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Early HIV-1 infection is marked by rapid evolution of both CD8(+) T lymphocyte (CTL) epitope targeting and viral sequences, while chronic infection demonstrates relative stability of these parameters. To examine the interactions of changing CTL targeting and viremia in early infection, we assessed CTL targeting and viremia levels in persons during early HIV-1 infection (estimated 15-271 days post-infection) who were placed on effective antiretroviral therapy. Pre-therapy, CTL targeting of viral proteins varied between persons depending on time after infection. Across individuals, increasing time after infection was associated with increasing Gag and Pol targeting, suggesting increasing targeting of conserved sequences. The intensity of Gag targeting correlated to lower viremia levels, while Env targeting correlated to higher viremia levels during early infection. This suggested that shifted targeting towards more conserved sequences is involved with the drop of viremia during early infection, consistent with prior observations of correlation between Gag targeting and lower viremia during chronic infection. After suppressive antiretroviral therapy, CTL targeting was generally static, indicating that HIV-1 replication and evolution drives the evolution of CTL targeting in early infection. Overall, these data suggest that early CTL targeting is directed towards more variable epitopes, causing escape and re-targeting until more conserved epitopes are recognized stably in chronic infection. Circumventing this natural history by pre-targeting CTL against more conserved epitopes with a vaccine could minimize the initial period of viral escape and immune damage during acute infection, improving long-term containment of HIV-1.

Foxp3 plays a critical role in development of CD4+ regulatory T lymphocytes (Tregs). It was originally proposed as a specific marker for Tregs, but recent studies have shown that Foxp3 can be expressed in proliferating CD8+ and CD4+ T lymphocytes. We further investigated the association between Foxp3 expression and proliferation of peripheral blood CD4+ and CD8+ T lymphocytes and focused on virus-specific memory CD8+ T lymphocytes. We found that resting peripheral blood bulk and cytomegalovirus- or HIV-1-specific CD8+ T lymphocytes do not normally express Foxp3. However, stimulation in vitro triggered these cells to express Foxp3 as well as CD25, and the addition of interleukin-2 possibly enhanced the expression of Foxp3. These data demonstrate that proliferation itself is sufficient to induce the Treg-like phenotype. Given that others have demonstrated Treg functional activity in such "induced Tregs," these results suggest that virus-specific CD8+ T lymphocytes have the capacity to acquire regulatory functions. Although the implications of Foxp3 expression in virus-specific CD8+ T lymphocytes in the immunologic control of persistent HIV-1 viremia remain to be determined, our results are consistent with Foxp3 expression playing an essential role in regulation of cell proliferation and functional outcomes for HIV-1-specific CD8+ T lymphocytes.