The contribution of CD8 T cells targeting Cryptic Epitopes on viral evolution during acute HIV-1 infection.

Abstract

Abstract Alternative reading frames (ARF) of HIV, in both sense and antisense directions, have been shown to produce polypeptides of unknown functions. These peptides, known as cryptic epitopes (CE), commonly induce CD8 T cell responses in HIV; however, their role in controlling HIV-1 infection remains unclear. We hypothesized that CD8 T-cells target CE shortly following acute HIV infection and force viral escape. Such a finding would indicate that CE may serve as viable immunogens for inclusion in preventative HIV-1 vaccines. Using an HLA-I binding prediction algorithm applied to fixed mutations in ARF during the first two years of infection in a Zambian patient cohort, we predicted 66 CD8 T-cell escape mutations within gag, pol, and nef, which we further tested for immunogenicity. 8/32 chronic patient samples responded to at least one predicted CE as shown by IFNγ ELISpot. Furthermore, all ten immunogenic CE identified in the study were derived from a single antisense reading frame within the coding region of pol. Longitudinal studies failed to show any evidence of early viral escape to CE, as evaluation of these CE-specific CD8 T-cells following acute infection was not temporally associated with the occurrence of potential escape mutations. Our data suggest that although T-cell responses to CE can be detected during early HIV infections, they rarely establish HIV-1 escape mutations. As such their contribution to viral control is likely limited. Potential reasons for their limitations in forcing escape mutations include their infrequent expression and the weak magnitude of T-cell responses generated. Nevertheless, these data indicate that cryptic epitopes are not optimal targets for a preventative HIV vaccine.