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Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire

Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire
Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire
Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLAB*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.
1664-3224
Illing, Patricia
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van Hateren, Andy
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Darley, Rachel
840a775a-867e-42ba-a7cb-d131c9fdb9c6
Croft, Nathan
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Mifsud, Nicole
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King, Samuel
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Kostenko, Lyudmila
e1875855-a42e-446a-b0ac-8864b4146a42
Bharadwaj, Mandvi
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McCluskey, James
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Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Purcell, Anthony
e2edc5f2-5d01-4421-ab72-b1e20ae1db70
Illing, Patricia
35d90e29-ef24-48c1-b4f2-cd1bb548e51b
van Hateren, Andy
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Darley, Rachel
840a775a-867e-42ba-a7cb-d131c9fdb9c6
Croft, Nathan
6792a193-e691-4a26-a1ef-35012d7f00ec
Mifsud, Nicole
09fc6cb9-e6c4-460c-bf90-531c9e285bf5
King, Samuel
a3102fbf-6f85-432c-85e3-2eecac5e0511
Kostenko, Lyudmila
e1875855-a42e-446a-b0ac-8864b4146a42
Bharadwaj, Mandvi
2342b1f5-7fe6-45e5-b704-c255b5c3c7a3
McCluskey, James
9c0fad9d-b56d-4c53-bedb-adf49943e74f
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Purcell, Anthony
e2edc5f2-5d01-4421-ab72-b1e20ae1db70

Illing, Patricia, van Hateren, Andy, Darley, Rachel, Croft, Nathan, Mifsud, Nicole, King, Samuel, Kostenko, Lyudmila, Bharadwaj, Mandvi, McCluskey, James, Elliott, Timothy and Purcell, Anthony (2021) Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire. Frontiers in Immunology. (doi:10.3389/fimmu.2021.672737).

Record type: Article

Abstract

Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLAB*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.

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Accepted/In Press date: 26 April 2021
e-pub ahead of print date: 19 May 2021

Identifiers

Local EPrints ID: 450797
URI: http://eprints.soton.ac.uk/id/eprint/450797
ISSN: 1664-3224
PURE UUID: 7ee9770e-2f25-4541-bd56-631da3c38821
ORCID for Andy van Hateren: ORCID iD orcid.org/0000-0002-3915-0239
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222

Catalogue record

Date deposited: 12 Aug 2021 16:30
Last modified: 13 Aug 2021 01:41

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Contributors

Author: Patricia Illing
Author: Rachel Darley
Author: Nathan Croft
Author: Nicole Mifsud
Author: Samuel King
Author: Lyudmila Kostenko
Author: Mandvi Bharadwaj
Author: James McCluskey
Author: Timothy Elliott ORCID iD
Author: Anthony Purcell

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