Host cell reprogramming by oncogenic human papillomavirus

据估计，病毒感染在所有癌症中占十分之一以上，每年在全世界造成130多万人死亡。这种病毒诱导的癌症负担的最重要贡献者之一是人乳头瘤病毒（HPV）；这些癌症中几乎有一半是由HPV感染引起的，包括子宫颈癌和生殖器癌，以及口腔和喉咙的口腔癌。虽然HPV与癌症发展之间的因果关系已经确立，但在HPV感染中发生的驱动HPV肿瘤形成的具体变化尚不清楚。了解这些变化非常重要，这样才能开发出治疗HPV感染和癌症的新疗法，以及用于早期疾病检测的诊断工具。人类乳头瘤病毒有数百种不同的类型，但只有极少数被世界卫生组织列为致癌物质。大多数子宫颈癌和口腔癌是由16型人乳头瘤病毒引起的，而18型人乳头瘤病毒是子宫颈癌的第二大常见原因，但在口腔癌中很少发现。这种差异的原因尚不清楚，但我们假设HPV 16型和18型在不同解剖部位不同地操纵宿主细胞，导致观察到的临床结果差异。所有的病毒都通过操纵宿主细胞环境来增强传染性后代的产生。我们已经证明，在自然宿主细胞中建立HPV感染显着改变宿主细胞基因子集的表达。这种HPV驱动的基因表达“重编程”是HPV感染持续存在的基础，HPV感染是癌症发展的重要危险因素。重要的是，在持续HPV感染的自然史早期发生的许多基因表达变化增加了受感染细胞的生长速度和寿命，因此很可能导致疾病进展。本提案中描述的实验旨在回答长期存在的问题，即HPV16和18在口腔或子宫颈的正常感染中如何表现。我们将充分描述hpv诱导的基因表达变化的分子基础，并确定哪些变化对病毒在每个身体部位的持续存在和疾病进展是重要的。利用hpv相关肿瘤的癌细胞系和临床样本，我们将探索在hpv驱动的肿瘤中癌细胞生长和持续是否需要新的病毒特异性变化。这些实验将为临床相关身体部位HPV感染的正常生命周期提供急需的新见解，并确定驱动疾病进展的病毒特异性事件。

Viral infections are estimated to cause over 1 in 10 of all cancers, resulting in over 1.3 million deaths a year, worldwide. One of the most significant contributors to this virally-induced cancer burden are human papillomaviruses (HPV); HPV infections cause almost half of these cancers, including cancers of the uterine cervix and genitals, and oral cancers in the mouth and throat. While the 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. It is important to understand these changes so that new therapies to treat HPV infections and cancers, and diagnostic tools for early disease detection, can be developed. There are hundreds of distinct types of HPV, but only a very small number of these are classified by the World Health Organisation as carcinogenic. HPV type 16 causes the majority of cervical and oral cancers whereas HPV type 18 is the second most common cause of cervical cancer but is rarely found in oral cancers. The reasons for this disparity are unknown but we hypothesise that HPV types 16 and 18 differentially manipulate host cells at different anatomical sites resulting in the observed differences in clinical outcome. All viruses manipulate their host cell environment to enhance production of infectious progeny. We have shown that establishment of HPV infection in the natural host cells significantly alters the expression of a subset of host cell genes. This HPV-driven gene expression 'reprogramming' is fundamental to persistence of HPV infection, a significant risk factor for cancer development. Importantly, many of the gene expression changes that occur early in the natural history of persistent HPV infections increase the growth rate and life span of the infected cells, and therefore are very likely contribute to disease progression. The experiments described in this proposal are designed to answer long-standing questions about how HPV16 and 18 behave in a normal infection of the oral cavity or uterine cervix. We will fully characterise the molecular basis of HPV-induced gene expression changes and determine which of these changes are important for viral persistence and disease progression at each body site. Using cancer cell lines and clinical samples of HPV-associated tumours, we will explore whether novel virus-specific changes are required for cancer cell growth and sustained in HPV-driven tumours. These experiments will provide much needed novel insight into the normal life cycle of HPV infections at clinically relevant body sites and identify virus-specific events that drive disease progression.