McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Department of Pathology and Laboratory Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
J Virol. 2024 Jul 23;98(7):e0017424. doi: 10.1128/jvi.00174-24. Epub 2024 Jun 13.
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: , , or and are also known as and respectively. Little is known about the biochemical activities of gene products or their roles in facilitating EV in conjunction with β-HPV infection. To investigate the potential effect of genes on papillomavirus infection, we pursued infection studies by infecting -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 -null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between -null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in -null mice compared with wild-type mice. These studies demonstrate that -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 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 -null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected -null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these -null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in -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.
疣状表皮发育不良（EV）是一种罕见的遗传性皮肤疾病，其特征是存在由人乳头瘤病毒（HPV）诱导的皮肤病变，这些病变可能进展为鳞状细胞癌（SCC）。某些高危、皮肤β属人乳头瘤病毒（β-HPV），特别是 HPV5 和 HPV8，与诱导 EV 有关，而 EV 则发生在携带与该疾病相关的三个基因之一的纯合突变的个体中： 、 或 。已知的 基因产物的生化活性及其在与 β-HPV 感染协同促进 EV 方面的作用知之甚少。为了研究 基因对乳头瘤病毒感染的潜在影响，我们通过感染 -null 小鼠的小鼠乳头瘤病毒（MmuPV1）进行了 感染研究。MmuPV1 与 β-HPV 具有相似的特征，包括相似的基因组结构、早期、E6 和 E7、致癌蛋白的共同分子活性、缺乏病毒 E5 基因以及导致可进展为 SCC 的皮肤病变的能力。在存在和不存在 UVB 照射的情况下进行了 MmuPV1 感染，已知 UVB 照射会增加 MmuPV1 诱导发病的风险。MmuPV1 感染野生型和 -null 小鼠均诱导皮肤损伤，无论是否存在 UVB。两种基因型的许多病变均进展为恶性病变，-null 和野生型小鼠之间的疾病严重程度没有差异。然而，有些出人意料的是，与野生型小鼠相比，-null 小鼠中的病变生长和病毒转录减少，病变消退增加。这些研究表明，感染 MmuPV1 的 -null 小鼠并未表现出与感染 β-HPV 的人类 EV 患者相同的表型。
重要性：携带 基因纯合突变的人类会患上疣状表皮发育不良（EV），这种疾病的特征是易患持续性β属人乳头瘤病毒（β-HPV）皮肤感染，可进展为皮肤癌。为了研究 EVER2 如何赋予对乳头瘤病毒的保护作用，我们用小鼠乳头瘤病毒 MmuPV1 感染了纯合 -null 小鼠的皮肤。与 EV 患者一样，感染的 -null 小鼠也会出现皮肤损伤，这些损伤可能会发展为癌症。与 EV 患者不同的是，这些 -null 小鼠的病变生长速度较慢，消退频率较高，与野生型小鼠相比。野生型小鼠中的 MmuPV1 转录水平高于 -null 小鼠，表明小鼠 EVER2 并不能赋予对乳头瘤病毒的保护作用。这些发现表明，MmuPV1 和 β-HPV 之间以及小鼠和人类 EVER2 之间存在功能差异。
