University of New Mexico Interdisciplinary HPV Prevention Center

描述(申请人提供)：每年报告超过600万例性传播人乳头瘤病毒(HPV)感染的新病例，使HPV成为全球最常见的性传播病原体。然而，至少有15种致癌HPV类型会导致几乎所有的宫颈癌；2006年获得许可的昂贵的HPV疫苗仅覆盖HPV6/11/16/18型，对已确定的感染没有治疗作用。因此，所有妇女必须继续进行常规的宫颈筛查，美国每年的费用为40-50亿美元。更重要的是，今天在世的大多数女性仍有患宫颈癌的风险。此外，目前的疫苗计划使所有男性都得不到保护。鉴于这些考虑，以及宫颈癌是一种差异疾病的事实，目前的战略不太可能实现预期的疾病减少。目前美国HPV疫苗的实施和有效性仍需要一些项目，继续努力更好地了解HPV生物学并为现有感染制定广泛的保护性预防策略和治疗方法仍然至关重要。这项申请的具体目标是：1)建立新墨西哥大学跨学科HPV预防中心，该中心采用研究方法来解决这些知识差距。2)资助和支持代表一系列跨学科方法的4个项目，包括：a)在3个维度对光伏-宿主相互作用进行建模，以确定有助于感染发病机制和预防的上皮细胞生物学和免疫要素；b)利用基于病毒显示技术的新型疫苗策略，产生针对大多数HPV感染的广泛保护；c)利用独特的生物信息学系统，该系统捕获美国基于人口的宫颈筛查计划的所有事件，以表征主要和次要HPV干预措施的实施情况和有效性；以及d)开发一套基于网络的工具，以促进知情地采用HPV和其他性传播感染预防措施。3)建立2个共享资源的核心，以支持这些跨学科研究方法：A)生物统计学和生物信息学核心，B)病毒感染核心，支持病毒生产、定量和动物成像技术，并容纳生物标本资源。 项目1：上皮组织中的生殖器乳头瘤病毒感染(OZBUN，M.) 项目1描述(申请人提供)：超过100种类型的人乳头瘤病毒(HPV)感染粘膜和皮肤上皮，导致良性肿瘤和恶性肿瘤。每年约有620万新增人乳头瘤病毒性传播感染(STI)病例；美国目前有2000万人感染，HPV被认为是全球最常见的性传播感染。总体而言，数据表明，单一的性行为可以促进感染，这表明病毒在体内是相当有效的传播剂。最近，我们已经能够在实验室中生产出高滴度的HPV疫苗。我们在细胞培养研究中使用传染性HPV病毒粒子的研究以及我们同事对动物PV的研究表明，这些病毒在体外引起感染的能力一般较差。因此，我们推测，目前的单层细胞培养PV感染模型系统不能准确地概括体内的感染过程。事实上，生殖器HPV相关感染研究的主要缺陷包括缺乏高滴度的感染性病毒库存，以及缺乏适当的组织模型系统来研究早期感染、发病机制和干预措施。我们的中心假设是，单层细胞培养不能显示上皮组织HPV感染的基本特征，HPV感染建立的重要特征可以从三维(3-D)组织模型中确定。我们将使用高滴度HPV病毒库来实现这一计划的目标，即建立更具生理学意义的HPV生殖器感染的三维组织模型，并回答有关启动生产性HPV感染的基本和基本问题。为了解决我们的中心假设，我们将追求具体的目标，包括关于性传播PV感染的三个生物集成的、日益复杂的系统。在目标1中，我们将定义体外分化上皮细胞对HPV感染的要求。在目标2中，我们将使用啮齿动物生殖器感染模型来识别对HPV感染敏感的细胞类型，并进一步确定创伤如何加强体内感染。在目标3中，我们将在我们的非人类STI HPV感染模型的背景下评估生殖器PV感染的建立，在该模型中，可以评估灵长类动物的解剖和免疫反应。关于生殖器PV结合和感染的特定方面的假设被提出，以便无论支持或驳斥，我们都将增加我们对HPV-靶细胞相互作用的分子机制和上皮组织感染的生物学的理解，这些领域的研究很少。我们预计这项工作将直接影响未来广泛交叉保护的预防和治疗策略的发展，以防止持续性HPV STI。

DESCRIPTION (provided by applicant): Over 6 million new cases of sexually transmitted human papillomavirus (HPVs) infections are reported every year making HPV the most common sexually transmitted agent world-wide. At least 15 carcinogenic HPV types cause virtually all cervical cancers however; the costly HPV vaccine licensed in 2006 covers only HPV types 6/11/16/18 and has no therapeutic effect on established infections. Thus all women must continue routine cervical screening at a US cost of $4-5 billion annually. More importantly, the majority of women alive today are still at risk for developing cervical cancer. In addition, the current vaccine program presently leaves all men unprotected. Given these considerations and the fact that cervical cancer is a disease of disparities, it is unlikely that projected disease reductions will be realized with current strategies. Programs to characterize current US HPV vaccine implementation and effectiveness are needed and continuing efforts to better understand HPV biology and to develop broadly protective prevention strategies and therapeutics for existing infections remain critical. The specific aims of this application are: 1) To establish the University of New Mexico Interdisciplinary HPV Prevention Center that incorporates research approaches to address these gaps in knowledge. 2) To fund and support 4 projects representing a spectrum of interdisciplinary approaches including: A) modeling of PV-host interactions in 3 dimensions to define elements of epithelial cell biology and immunity that contribute to the pathogenesis and prevention of infections; B) utilizing novel vaccine strategies based on virus-display technology to generate broad protection against a majority of HPV infections; C) utilizing a unique bioinformatics system that captures all events of a US population-based cervical screening program to characterize implementation and effectiveness of primary and secondary HPV interventions; and D) developing a set of web-based tools to promote the informed adoption of HPV and other STI prevention. 