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 ϳ7-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. IMPORTANCE 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. P rimary infection by varicella-zoster virus (VZV) results in the common childhood disease varicella (chickenpox). VZV persists as a latent infection in dorsal root ganglion cells with minimal gene transcription (1). Clinical reactivation of VZV typically results in a characteristic painful dermatomal rash and is termed shingles or herpes zoster (HZ). Furthermore, HZ patients transmit VZV and thus could cause chickenpox in susceptible individuals, thereby reigniting the epidemiological VZV cycle (2, 3). It is estimated that ϳ10% to 30% of individuals will develop HZ in their lifetimes, with the frequency increasing to 50% for those Ͼ85 years of age (4). For many of these patients, the affected region remains painful for months or, exceptionally, years after the HZ rash reso...

Association of human leukocyte antigen with postherpetic neuralgia in Koreans

“…Associations of HLA alleles with PHN in Japanese have been reported in three independent studies . Meysman et al recently performed a meta‐analysis of these Japanese studies and compared the HLA frequencies in PHN patients with those in HZ patients without developing PHN and controls . Significant changes in PHN patients either in the meta‐analysis data of Japanese or in the present study of Koreans are shown in Table .…”

“…Association of HLA alleles with PHN may be explained from another view point in that differences in varicella‐zoster virus peptide binding affinity of different HLA molecules may confer susceptibility or protection to the development of PHN in HZ patients. In this context, Meysman et al performed prediction of the virus peptide affinity for four different HLA alleles after the aforementioned meta‐analysis of the Japanese studies . They chose HLA‐A*02 and B*40 (both depleted in PHN) and A*33 and B*44 alleles (both enriched in PHN) as candidate alleles conferring protection and susceptibility to the development of PHN, respectively (Table ).…”

Integrating between-host transmission and within-host immunity to analyze the impact of varicella vaccination on zoster

“…Although our IBM has given us valuable insights into between-host and within-host VZV dynamics, other influential factors could be introduced in future versions. These factors could relate to CMV-immunosenescence ( Ogunjimi et al, 2014 ), maternal antibodies, reduced VZV-CMI induction if infected during the first year of life as this might improve the prediction of the teenage group ( Terada et al, 1994 ), co-infection with other viruses ( Ogunjimi et al, 2015 ), risk groups (for e.g., immunosuppressed individuals) and HLA types ( Meysman et al, 2015 ). Although current deterministic compartmental models should be able to partially account for these effects, a VZV IBM seems better suited to directly model the influence of these immunity-perturbing factors.…”

Cytomegalovirus seropositivity is associated with herpes zoster

“…5,6 In addition, certain HLA types have been shown to be enriched in individuals with prolonged HZ (post-herpetic neuralgia). 7 Cytomegalovirus (CMV), another human herpesvirus (HHV) with latency-reactivation cycles, is well known for its modulating effects on immunity. For e.g., VZV-specific T-cells, but also T-cells against other HHV, from CMV-seropositive individuals are more mature, further differentiated and thus possibly less responsive compared to the VZV-specific T-cells from CMVseronegative individuals.…”