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Abstract
Promiscuous binding of viral CTL epitopes: an approach to refine HLA supertypes and to identify HIV CTL epitopes shared by HLA class I alleles differentially associated with slow or fast HIV disease progression
N Frahm1, T Woodberry1, P T Hraber2, K Yusim2, L M Henry1, K Sango1, C H Linde1, A G Wurcel3, E Pae4, B D Walker1, B T Korber2, C Brander1
1Massachusetts General Hospital, Charlestown, MA, United States; 2Los Alamos National Laboratory, Los Alamos, NM, United States; 3Lemuel Shattuck Hospital, Boston, MA, United States; 4Fenway Community Health Center, Boston, MA, United States
Background: The molecular structure of the peptide-binding cleft of HLA molecules largely determines the binding of cytotoxic T lymphocyte (CTL) epitopes. While each HLA allele displays its specific binding motif, alleles with similar motifs can be grouped into HLA supertypes. These HLA supertypes focus on HLA class I alleles frequently found in the Caucasian population and do not include HLA-C alleles.
Methods: 80 HIV-infected individuals were tested in IFN-γ ELISpot assays using a set of 184 optimally defined, HIV derived CTL epitopes. Similarly, responses to 86 optimal EBV CTL epitopes were tested in 50 EBV-positive individuals. Individuals were tested against all peptides, regardless of their HLA type and the epitope's HLA restriction.
Results: 35% of all HIV epitope specific responses (1500 total) were detected in individuals who did not express the originally described, restricting HLA allele, nor an allele that fell into the same HLA supertype as the original allele. A similarly high degree of promiscuous binding to HLA class I molecules was observed for the EBV derived CTL epitopes. Multiple HIV epitopes that bound to at least 5 different HLA class I alleles were identified. Interestingly, some epitopes were presented by HLA class I alleles differentially associated with slow or fast HIV disease progression, suggesting that in these cases, the epitope itself did not determine the rate of HIV disease progression.
Conclusions: The present data reveal an unprecedented degree of HLA class I epitope binding promiscuity, which allows for the definition of more comprehensive and functionally defined HLA supertypes and permits to identify viral CTL epitopes that provide a significantly higher population coverage than previously assumed. The identification of epitopes shared by alleles differentially associated with HIV disease progression also provides candidates to investigate the impact of HLA diversity on the evolving CTL response and its potential role in HIV control.
The XV International AIDS Conference
Abstract no.
ThOrA1396
Suggested Citation
" N Frahm , , et al.
Promiscuous binding of viral CTL epitopes: an approach to refine HLA supertypes and to identify HIV CTL epitopes shared by HLA class I alleles differentially associated with slow or fast HIV disease progression.
Oral Abstract session:
The XV International AIDS Conference:
Abstract no.
ThOrA1396"
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