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PLoS One. 2015 May 29;10(5):e0124878. doi: 10.1371/journal.pone.0124878. eCollection 2015.

Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity.

Author information

  • 1Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
  • 2Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America.
  • 3Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; Graduate School of Computational Systems Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
  • 4Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 5Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
  • 6Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 7Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, United States of America.
  • 8Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
  • 9Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America; Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
  • 10Charite-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.

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.

PMID:
26024233
PMCID:
PMC4449000
DOI:
10.1371/journal.pone.0124878
[PubMed - indexed for MEDLINE]
Free PMC Article
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