Development of a Primate Model for Genital Papillomavirus Infection

描述(申请人提供)：生殖器乳头瘤病毒感染是美国和全世界女性中最常见的性传播感染(STI)。除了导致生殖器尖锐湿疣，持续的宫颈感染致癌的阿尔法乳头瘤病毒可能导致宫颈癌。基本上，所有宫颈发育不良和癌症病例都是由特定类型的人类乳头瘤病毒(HPV)引起的。性传播生殖器乳头瘤病毒需要一个复杂的细胞环境，这种环境在组织培养或啮齿动物模型中不易复制，限制了对HPV宫颈感染的分子事件、导致持续感染的危险因素以及新的预防和治疗方式的开发和测试的研究。我们最近利用雌性食蟹猴确定了一种新的宫颈阴道乳头瘤病毒感染的灵长类动物模型。研究表明，这些动物可能会发展成与PV相关的发育不良和肿瘤性宫颈病变，与女性相似。我们已经确定了与高危致癌HPV类型在亲缘关系上密切相关的特定猕猴PV(MPV)类型，并表明一种常见的持续性MPV类型RhPV-d可能通过实验传播。通过鉴定受体动物体内的病毒DNA和RNA证明了这一点。最近，我们开发了一种检测RhPV-d的血清学方法，并显示了实验性感染时的血清转换。虽然HPV16型和18型预防性疫苗已被证明可以预防HPV感染和由这些特定类型的HPV引起的宫颈癌；但是，高昂的成本、已经感染的妇女缺乏活动、有限的病毒覆盖率和必要的冷链限制了这些疫苗的使用，特别是在发展中国家，因为宫颈癌仍然是一个紧迫的公共卫生问题。这项研究的目标是开发猕猴模型，以便在科学/医学界的光伏研究中广泛使用。为了在R21发展研究基金的背景下实现这一点，我们有以下具体目标：(1)使用两种不同的实验方法产生可再生的RhPV-d感染种群；(2)优化雌性猕猴中乳头瘤病毒感染的实验方法。该模型应有助于了解生殖器乳头瘤病毒的发病机制、宿主免疫反应以及制定减少生殖器PV感染和PV相关肿瘤的策略。公共卫生相关性：生殖器人类乳头瘤病毒(HPV)感染是最常见的性传播感染。生殖器HPV感染可导致生殖器疣和生殖器癌(例如，宫颈癌)。我们建议开发一种新的生殖器乳头瘤病毒感染的猕猴模型，以便于研究生殖器乳头瘤病毒感染的自然历史，并测试新的治疗方法和疫苗，以减少人类因这种感染而遭受的痛苦和死亡。

DESCRIPTION (provided by applicant): Genital papillomavirus infections are the most common sexually transmitted infections (STIs) among women in the United States and throughout the world. In addition to causing genital warts, persistent cervical infection with oncogenic alpha papillomaviruses can result in cervix cancer. Essentially all cases of cervix dysplasia and cancer are caused by specific types of human papillomavirus (HPV). Sexually transmitted genital papillomavirus requires a complex cellular environment which is not easily replicated in tissue culture or rodent models, limiting the study of the molecular events of HPV cervical infection, risk factors that lead to persistent infection and development and testing of novel prophylactic and therapeutic modalities. We have recently identified a novel primate model for cervicovaginal papillomavirus infection using female cynomolgus macaques. Studies indicate that these animals can develop PV-associated dysplastic and neoplastic cervical lesions similar to those found in women. We have identified specific macaque PV (MPV) types that are closely related phylogenetically to high-risk oncogenic HPV types and showed that a common persistent type of MPV called RhPV-d may be transmitted experimentally. This was demonstrated by identifying viral DNA and RNA in recipient animals. Recently, we have developed a serologic assay for RhPV-d and show seroconversion with experimental infection. Although prophylactic vaccines of HPV types 16 and 18 have been shown to prevent HPV infection and cervical cancer resulting from these specific types of HPV; however, high cost, lack of activity in already infected women, limited viral coverage, and requisite cold-chain have limited the use of these vaccines, particularly in developing nations where cervical cancer remains an urgent public health problem. The goal of this study is to develop the macaque model for widespread use in PV research for the scientific/medical community. To accomplish this within the context of an R21 Developmental Research Grant, we have the following specific aims: (1) To generate a renewable infectious stock of RhPV-d using two different experimental approaches; (2) to optimize experimental methods of papillomavirus infection in female macaques. This model should facilitate the understanding of genital papillomavirus pathogenesis, host immune response and development of strategies to reduce genital PV infection and PV-associated neoplasia. PUBLIC HEALTH RELEVANCE: Genital human papillomavirus (HPV) infections are the most common Sexually Transmitted Infections. Genital HPV infections can cause genital warts and genital cancers (e.g, cervical cancer). We propose to develop a novel macaque model of genital papillomavirus infection to allow studies on the natural history of genital papillomavirus infection and for testing new therapies and vaccines to reduce suffering and death in the human population from this infection.