New Genetic Predictors for Abacavir Tolerance in HLA-B*57:01 Positive Individuals

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Abstract

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n=95) and ABC tolerant (n=43) HLA-B*57:01+ patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p=0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

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Journal

Journal ID (nlm-journal-id): 8010936

Journal ID (pubmed-jr-id): 4052

Journal ID (nlm-ta): Hum Immunol

Journal ID (iso-abbrev): Hum. Immunol.

Title: Human immunology

ISSN (Print): 0198-8859

ISSN (Electronic): 1879-1166

Publication date Nihms-submitted: 7 May 2020

Publication date (Electronic): 12 March 2020

Publication date (Print): June 2020

Publication date PMC-release: 03 June 2020

Volume: 81

Issue: 6

Pages: 300-304

Affiliations

[1 ]Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia,

[2 ]Telethon Kids Institute, Western Australia, Australia,

[3 ]School of Human Sciences, University of Western Australia, Western Australia, Australia,

[4 ]Department of Clinical Immunology, Royal Perth Hospital, Western Australia, Australia,

[5 ]Celgene Corporation, New Jersey, USA,

[6 ]ViiV Healthcare at Research Triangle Park, North Carolina, USA,

[7 ]Inselspital, Bern, Switzerland,

[8 ]British Columbia Centre for Excellence in HIV/AIDS, Vancouver British Columbia, Canada,

[9 ]Sunnybrook Health Sciences Centre, Toronto, Canada,

[10 ]University of Toronto,Toronto, Canada,

[11 ]Department of Haematology, Fiona Stanley Hospital, Western Australia, Australia

[12 ]Institute for Respiratory Health, University of Western Australia, Western Australia, Australia,

[13 ]Vanderbilt University Medical Centre, Nashville, USA.

Author notes

Authorship

Research design: RP, AC, SL, DN, DT, MS, AR, JM, AR, IJ, AR, SG, SM, EP; Experimental work : RP, LC, KS, CA; Data analysis: RP, PD, AC, SL, DD, IJ, YL, SG, EP; Writing of manuscript: RP, PD, SG,EP; All the authors have approved the submitted manuscript.

Address for correspondence: Elizabeth J. Phillips, M.D., Vanderbilt University Medical Centre, A2200 MCN, 1161 21 ^st Ave. S., Nashville, TN, USA 37232, elizabeth.j.phillips@ 123456vumc.org

Article

Accession ID: PMC7266722 Pmcid ID: PMC7266722 Pmc-uid ID: 7266722 Manuscript ID: nihpa1590559

DOI: 10.1016/j.humimm.2020.02.011

PMC ID: 7266722

PubMed ID: 32173028

SO-VID: bb9e3829-b5ef-4c63-9eec-9bce5b30a405

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