Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Acyclovir has low but detectable influence on HLA-B*57:01 specificity without inducing hypersensitivity

[img] PDF (Original Text (open access)) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
1MB
[img] Other (Supplementary Information)
358kB

Item Type:Article
Title:Acyclovir has low but detectable influence on HLA-B*57:01 specificity without inducing hypersensitivity
Creators Name:Metushi, I.G. and Wriston, A. and Banerjee, P. and Gohlke, B.O. and English, A.M. and Lucas, A. and Moore, C. and Sidney, J. and Buus, S. and Ostrov, D.A. and Mallal, S. and Phillips, E. and Shabanowitz, J. and Hunt, D.F. and Preissner, R. and Peters, B.
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.
Keywords:Acyclovir, Antiviral Agents, Cultured Cells, Drug Hypersensitivity, HLA-B Antigens, Protein Binding
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:10
Number:5
Page Range:e0124878
Date:29 May 2015
Official Publication:https://doi.org/10.1371/journal.pone.0124878
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library