3) To establish 2 cores housing shared resources to support these interdisciplinary research approaches: A) a biostatistics and bioinformatics core and B) a virus infection core supporting technologies for virus production, quantitation, and animal imaging and housing a biospecimen resource. PROJECT 1: GENITAL PAPILLOMAVIRUS INFECTIONS IN EPITHELIAL TISSUES (OZBUN, M.) PROJECT 1 DESCRIPTION (provided by applicant): Over 100 types of human papillomaviruses (HPVs) infect mucosal and cutaneous epithelium, causing benign and malignant tumors. About 6.2 million new cases of HPV sexually transmitted infections (STIs) are reported every year; >20 million people in the US are currently infected, and HPV is considered as the most common known STI worldwide. Overall, data suggest that a single sexual act can promote infection, indicating that the viruses are quite effective transmissible agents in vivo. Recently, we have been able to produce high-titer HPV stocks in the laboratory. Our studies using infectious HPV virions in cell culture studies and our colleagues' work with animal PVs indicate the viruses in general are poor at causing infections in vitro. We therefore postulate that the current monolayer cell culture PV infection model systems fail to accurately recapitulate the infectious process in vivo. Indeed, the major deficiencies in the study of genital HPV-related infections have included the lack of high titer infectious viral stocks and the lack of appropriate tissue-based model systems with which to study early infections, pathogenesis, and interventions. Our CENTRAL HYPOTHESIS is that monolayer cell cultures fail to display essential aspects of epithelial tissue HPV infections and important features of HPV infection establishment can be determined from 3-dimensional (3-D) tissue-based models. We will use high titer HPV virion stocks to pursue this program's goals, which are to establish more physiologically relevant 3-D tissue models of HPV genital infections and to answer basic and essential questions about the initiation of productive HPV infections. To address our central hypothesis, we will pursue SPECIFIC AIMS that encompass three biologically integrated, and increasingly complex systems with regard to sexually transmitted PV infections. In Aim 1 we will define requirements for HPV infection of cells in differentiated epithelium in vitro. In Aim 2 we will use a rodent genital infection model to identify the cell types that are susceptible to HPV infection and to further determine how wounding potentiates infection in vivo. In Aim 3 we will evaluate genital PV infection establishment in the context of our non-human model of STI HPV infections wherein primate anatomy and immune response can be assessed. Hypotheses regarding specific aspects of genital PV binding and infection are posed so that whether supported or refuted, we will increase our understanding of the molecular mechanisms of HPV-target cell interactions and the biology of epithelial tissue infection, areas vastly understudied. We expect this work will directly impact future development of broadly cross-protective prophylactic and therapeutic strategies for preventing persistent HPV STIs.