Abstract：
Epidermodysplasia verruciformis (EV) is a rare genetic skin disorder that is characterized by the development of papillomavirus-induced skin lesions that can progress to squamous cell carcinoma (SCC). Certain high-risk, cutaneous β-genus human papillomaviruses (β-HPVs), in particular HPV5 and HPV8, are associated with inducing EV in individuals who have a homozygous mutation in one of three genes tied to this disease: EVER1, EVER2, or CIB1. EVER1 and EVER2 are also known as TMC6 and TMC8, respectively. Little is known about the biochemical activities of EVER gene products or their roles in facilitating EV in conjunction with β-HPV infection. To investigate the potential effect of EVER genes on papillomavirus infection, we pursued in vivo infection studies by infecting Ever2-null mice with mouse papillomavirus (MmuPV1). MmuPV1 shares characteristics with β-HPVs including similar genome organization, shared molecular activities of their early, E6 and E7, oncoproteins, the lack of a viral E5 gene, and the capacity to cause skin lesions that can progress to SCC. MmuPV1 infections were conducted both in the presence and absence of UVB irradiation, which is known to increase the risk of MmuPV1-induced pathogenesis. Infection with MmuPV1 induced skin lesions in both wild-type and Ever2-null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between Ever2-null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in Ever2-null mice compared with wild-type mice. These studies demonstrate that Ever2-null mice infected with MmuPV1 do not exhibit the same phenotype as human EV patients infected with β-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent β-genus human papillomavirus (β-HPV) skin infections, which can progress to skin cancer. To investigate how EVER2 confers protection from papillomaviruses, we infected the skin of homozygous Ever2-null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected Ever2-null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these Ever2-null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in Ever2-null mice, indicating that mouse EVER2 does not confer protection from papillomaviruses. These findings suggest that there are functional differences between MmuPV1 and β-HPVs and/or between mouse and human EVER2.
摘要：
疣状表皮发育不良（EV）是一种罕见的遗传性皮肤病，其特征是乳头状瘤病毒诱导的皮肤病变的发展，可发展为鳞状细胞癌（SCC）。某些高风险，皮肤β属人乳头瘤病毒（β-HPV），特别是HPV5和HPV8与在与该疾病相关的三个基因之一的纯合突变个体中诱导EV相关:EVER1,EVER2或CIB1.EVER1和EVER2也分别称为TMC6和TMC8。关于EVER基因产物的生化活性或它们在促进EV与β-HPV感染中的作用知之甚少。探讨EVER基因对乳头瘤病毒感染的潜在影响,我们通过用小鼠乳头瘤病毒(MmuPV1)感染Ever2-null小鼠进行体内感染研究.MmuPV1与β-HPV具有相似的基因组组织，他们早期的共享分子活动，E6和E7，癌蛋白，缺乏病毒E5基因，以及引起皮肤损伤并进展为SCC的能力。MmuPV1感染在有和没有UVB照射的情况下进行，已知这会增加MmuPV1诱导的发病机制的风险。用MmuPV1感染在有和没有UVB的野生型和Ever2-null小鼠中均诱导皮肤损伤。两种基因型的许多病变进展为恶性肿瘤，Ever2-null小鼠和野生型小鼠之间的疾病严重程度没有差异。然而,有些令人惊讶的是，病变生长和病毒转录减少，与野生型小鼠相比，Ever2-null小鼠的病变消退增加。这些研究表明,感染MmuPV1的Ever2无效小鼠不表现出与感染β-HPV的人EV患者相同的表型。具有EVER2基因纯合突变的人类发展为疣状表皮发育不良（EV），一种以持续β-人乳头瘤病毒（β-HPV）皮肤感染倾向为特征的疾病，会发展成皮肤癌.为了研究EVER2如何赋予对乳头瘤病毒的保护，我们用小鼠乳头瘤病毒MmuPV1感染纯合Ever2-null小鼠的皮肤。就像有EV的人类一样，受感染的Ever2-null小鼠出现皮肤损伤，可能进展为癌症。与EV的人类不同，与野生型小鼠相比，这些Ever2-null小鼠的病变生长更慢，消退更频繁。野生型小鼠的MmuPV1转录高于Ever2-null小鼠，表明小鼠EVER2不能提供对乳头瘤病毒的保护。这些发现表明MmuPV1和β-HPV之间和/或小鼠和人EVER2之间存在功能差异。
