Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes

Abstract

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…In doing so, dominant epitopes may have ironically preserved efficacious subdominant target sequences within the viral genome. Consistent with this notion, subdominant epitopes that can control virus in vivo were recently reported in infected patients (21).…”

“…This has led to the suggestion that useful HLA-A2-restricted epitopes in circulating clade B viruses may have been lost because the clade B epidemic is historically older than the clade C epidemic and HLA-A2 is more prevalent in the West than in Africa (19,20). Loss of epitopes restricted by MHC alleles with high frequencies was also supported by studies in HIV-1 clade C-infected cohorts (21,22) and in SIV-infected macaques (23).…”

“…Reactivity to TV9 was sought with a set of 410 OLPs spanning the entire HIV-1 protein sequence in a cohort of 313 patients (21). HLA typing was possible for 280 of these samples, of which 121 were HLA-A2 ϩ .…”

“…21 were identified with peptide test sets consisting of a peptide matrix containing 410 OLPs spanning the entire HIV-1 clade B and clade C consensus sequences as described previously (21). PBMCs (100,000) were incubated for 16 h with nonameric TV9 peptide at serial 10-fold dilutions from 100 g/ml to 10 pg/ml in ELISPOT plates.…”

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

“…While much of the research focus has been on the more readily analyzed large, dominant CTL populations, it has become apparent that subdominant responses can also play a key role in immunity (2), particularly in situations where a diverse array of "minor" epitopes is being recognized (2,3) or there is the potential for mutational escape from immune control. Given that protection and recovery from any given virus infection is likely to depend on the overall breadth and extent of immunity (2)(3)(4)(5), developing a better understanding of factors that determine CTL immune magnitude is essential, particularly for the design of novel vaccination and immunotherapy strategies that make optimal use of subdominant CTL responses.…”