The majority of currently circulating human immunodeficiency virus type 1 clade B viruses fail to prime cytotoxic T-lymphocyte responses against an otherwise immunodominant HLA-A2-restricted epitope: implications for vaccine design

Abstract

Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr59-67) that is targeted by acute-phase HIV-1-specific CD8+ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I60L variant all developed these responses. The I60L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic T-lymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.

FIG. 1.

Percentage of study subjects targeting HLA-A2-restricted HIV-1-specific CD8⁺ T-cell epitopes during primary and chronic HIV-1 infections. The percentages of individuals with detectable CD8⁺ T-cell responses against the 16 tested (and described as optimal) HIV-1-specific CTL epitopes restricted by HLA-A2 are shown during primary HIV-1 infection (n = 14) and chronic HIV-1 infection (n = 74).

FIG. 2.

Better recognition of the ALIRILQQL variant by HIV-1-specific CD8⁺ T cells. (A) Seven Vpr59-67-specific CD8⁺ T-cell clones were generated from study subjects AC-04 and AC-13 by limiting-dilution techniques. All seven CD8⁺ T-cell clones lysed autologous BCL pulsed with the ALIRILQQL variant peptide better at lower peptide concentrations than BCL pulsed with the consensus AIIRILQQL variant peptide, as shown for one representative clone. (B) PBMC from AC-04, AC-13, and AC-75 were tested in an ELISPOT assay for recognition of the ALIRILQQL and AIIRILQQL variant peptides, with log dilutions of the peptides. In each subject, the ALIRILQQL variant peptide was recognized better at lower peptide concentrations.