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Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.

Original publication

DOI

10.1073/pnas.2013554117

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

11/2020

Volume

117

Pages

28232 - 28238

Addresses

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.

Keywords

T-Lymphocytes, Cytotoxic, Humans, HIV-1, HIV Infections, Peptides, Membrane Transport Proteins, Histocompatibility Antigens Class I, Viral Load, Antigen Presentation, Human Immunodeficiency Virus Proteins