Unravelling the immune signature of herpes zoster: Insights into pathophysiology and the HLA risk profile

The varicella-zoster virus (VZV) infects over 95% of the population and establishes latency afterwards. Reactivation of VZV causes herpes zoster (HZ), commonly known as shingles, which presents as a painful rash in mostly the elderly and people with a weakened immune system. However, HZ might occur in otherwise healthy individuals too. In this study, we have analyzed the immune signature of HZ to better understand HZ's pathophysiology. We provide a general overview of the antiviral state and the activation of innate and adaptive immune responses during HZ. An extensive exome-wide association study of HZ, incorporating UK Biobank data across white, black and Asian cohorts highlights the MHC locus as a risk factor for HZ development. Therefore, we conducted one of the largest human leukocyte antigen (HLA) association studies on HZ to date (n=138,701 participants) using Fisher's exact test and identified five protective and four risk HLA alleles associated with the development of HZ. Additionally, differential gene expression and gene ontology analyses revealed upregulation of several genes and host immune pathways during herpes zoster, especially related to type I interferon response but also involved with adaptive immune responses. Intriguingly, no differences in gene expression were noted during convalescence between HZ patients and controls. Our research reveals that HZ susceptibility is largely governed by a complex pattern of variations in the major histocompatibility complex, resulting in modified antigen recognition in HZ patients. Further, we identified key genes and pathways involved in the host immune response to symptomatic VZV reactivation and provided new molecular insights into the development of HZ and its associated risk factors. Overall design: A total cohort of twenty-six herpes zoster patients aged between 18 and 70 years (median age 51 years; 13 men, 13 women) were prospectively recruited during an active HZ episode, as confirmed by a positive VZV PCR on skin swab or saliva or by significantly elevated (> 4 times) VZV IgG serum titers. Age (± 1 birth year) and sex matched controls without a history of HZ were recruited for each HZ patient and donated blood around the one-year timepoint. To optimize the inclusion of controls, PAXgene RNA of three of the controls was collected during sampling via another study with approval by the Institutional Review Board. Six of the controls also donated a PAXgene RNA tube one year earlier around the same time as blood collection from their matched HZ patients during the active HZ episode, which served as an internal quality control for storage and handling.