Despite the dominance of HIV-1 subtype C worldwide, the evolution of virologic and immunologic parameters in acute HIV-1C infection have not been extensively characterized. By RNA screening of persons testing negative by standard antibody assays, we were able to recruit 20 subjects before seroconversion and characterize viral kinetics and evolving HIV-specific CD8+
T-cell responses during acute infection. Despite high viremia, responses were narrowly directed, and the majority of epitopes targeted in chronic infection [30
] did not induce detectable responses during the rapid decline of viremia. Although the ELISPOT assay can underestimate the true magnitude of T-cell responses [14
] and autologous virus sequences can differ from the reference strains used, HIV-1–specific CD8+
responses ultimately arose in these persons, indicating that many immunogenic epitopes are not targeted in the earliest stages of infection, at a time when viral load is rapidly declining.
Longitudinal assays for responses during and following acute infection allowed us to address not only the specificity of responses but also their persistence. In the entire cohort, responses to Nef-derived peptides were dominant in the earliest stages of infection, consistent with other data [38
]. However, only approximately half of the individuals tested targeted Nef in the early stages, although 82% targeted this protein at some time during the average 5 months of follow-up (data not shown), again suggesting impaired induction of responses in acute infection. A trend was observed where high T-cell responses against the Nef proteins correlated positively with high viral loads, as has been reported in other studies [38
], suggesting that these responses are driven by level of antigenemia, rather than being causal in lowering viral load, again suggesting impaired functional CD8+
T-cell responses in the earliest stages of acute infection. However, there was no correlation between the magnitude and breadth of CD8+
T-cell responses for other viral proteins and the concurrent plasma viral load, consistent with other reports [17
By assessing responses using peptides representing optimal epitopes, we were able to assess the hierarchy in the development of epitope-specific CD8+
T-cell responses restricted by specific HLA alleles, their immunodominance patterns, and the timing of induction of these responses. Within a month of the estimated time of infection, CD8+
T-cell responses were detected against 44% of peptide epitopes matched for each subject’s HLA and against 56% of the epitopes presented by their expressed alleles at 3 months. These data confirmed that the detectable responses in early infection are largely maintained, although immunodominance often shifts. Further investigation is required to determine whether the changes in the magnitude of responses and immunodominance are the result of sequence evolution within targeted epitopes or their flanking regions [24
], immunoregulation [47
], or other mechanisms.
In conclusion, we demonstrate that HIV-1–specific CD8+ T-cell responses can be detected before complete seroconversion, but many of the epitopes that elicit responses in chronic infection are not immunogenic during acute infection. We also confirm previous studies showing that the initial HIV-1–specific immune responses are narrowly directed, and extend these by showing the paucity of responses even when dramatic drops in viremia have occurred. Moreover, although response breadth and magnitude expand with duration of infection, a significant proportion of individuals are still unable to make responses despite the presence of cognate peptides restricted by the corresponding HLA allele. Further studies are needed to address why recognition of HIV-1 peptides appears to be selective during acute infection as the lack of recognition may contribute to the failure to control viremia to a low set point. The paucity of responses during the dramatic reduction in viremia suggests that tissue-specific responses as well as measures of CD8+ T-cell function other than IFN-γ should be examined to better define the role of HIV–specific CD8+ T-cells in the initial decline in viremia. Further studies are needed to understand the determinants and role of HIV-1–specific CD8+ T-cell responses in high-burden settings where an effective HIV-1 vaccine is urgently needed.