Whole transcriptome–based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections

Abstract

Human papillomaviruses (HPVs), are DNA viruses, including ~450 types, classified into five genera (α-, β-, γ-, µ-, and 𝜈-HPV). The γand β-HPVs are present in low-copy numbers in healthy individuals, however, in patients with an inborn error of immunity, certain species of β-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either "typical" or "atypical". Manifestations in typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to β-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, on RNA extracted from normal-appearing skin and wart samples of patients with typical EV, to explore the viral and human genetic determinants. In 26 patients, nine distinct biallelic mutations in TMC6 (5), TMC8 (1), and CIB1 (3), seven being previously unreported, were detected. Additionally, 20 different HPV species, including three α-, 16 β-, and one γ-HPVs, were detected, eight of which are being reported for the first time in EV patients (β-HPV-37, -47, -80, -151, -159, α-HPV-2, -57, and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.

Rubella virus chronic inflammatory disease and other unusual viral phenotypes in inborn errors of immunity

“…About 35%–50% of patients by middle age will have Bowen's‐type carcinoma or invasive squamous cell carcinoma 161 . The HPV can be diverse but beta‐HPVs 5 and 8 are the most commonly isolated 162 . Gamma‐HPV are much less frequently seen in lesions.…”

“…161 The HPV can be diverse but beta-HPVs 5 and 8 are the most commonly isolated. 162 Gamma-HPV are much less frequently seen in lesions. When EV occurs related to medical immunosuppression, the age of appearance relates to the age when the immunosuppression occurred.…”

Viral infections and inborn errors of immunity

“…This rare condition presents in childhood with diffuse and intractable warts that may progress to basal and squamous cell carcinoma [5]. EV results from a biallelic mutation in either TMC6, TMC8, or CIB1, the genes encoding the respective proteins forming the EVER1–EVER2–CIB1 complex in keratinocytes [19,20 ▪ ]. Mutations impact local immunity to beta-HPV infections, a genera of HPV that does not typically cause disease in immunocompetent individuals [20 ▪ ].…”

“…Saeidian et al recently described a novel diagnostic technique that can simultaneously detect host and viral genetic material from full-thickness skin biopsies through whole-transcriptome sequencing [20 ▪ ,21]. This technique has proved especially helpful in detecting uncommonly reported genera of HPV in patients with EV.…”

HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses

“…The virome is unaffected by antibiotics, yet similar to the bacterial microbiome, expansion, and diversification are observed with impaired immunity. Relative to healthy individuals, subtle shifts in immune function such as in epidermodysplasia verruciformis (EV) or dedicator of cytokinesis 8 (DOCK8) deficiency, directly alter the virome leading to increased diversity and expanded representation of skin tropic b and g human papillomavirus (HPV) types, which in turn increase the risk of skin cancer (12)(13)(14)(15). Similarly, alterations in virome have been observed among solid organ transplant recipients on immunosuppression, who exhibit a 60-250-fold increased risk of skin cancer (16)(17)(18)(19)(20)(21)(22).…”