Background: HIV-infected subjects expressing the class I allele, HLA-B*57, are among those who progress to AIDS more slowly when compared to other individuals.  However, no data exist in infected subjects to suggest that favorable alleles are associated with different HIV-specific CD8+ T-cell responses when compared to individuals with unfavorable alleles. 

Methods: Chronically infected subjects were recruited from the REACH clinical sites and were comprised of a group of minority adolescents.  We measured HIV-specific gamma interferon (IFN-g) responses using the ELISPOT assay in PBMC taken from subjects with HLA-B*57 (7 subjects) and compared them to subjects with alleles associated with rapid progression of disease (HLA-B*35 and B*53; 16 total subjects).  PBMC were stimulated overnight with overlapping HIV-1 peptides spanning the Gag, Pol, Env, and Nef proteins.  Positive T-cell responses were then mapped to the 20-mer peptide.  Statistical analysis was performed using Wilcoxon signed-rank and Fischer exact test. 

Results: HLA-B*57 subjects had lower plasma viral loads (VL) and higher CD4+ T-cell counts when compared with HLA B*35 and B*53 subjects (median VL, 170 vs 4700 copies/mL; median CD4, 705 vs 613/mL, respectively).  A higher proportion of HLA-B*57 subjects had Gag-specific responses when compared with the HLA-B*35 or B*53 individuals (86% vs 56%, p = 0.09).  Response to Gag was immunodominant in 6/7 (86%) of the HLA-B*57 subjects while it was dominant in only 3/16 (19%) of subjects in the HLA-B*35 and B*53 groups (p = 0.01) and in only 16/49 (33%) of the subjects that did not express HLA-B*57 (p = 0.01).  All but one of the HLA-B*57 subjects had immunodominant responses to Gag that mapped to either of 2 highly conserved HLA-B*57-restricted epitopes in p24 (ISPRTLNAW; aa147-155 or KAFSPEVIPMF; aa 162-172). 

Conclusions: Our data support the hypothesis that immunodominant responses to highly conserved epitopes protect against disease progression seen in HLA-B*57 positive individuals.  While other factors are likely to also be important, these findings have important implications for HIV pathogenesis and could have an impact on the design of future HIV-specific treatment.