Epidermodysplasia verruciformis (EV), an autosomal recessive genodermatosis, is characterized by persistent cutaneous infections of human papilloma viruses (HPVs) of the β-genus (de Jong et al., 2018a, Huang et al., 2018). The early clinical manifestations include thin, tinea versicolor-like lesions and flat warts that develop to protruding tumors. Cutaneous malignancies, particularly squamous cell carcinomas, can develop on these lesions, primarily on sun-exposed areas. EV is considered typical, or classic, when the β-HPV infection in the skin is an isolated clinical feature and there is no evidence of compromised T cell-mediated immunity. In atypical, or nonclassic, forms of EV, the cutaneous lesions are associated with widespread viral, bacterial, or fungal infections and development of hematologic malignancies due to compromised T-cell immunity (Youssefian et al., 2019).

The genetic basis of β-HPV infection in patients with the typical form of EV was initially shown to consist of biallelic mutations in the TMC6 and TMC8 genes, which encode EVER1 and EVER2, respectively (Ramoz et al., 2002, Youssefian et al., 2018). Quite recently, mutations in a third gene, CIB1, which encodes CIB1, with a ubiquitous pattern of expression and pleiotropic functions, have been identified in other patients with typical EV (de Jong et al., 2018b). CIB1, EVER1, and EVER2 form a complex that serves physiologically as a restriction factor in the skin, limiting infections by β-HPVs, which are widespread and asymptomatic in the general population. Thus, the human CIB1-EVER1-EVER2 complex governs innate, keratinocyte-intrinsic immunity to β-HPVs (de Jong et al., 2018b).