Background:

Cryptic epitopes (CEs) are peptides derived from the translation of 1 or more of the 5 alternative reading frames (ARFs; 2 sense and 3 antisense) of genes. Here, we compared response rates to HIV-1–specific CE predicted to be restricted by HLA-I alleles associated with protection against disease progression to those without any such association.

Methods:

Peptides (9mer to 11mer) were designed based on HLA-I–binding algorithms for B* 27, B* 57, or B* 5801 (protective alleles) and HLA-B* 5301 or B* 5501 (nonprotective allele) in all 5 ARFs of the 9 HIV-1 encoded proteins. Peptides with> 50% probability of being an epitope (n= 231) were tested for T-cell responses in an IFN-γ enzyme-linked immunosorbent spot (ELISpot) assay. Peripheral blood mononuclear cell samples from HIV-1 seronegative donors (n= 42) and HIV-1 seropositive patients with chronic clade B infections (n= 129) were used.

Results:

Overall, 16%, 2%, and 2% of chronic HIV infected patients had CE responses by IFN-γ ELISpot in the protective, nonprotective, and seronegative groups, respectively (P= 0.009, Fischer exact test). Twenty novel CE-specific responses were mapped (median magnitude of 95 spot forming cells/10 6 peripheral blood mononuclear cells), and most were both antisense derived (90%) and represented ARFs of accessory proteins (55%). CE-specific CD8 T cells were multifunctional and proliferated when assessed by intracellular cytokine staining.

Conclusions:

CE responses were preferentially restricted by the protective HLA-I alleles in HIV-1 infection, suggesting that they may contribute to viral control in this group of patients.