, Volume 57, Issue 5, pp 315-325
Date: 04 May 2005

A biochemical and structural analysis of genetic diversity within the HLA-A*11 subtype

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Abstract

The HLA-A*11 subtype includes 17 naturally occurring variants (-A*1101 to -A*1117) distributed among different ethnic groups worldwide. At present, only HLA-A*1101 has been characterized at the molecular, structural, and immunological level. Developing similar knowledge on other HLA-A*11 alleles is highly important for bone marrow and graft transplantation. This is also important to better understand disease linkages within the HLA-A*11 subtype given that HLA-A*11 molecules are associated with resistance to acquisition of HIV-1 infection and various autoimmune diseases. To broaden our understanding of HLA-A*11 molecules, we have determined the impact of natural polymorphism on the peptide-binding properties of several HLA-A*11 molecules: -A*1103, -A*1106, -A*1108, -A*1110, -A*1111, and -A*1114. We used an approach that combines data from thermal stability studies of recombinant, soluble forms of these molecules in complex with HIV-1 peptides, together with a detailed structural analysis of the resulting HLA-A*11 molecule/peptide complexes based on crystal and molecular model structures. Our analysis shows that natural polymorphism within the HLA-A*11 subtype is distributed along the α1 and α2 helices of the peptide-binding groove, in marked contrast to the pattern of polymorphism in HLA-A*2 and HLA-B*27 subtypes. Natural polymorphism greatly altered the abilities of individual -A*11 molecules to form stable complexes with HIV-1 peptides. In comparison to -A*1101, natural polymorphism altered the peptide-presenting properties of -A*1103, -A*1108, and -A*1114 and has the potential to affect the peptide-selecting properties of -A*1106, -A*1110, and -A*1111 as well. Overall, our findings suggest that HLA-A*11 molecules may stimulate alloreactive CD8+ cytotoxic T-cell responses.