Distinct assembly profiles of HLA-B molecules syed monem rizvi1

Nasir Salam, Jie Geng, Ying Qi, Jay H. Bream, Priya Duggal, Shehnaz K. Hussain, Jeremy Martinson, Steven M. Wolinsky, Mary Carrington, Malini Raghavan

Research output: Contribution to journalArticle

Abstract

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 HIVinfected 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.

Original languageEnglish (US)
Pages (from-to)4967-4976
Number of pages10
JournalJournal of Immunology
Volume192
Issue number11
DOIs
StatePublished - Jun 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Distinct assembly profiles of HLA-B molecules syed monem rizvi1'. Together they form a unique fingerprint.

  • Cite this

    Salam, N., Geng, J., Qi, Y., Bream, J. H., Duggal, P., Hussain, S. K., Martinson, J., Wolinsky, S. M., Carrington, M., & Raghavan, M. (2014). Distinct assembly profiles of HLA-B molecules syed monem rizvi1. Journal of Immunology, 192(11), 4967-4976. https://doi.org/10.4049/jimmunol.1301670