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2014 ; 192
(11
): 4967-76
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Distinct assembly profiles of HLA-B molecules
#MMPMID24790147
Rizvi SM
; Salam N
; Geng J
; Qi Y
; Bream JH
; Duggal P
; Hussain SK
; Martinson J
; Wolinsky SM
; Carrington M
; Raghavan M
J Immunol
2014[Jun]; 192
(11
): 4967-76
PMID24790147
show ga
MHC class I polymorphisms are known to influence outcomes in a number of
infectious diseases, cancers, and inflammatory diseases. Human MHC class I H
chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly
polymorphic, with the HLA-B locus being the most variable. Each HLA class I
protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T
cells. HLA-disease associations have been shown in some cases to link to the
peptide-binding characteristics of individual HLA class I molecules. 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. In particular, dependence on the assembly factor tapasin
is highly variable, with frequent occurrence of strongly tapasin-dependent or
independent allotypes. Several polymorphic HLA-B residues located near the
C-terminal end of the peptide are key determinants of tapasin-independent
assembly. 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. 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.
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.
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