title: Varicella-zoster virus-derived major histocompatibility complex class I-restricted peptide affinity is a determining factor in the HLA risk profile for the development of postherpetic neuralgia.
abstract: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster and is typified by a lingering pain that can last months or years after the characteristic herpes zoster rash disappears. It is well known that there are risk factors for the development of PHN, such as its association with certain HLA alleles. In this study, previous HLA genotyping results were collected and subjected to a meta-analysis with increased statistical power. This work shows that the alleles HLA-A*33 and HLA-B*44 are significantly enriched in PHN patients, while HLA-A*02 and HLA-B*40 are significantly depleted. Prediction of the varicella-zoster virus (VZV) peptide affinity for these four HLA variants by using one in-house-developed and two existing state-of-the-art major histocompatibility complex (MHC) class I ligand prediction methods reveals that there is a great difference in their absolute and relative peptide binding repertoires. It was observed that HLA-A*02 displays a high affinity for an ∼7-fold-higher number of VZV peptides than HLA-B*44. Furthermore, after correction for HLA allele-specific limitations, the relative affinity of HLA-A*33 and HLA-B*44 for VZV peptides was found to be significantly lower than those of HLA-A*02 and HLA-B*40. In addition, HLA peptide affinity calculations indicate strong trends for VZV to avoid high-affinity peptides in some of its proteins, independent of the studied HLA allele.
  
  
  OBJECTIVE
  Varicella-zoster virus can cause two distinct diseases: chickenpox (varicella) and shingles (herpes zoster). Varicella is a common disease in young children, while herpes zoster is more frequent in older individuals. A common complication of herpes zoster is postherpetic neuralgia, a persistent and debilitating pain that can remain months up to years after the resolution of the rash. In this study, we show that the relative affinity of HLA variants associated with higher postherpetic neuralgia risk for varicella-zoster virus peptides is lower than that of variants with a lower risk. These results provide new insight into the development of postherpetic neuralgia and strongly support the hypothesis that one of its possible underlying causes is a suboptimal anti-VZV immune response due to weak HLA binding peptide affinity.
authors.affiliation: Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium Biomedical Informatics Research Center Antwerp (Biomina), University of Antwerp/Antwerp University Hospital, Edegem, Belgium pieter.meysman@uantwerpen.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Meysman
authors.affiliation: Centre for Health Economics Research & Modeling Infectious Diseases, Vaccine Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Hasselt, Belgium.
authors.forename: Benson
authors.initials: B
authors.lastname: Ogunjimi
authors.affiliation: Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium Biomedical Informatics Research Center Antwerp (Biomina), University of Antwerp/Antwerp University Hospital, Edegem, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Naulaerts
authors.affiliation: Centre for Health Economics Research & Modeling Infectious Diseases, Vaccine Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beutels
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Viggo
authors.initials: V
authors.lastname: Van Tendeloo
authors.affiliation: Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium Biomedical Informatics Research Center Antwerp (Biomina), University of Antwerp/Antwerp University Hospital, Edegem, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Laukens
mesh_terms: D004198:Disease Susceptibility; D005787:Gene Frequency; D005838:Genotype; D014645:Herpesvirus 3, Human / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D051474:Neuralgia, Postherpetic / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D012307:Risk Factors
chemical_list: D015395:Histocompatibility Antigens Class I