persons. Consequently, despite evolutionary changes in HIV-1, CD8+ T cells can still be primed to viral variants. Hence, vaccination against late, mutated epitopes could be successful in enhancing primary reactivity of T cells for control of the residual reservoir of HIV-1 in persons on ART.


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