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

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.

[1]  S. Mallal,et al.  Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals , 2015, PloS one.

[2]  J. Shabanowitz,et al.  Protein derivatization and sequential ion/ion reactions to enhance sequence coverage produced by electron transfer dissociation mass spectrometry. , 2015, International journal of mass spectrometry.

[3]  J. Shabanowitz,et al.  Front-end electron transfer dissociation: a new ionization source. , 2013, Analytical chemistry.

[4]  Á. Santos-Briz,et al.  Eczema herpeticum with herpetic folliculitis after bone marrow transplant under prophylactic acyclovir: are patients with underlying dermatologic disorders at higher risk? , 2013, Transplant infectious disease : an official journal of the Transplantation Society.

[5]  Clemencia Pinilla,et al.  Measurement of MHC/Peptide Interactions by Gel Filtration or Monoclonal Antibody Capture , 2013, Current protocols in immunology.

[6]  S. Mallal,et al.  The structural basis of HLA‐associated drug hypersensitivity syndromes , 2012, Immunological reviews.

[7]  Elizabeth Phillips,et al.  HLA and pharmacogenetics of drug hypersensitivity. , 2012, Pharmacogenomics.

[8]  D. Margulies,et al.  Abacavir induces loading of novel self-peptides into HLA-B*57: 01 an autoimmune model for HLA-associated drug hypersensitivity , 2012, AIDS.

[9]  J. McCluskey,et al.  Immune self-reactivity triggered by drug-modified HLA-peptide repertoire , 2012, Nature.

[10]  S. Mallal,et al.  Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire , 2012, Proceedings of the National Academy of Sciences.

[11]  David Nolan,et al.  Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. , 2008, Immunity.

[12]  Arno Formella,et al.  Superimposé: a 3D structural superposition server , 2008, Nucleic Acids Res..

[13]  S. Mallal,et al.  HLA-B*5701 screening for hypersensitivity to abacavir. , 2008, The New England journal of medicine.

[14]  Bjoern Peters,et al.  Quantitative peptide binding motifs for 19 human and mouse MHC class I molecules derived using positional scanning combinatorial peptide libraries , 2008, Immunome research.

[15]  Kristie L. Rose,et al.  Methods for analyzing peptides and proteins on a chromatographic timescale by electron-transfer dissociation mass spectrometry , 2008, Nature Protocols.

[16]  Jürgen Bajorath,et al.  Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches. , 2007, Drug discovery today.

[17]  P. Kloetzel,et al.  Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding , 2005, Cellular and Molecular Life Sciences CMLS.

[18]  Brian K. Shoichet,et al.  ZINC - A Free Database of Commercially Available Compounds for Virtual Screening , 2005, J. Chem. Inf. Model..

[19]  S. Bryant,et al.  Open mass spectrometry search algorithm. , 2004, Journal of proteome research.

[20]  A. Barbaud,et al.  Systemic acyclovir reaction subsequent to acyclovir contact allergy: which systemic antiviral drug should then be used? , 2003, Contact dermatitis.

[21]  K. Lammintausta,et al.  Rapid systemic valaciclovir reaction subsequent to aciclovir contact allergy , 2001, Contact dermatitis.

[22]  John Sidney,et al.  Measurement of MHC/Peptide Interactions by Gel Filtration , 1999, Current protocols in immunology.

[23]  Rolf Apweiler,et al.  The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000 , 2000, Nucleic Acids Res..

[24]  John M. Barnard,et al.  Chemical Similarity Searching , 1998, J. Chem. Inf. Comput. Sci..

[25]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[26]  R. Demars,et al.  Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-C null human cell line. , 1989, Journal of immunology.

[27]  R. Demars,et al.  Isolation of an HLA-A:,B:,C Null Human Cell Line Capable of Expressing Transferred Class I Genes , 1989 .

[28]  D. Jeffries,et al.  Cutaneous adverse reactions to acyclovir: case reports. , 1985, Genitourinary medicine.