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

背景：HPV感染与影响两性的疾病有关，包括宫颈癌和头颈部鳞状细胞癌（HNSCC）。尽管有疫苗，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降低。为了确定新的治疗靶点以增强疫苗接种策略，对HPV的基本生物学有更深入的了解是至关重要的。HPV感染明显不同于其他病毒，因为它与感染角化细胞的分化状态有关。病毒粒子以上皮中增殖的基底干细胞为目标，而病毒编码的蛋白质将角质形成细胞的敌对环境转化为有利于慢性感染的环境。我们发现HPV E5蛋白是非预定DNA复制和角化细胞分化延迟的驱动因素，这两者都是在终末分化的角化细胞中有效的HPV复制所必需的。拟议的研究将破译这些观察的分子基础。

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.