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

Area of Science:

• Immunology
• Pharmacology
• Genetics

Background:

• Immune-mediated adverse drug reactions (IM-ADRs) are a significant cause of patient morbidity.
• Specific human leukocyte antigen (HLA) alleles are associated with IM-ADRs, such as abacavir hypersensitivity mediated by HLA-B*57:01.
• Abacavir alters the peptide-binding repertoire of HLA-B*57:01 by increasing self-peptide affinity.

Purpose of the Study:

• To investigate if acyclovir, like abacavir, alters the peptide-binding repertoire of HLA-B*57:01.
• To determine if acyclovir can trigger IM-ADRs.
• To propose a pre-clinical screening strategy for predicting drug-induced IM-ADRs.

Main Methods:

• Assessed the dose-dependent effect of acyclovir on peptide binding affinity to HLA-B*57:01.
• Performed HLA-B*57:01 peptide-elution studies in the presence of acyclovir.
• Conducted in vitro functional studies measuring IFN-γ production in HLA-B*57:01+ PBMCs.

Main Results:

• Acyclovir increased peptide affinity for HLA-B*57:01 in a dose-dependent manner, particularly for peptides with C-terminal valine and isoleucine.
• Peptide-elution studies confirmed an increased number of endogenously bound peptides with C-terminal isoleucine in the presence of acyclovir.
• The effect of acyclovir on peptide binding affinity (2-5 fold) was significantly smaller than that of abacavir (up to 1000-fold).
• Acyclovir did not induce IFN-γ production in HLA-B*57:01+ PBMCs, unlike abacavir.

Conclusions:

• Acyclovir's modest effect on HLA-B*57:01 binding affinity is insufficient to trigger hypersensitivity syndrome.
• The magnitude of drug-induced changes in MHC-peptide binding is critical for predicting IM-ADRs.
• A pre-clinical screening strategy using MHC-peptide binding assays with defined thresholds can predict the likelihood of drug-induced IM-ADRs.