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

人乳头瘤病毒引起广泛的问题损害，包括相当数量的人类癌症，以及生殖器疣、呼吸道乳头状瘤和顽固性皮肤损害。与癌症相关的HPV类型通常被称为高危类型，约占所有人类癌症的6%，其中宫颈癌是最重要的。宫颈癌是影响年轻女性的最常见癌症，每年导致全球约25万人死亡。高危HPV还会导致口咽癌、肛门癌和癌。目前还没有可以治愈高风险或低风险HPV相关疾病的抗病毒疗法，尽管自2008年以来，英国已经推出了预防一些高风险和一些低风险HPV类型的疫苗。宫颈癌也是通过宫颈筛查来管理的，如果发现癌前病变，就会进行手术切除。接种疫苗或筛查在预防疾病方面都不是完全有效的，而且仍未在全球范围内广泛实施。我们的工作的很大一部分是针对“脆弱的上皮部位”，如子宫颈，在这些部位，高危HPV类型会导致癌前病变和癌症。我们怀疑病毒基因的表达从一开始就可以在这些上皮处被破坏，这种放松管制对癌症风险有重大影响。我们的首要任务是研究特定部位失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的表达和目标细胞，首先是宫颈，然后是身体内其他各种易受攻击的部位。我们还将检查亚临床感染期间与免疫系统成分相关的病毒基因表达，并与活动性感染、消退性病变和从头感染进行比较。我们的联合方法旨在更准确地了解疾病进展的生物学，以支持筛查和潜在治疗的未来发展。

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.