Discussion
infection, HIV infection
INFECTION, HIV INFECTION
Previous studies demonstrated that HIV-specific pre-existing antibody responses can be protective in non-controllers (We found that the C epitope (gp41, HR2) was targeted more frequently prior to infection in controllers vs. viremic non-controllers (23.1% vs. 3.7%). Pre-infection reactivity to this epitope was also associated with higher overall HIV-specific antibody responses prior to infection, suggesting that production of C epitope antibodies was stimulated by HIV exposure without infection. At follow-up (infection duration: 1-2 years), pre-infection responses were boosted and all participants had reactivity to this epitope. Pre- and post-infection reactivity to the C epitope were also associated with lower VL after infection.The 12 peptides with the C epitope overlap with an HR2 epitope that was targeted in controllers with established HIV infection in our prior study (Antibodies to V epitope (gp120, C2) were only present prior to infection in viremic non-controllers. In contrast to the C epitope, pre-infection reactivity to this epitope was not associated with pre-infection reactivity to other HIV peptides, suggesting that production of V epitope antibodies was triggered by a mechanism other than HIV exposure. Changes in reactivity to the V epitope over time were also different from those observed for the C epitope. At follow-up, pre-infection responses to the V epitope were not boosted or consistently maintained, and only three participants developed V epitope reactivity after infection. Overall, these data suggest that V epitope reactivity was triggered by an unidentified, non-HIV antigen.The nine peptides with the V epitope (C2 target) did not overlap with epitopes identified in our previous work. However, in the RV144 trial (NCT00223080; Thailand), vaccination induced protective antibodies targeting C2; these antibodies were associated with higher levels of ADCC and reduced HIV acquisition risk (Pre-existing non-neutralizing or cross-reactive antibodies can sometimes facilitate viral entry by interacting with complement and/or the Fc receptor through antibody dependent enhancement (ADE) (This study had several limitations. First, negative HIV status pre-infection was determined using a sensitive antigen/antibody assay and an RNA assay with a LOD of 400 copies/mL; it is possible that some participants with low RNA and antibody levels could have been misclassified as uninfected. Second, the controller cohort used for peptide discovery was very small (n=13); this may have limited our ability to identify other pre-infection antibody specificities associated with HIV control. Third, the study cohort only included participants with presumed HIV subtype C; as inter-subtype genetic diversity may influence antibody responses, further studies are needed to assess generalizability of the findings in this study to persons with other HIV subtypes. Fourth, the VirScan assay measures antibody binding to unglycosylated, linear epitopes; antibody binding detected with VirScan may not correlate with antibody binding to the native HIV envelope trimer. Fifth, the phage-display library used in this report did not include HIV antisense protein peptides (