Understanding the Epithelial Site-Specific Origin of HPV Neoplasia and its Control

人类乳头瘤病毒引起广泛的有问题的病变，包括大量的人类癌症，以及生殖器疣、呼吸道乳头瘤和顽固性皮肤病变。与癌症相关的HPV类型通常被称为“高风险”类型，约占所有人类癌症的6%，其中宫颈癌是最重要的。子宫颈癌是影响年轻妇女的最常见癌症，每年在全世界造成约25万人死亡。高危hpv也会导致口咽癌、肛门癌和阴茎癌。目前还没有抗病毒疗法可以治愈高风险或低风险的HPV相关疾病，尽管自2008年以来，英国已经有疫苗可以预防一些高风险和低风险的HPV类型。宫颈癌也通过子宫颈筛查进行治疗，如果发现“癌前病变”，则通过手术切除。疫苗接种和筛查都不能完全有效地预防疾病，而且仍未在世界范围内广泛实施。我们工作的重要部分是针对“脆弱的上皮部位”，如子宫颈，高危HPV类型导致癌前和癌症。我们怀疑病毒基因表达从一开始就在这些上皮位点被破坏，这种解除管制对癌症风险有重大影响。我们的主要重点是研究位点特异性解除调控的人乳头瘤病毒基因表达如何导致疾病。我们将比较病毒基因表达和靶细胞，主要是在子宫颈，然后是在体内其他易受感染的部位。我们还将研究在亚临床感染期间，与活动性感染、退行性病变和新生感染相比，病毒基因表达与免疫系统成分的关系。我们的联合方法旨在更准确地了解疾病进展的生物学，为筛查和潜在治疗的未来发展奠定基础。

Human papillomaviruses cause a wide range of problematic lesions, including a significant number of human cancers, as well as genital warts, respiratory papillomas, and recalcitrant skin lesions. The cancer-associated HPV types are often referred to as 'high-risk' types and are responsible for about 6% of all human cancers, with cervical cancer being the most significant of these. Cervical cancer is the most common cancer to affect young women, and causes approximately a quarter of a million deaths per year worldwide. High risk HPVs can also cause oropharyngeal, anal and penile cancer. There are currently no antiviral therapies that can cure either high or low-risk HPV-associated disease, although since 2008, vaccines have been available in the UK that protect against some high and some low-risk HPV types. Cervical cancer is also managed with cervical screening, with 'precancerous lesions' being surgically excised if they are detected. Neither vaccination nor screening are totally effective in preventing disease, and are still not widely implemented worldwide. A significant part of our work addresses 'vulnerable epithelial sites' such as the uterine cervix, where high risk HPV types cause pre-cancers and cancers. We suspect that viral gene expression can be disrupted at these epithelial sites from the outset, with this deregulation having a major influence on cancer risk. Our main priority is to examine how site-specific deregulated human papillomaviruses gene expression can lead to disease. We will compare viral gene expression and the target cell primarily at the cervix and then at the various other vulnerable sites within the body. We will also examine viral gene expression in relation to the immune system components during subclinical infection, compared with active infections, regressing lesions and de novo infections. Our combined approach aims to understand more accurately the biology of disease progression, to underpin future developments in screening and potential treatments.