Understanding the role of the chromatin insulator CTCF in human papillomavirus gene expression and disease progression

据估计，病毒感染在所有癌症中占十分之一以上，每年导致全球130多万人死亡。人类乳头瘤病毒（HPV）感染导致几乎一半的癌症，包括宫颈癌，生殖器癌以及口腔和咽喉癌。虽然HPV和癌症发展之间的因果关系已经得到了很好的确立，但HPV感染中发生的驱动HPV肿瘤形成的具体变化还没有得到很好的理解。因此，重要的是要了解这些变化，以便开发治疗HPV感染和癌症的新疗法，以及早期疾病检测的诊断工具。我们的工作表明，宿主细胞蛋白CTCF与HPV基因组结合，并限制导致宿主细胞生长和癌症发展增加的病毒蛋白的产生。因此，我们假设在正常的HPV感染中，CTCF是病毒基因表达的关键调节因子，并使病毒完成感染周期并产生新的病毒。我们预测CTCF对HPV诱导的细胞生长的控制在HPV驱动的癌症中丢失。本提案中描述的实验旨在回答长期存在的问题，即病毒在正常感染中的行为以及这种新型病毒-宿主相互作用如何有助于病毒生产力。使用HPV相关疾病的临床样本，我们还将探索这种病毒-宿主相互作用如何在HPV驱动的癌症中被破坏。

Viral infections are estimated to cause over 1 in 10 of all cancers, resulting in over 1.3 million deaths a year, worldwide. Human papillomavirus (HPV) infections cause almost half of these cancers, including cancer of the uterine cervix, genitals and in the mouth and throat. While this causal link between HPV and the development of cancer is well established, the specific changes that occur in HPV infections that drive the formation of HPV tumours are not well understood. Thus, it is important to understand these changes so that new therapies to treat HPV infections and cancer, and diagnostic tools for early disease detection, can be developed. Our work has shown that a host cell protein, CTCF, binds to the HPV genome and limits production of viral proteins that cause increased host cell growth and cancer development. Therefore, we hypothesize that in normal HPV infections CTCF is a key regulator of viral gene expression and works to allow the virus to complete the infectious cycle and produce new virus. We predict that the control of HPV-induced cell growth by CTCF is lost in HPV-driven cancers. The experiments described in this proposal are designed to answer long-standing questions about how the virus behaves in a normal infection and how this novel virus-host interaction contributes to virus productivity. Using clinical samples of HPV-associated disease, we will also explore how this virus-host interaction is disrupted in HPV-driven cancer.