HLA class I molecules are known to exert profound influences on disease progression in a number of infectious diseases and cancers (reviewed in Refs. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B–folding patterns upon infectious disease outcomes. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes.
In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8 + T cells. These genes are highly polymorphic, with the HLA-B locus being the most variable. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases.
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