PMID- 26024233 OWN - NLM STAT- MEDLINE DCOM- 20160425 LR - 20201217 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 5 DP - 2015 TI - Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity. PG - e0124878 LID - 10.1371/journal.pone.0124878 [doi] LID - e0124878 AB - 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-gamma 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. FAU - Metushi, Imir G AU - Metushi IG AD - Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. FAU - Wriston, Amanda AU - Wriston A AD - Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. FAU - Banerjee, Priyanka AU - Banerjee P AD - Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; Graduate School of Computational Systems Biology, Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Gohlke, Bjoern Oliver AU - Gohlke BO AD - Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. FAU - English, A Michelle AU - English AM AD - Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. FAU - Lucas, Andrew AU - Lucas A AD - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia. FAU - Moore, Carrie AU - Moore C AD - Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. FAU - Sidney, John AU - Sidney J AD - Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. FAU - Buus, Soren AU - Buus S AD - Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Ostrov, David A AU - Ostrov DA AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, United States of America. FAU - Mallal, Simon AU - Mallal S AD - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America. FAU - Phillips, Elizabeth AU - Phillips E AD - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America. FAU - Shabanowitz, Jeffrey AU - Shabanowitz J AD - Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America. FAU - Hunt, Donald F AU - Hunt DF AD - Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America; Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America. FAU - Preissner, Robert AU - Preissner R AD - Charite-University Medicine Berlin, Institute of Physiology & Experimental Clinical Research Center, Berlin, Germany; Graduate School of Computational Systems Biology, Humboldt-Universitat zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. FAU - Peters, Bjoern AU - Peters B AD - Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America. LA - eng GR - R01 AI033993/AI/NIAID NIH HHS/United States GR - R01 AI103348/AI/NIAID NIH HHS/United States GR - R37 AI033993/AI/NIAID NIH HHS/United States GR - AI 33993/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150529 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antiviral Agents) RN - 0 (HLA-B Antigens) RN - 0 (HLA-B57 antigen) RN - X4HES1O11F (Acyclovir) SB - IM MH - Acyclovir/*immunology/*metabolism MH - Antiviral Agents/*immunology/*metabolism MH - Cells, Cultured MH - Drug Hypersensitivity/*immunology MH - HLA-B Antigens/*metabolism MH - Humans MH - Protein Binding PMC - PMC4449000 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/05/30 06:00 MHDA- 2016/04/26 06:00 PMCR- 2015/05/29 CRDT- 2015/05/30 06:00 PHST- 2014/12/24 00:00 [received] PHST- 2015/03/06 00:00 [accepted] PHST- 2015/05/30 06:00 [entrez] PHST- 2015/05/30 06:00 [pubmed] PHST- 2016/04/26 06:00 [medline] PHST- 2015/05/29 00:00 [pmc-release] AID - PONE-D-14-57140 [pii] AID - 10.1371/journal.pone.0124878 [doi] PST - epublish SO - PLoS One. 2015 May 29;10(5):e0124878. doi: 10.1371/journal.pone.0124878. eCollection 2015.