How does the human papillomavirus (HPV) E5 protein control skin cell growth and differentiation during a productive life cycle?

背景：HPV感染与包括宫颈癌和头颈部鳞状细胞癌(HNSCC)在内的两性疾病有关。尽管有疫苗可用，但目前的预测表明，HPV相关疾病的发病率在几十年内不会显著下降。为了确定加强疫苗接种策略的新治疗靶点，对HPV的基本生物学有更多的了解是至关重要的。HPV感染与其他病毒显著不同，因为它与受感染角质形成细胞的分化状态有关。病毒粒子针对的是上皮细胞中增殖的基底干细胞，而病毒编码的蛋白质将角质形成细胞的不利环境转变为有利于慢性感染的环境。我们发现HPV E5蛋白是非程序DNA复制和角质形成细胞分化延迟的驱动力，这两者都是在终末分化的角质形成细胞中有效复制HPV所必需的。这项拟议的研究将破译这些观测的分子基础。

Background: HPV infections are associated with diseases that impact both sexes including cervical cancer and head and neck squamous cell carcinoma (HNSCC). Despite the availability of a vaccine, current projections suggest that HPV-associated disease rates will not reduce significantly for several decades. To identify novel therapeutic targets that augment the vaccination strategy, it is vital to gain a greater understanding of the fundamental biology of HPV. HPV infection differs significantly from that of other viruses as it is tied to the differentiation status of the infected keratinocyte. Virions target proliferating basal stem cells in the epithelium, whilst virus-encoded proteins transform the hostile environment of the keratinocyte into one conducive for chronic infection. We identified the HPV E5 protein as a driver of unscheduled DNA replication and a delay in keratinocyte differentiation, both of which are required for efficient HPV replication in terminally differentiated keratinocytes. The proposed research will decipher the molecular basis for these observations.