MmuPV1 infection of Tmc6/Ever1 or Tmc8/Ever2 deficient FVB mice as a model of βHPV in typical epidermodysplasia verruciformis.

Abstract

Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses, and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 (EVER1), TMC8 (EVER2) or CIB1. A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6-/-, Tmc8-/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6-/- and Tmc8-/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6-/- and Tmc8-/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6-/- or Tmc8-/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6-/-, Tmc8-/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies.