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| Item Type: | Article |
|---|---|
| Title: | Acyclovir has low but detectable influence on HLA-B*57:01 specificity without inducing hypersensitivity |
| Creators Name: | Metushi, I.G., Wriston, A., Banerjee, P., Gohlke, B.O., English, A.M., Lucas, A., Moore, C., Sidney, J., Buus, S., Ostrov, D.A., Mallal, S., Phillips, E., Shabanowitz, J., Hunt, D.F., 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 |
| 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 |
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