title: Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity.
abstract: Immune mediated adverse drug reactions (IM-ADRs) remain a significant source of patient morbidity that have more recently been shown to be associated with specific class I and/or II human leukocyte antigen (HLA) alleles. Abacavir-induced hypersensitivity syndrome is a CD8+ T cell dependent IM-ADR that is exclusively mediated by HLA-B*57:01. We and others have previously shown that abacavir can occupy the floor of the peptide binding groove of HLA-B*57:01 molecules, increasing the affinity of certain self peptides resulting in an altered peptide-binding repertoire. Here, we have identified another drug, acyclovir, which appears to act in a similar fashion. As with abacavir, acyclovir showed a dose dependent increase in affinity for peptides with valine and isoleucine at their C-terminus. In agreement with the binding studies, HLA-B*57:01 peptide-elution studies performed in the presence of acyclovir revealed an increased number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we have hypothesized that acyclovir acts by the same mechanism as abacavir, although our data also suggest the overall effect is much smaller: the largest changes of peptide affinity for acyclovir were 2-5 fold, whereas for abacavir this effect was as much as 1000-fold. Unlike abacavir, acyclovir is not known to cause IM-ADRs. We conclude that the modest effect of acyclovir on HLA binding affinity in contrast to the large effect of abacavir is insufficient to trigger a hypersensitivity syndrome. We further support this by functional in vitro studies where acyclovir, unlike abacavir, was unable to produce an increase in IFN-γ upon expansion of HLA-B*57:01+ PBMCs from healthy donors. Using abacavir and acyclovir as examples we therefore propose an in vitro pre-clinical screening strategy, whereby thresholds can be applied to MHC-peptide binding assays to determine the likelihood that a drug could cause a clinically relevant IM-ADR.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Imir G
authors.initials: IG
authors.lastname: Metushi
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wriston
authors.affiliation: Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; Graduate School of Computational Systems Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Bjoern Oliver
authors.initials: BO
authors.lastname: Gohlke
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: A Michelle
authors.initials: AM
authors.lastname: English
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lucas
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Moore
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Soren
authors.initials: S
authors.lastname: Buus
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shabanowitz
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America; Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hunt
authors.affiliation: Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; Graduate School of Computational Systems Biology, Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Preissner
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
mesh_terms: D000212:Acyclovir / Q000276:immunology* / Q000378:metabolism*; D000998:Antiviral Agents / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D004342:Drug Hypersensitivity / Q000276:immunology*; D015235:HLA-B Antigens / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding
chemical_list: D000998:Antiviral Agents; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D000212:Acyclovir