Papillomavirus Host Interation

描述（由申请人提供）：尽管最近开发了保护性病毒样颗粒（VLP）疫苗，但人乳头瘤病毒（HPV）感染将继续在患者群体中普遍存在和频繁发生。目前，该疫苗针对与上皮恶性肿瘤相关的15种以上HPV类型中的4种，并且仅对疫苗相关类型提供保护，对相关类型的交叉保护最小。人乳头状瘤病毒相关的恶性肿瘤包括宫颈癌、肛门生殖器粘膜癌、口腔粘膜癌和皮肤癌，全世界每年有50万人死于宫颈癌。因此，激活t细胞介导免疫的感染后治疗性疫苗将成为控制现有hpv相关疾病的关键辅助方法。然而，关于HPV感染的免疫清除机制的关键问题仍然没有答案。例如，我们还不知道：(i)哪种病毒抗原可以诱导最有效的免疫介导的HPV感染清除；（ii）哪种病毒表位对乳头瘤病毒感染和相关癌症产生最有效的保护性和治疗性免疫；（iii） CD8+ t细胞在控制和清除HPV感染中的作用，以及（iv）为什么对持续乳头瘤病毒感染自然产生的CMI反应不能清除这些病毒相关的肿瘤和癌症。我们研究项目的长期目标就是要回答这些问题。为了更好地了解宿主对乳头瘤病毒（PV）的免疫反应，我们需要有效的自然乳头瘤病毒（PV）感染的临床前模型，并随后发展为PV相关的恶性肿瘤。不幸的是，没有小型近亲繁殖的啮齿动物模型存在PV感染的免疫学和病毒学研究。在没有小鼠和大鼠PV模型系统的情况下，最有效的小实验动物模型是家兔，家兔易被嗜皮性棉尾兔PV （CRPV）和嗜黏膜性家兔口服PV （ROPV）感染。我们最近开发了一种新的HLA-A2.1转基因兔模型，以协助我们研究触发CD8 t细胞介导免疫的关键HPV和CRPV表位。我们将追求以下3个关键目标：1)在兔乳头瘤病毒肿瘤模型中评估cmi诱导的对乳头瘤病毒肿瘤抗原的治疗性和保护性免疫的作用。2)确定HLA-A2.1限制性乳头瘤病毒抗原表位在触发CD8 t细胞保护性和治疗性抗肿瘤免疫中的作用；3)确定对病毒肿瘤抗原的免疫应答机制，从而导致治疗性解决和/或增强乳头瘤病毒肿瘤和癌症。在这些实验结束后，我们期望目标1、2和3中提出的工作组合将直接转化为设计针对患者人群的HPV感染的改进治疗性疫苗。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infections will continue to be ubiquitous and frequent in patient populations despite the recent development of protective virus-like particle (VLP) vaccines. Currently, the vaccine targets 4 of the 15+ HPV types that are associated with epithelial malignancies, and provides protection only to the vaccine-related types with minimal cross-protection to related types. HPV-associated malignancies include cancers of the cervix, anogenital mucosa, oral mucosa and skin, with cervical cancer predominating at 500,000 deaths per year world-wide. Post-infection therapeutic vaccines that activate T-cell-mediated immunity therefore will be a key adjunct method to control existing HPV-associated disease. However, critical questions regarding the mechanism of immunological clearance of HPV infections remain unanswered. For example, we do not yet know: (i) which viral antigens can induce the most effective immune-mediated clearance of HPV infections; (ii) which viral epitopes produce the most potent protective and therapeutic immunity to papillomavirus infections and associated cancer; (iii) what role CD8+ T-cells play in control and clearance of HPV infections, and (iv) why naturally developing CMI responses to persistent papillomavirus infections fail to clear these viral-associated tumors and cancers. The long range goal of our research program is directed at answering these questions. To better understand host immune responses to papillomaviruses (PVs), we need effective preclinical models of natural papillomavirus (PV) infection with subsequent progression to PV-associated malignancies. Unfortunately, no small inbred rodent animal model of PV infections exists for immunological and virological studies. In the absence of mouse and rat PV model systems, the most effective small laboratory animal model is the domestic rabbit which is susceptible to infection by the cutaneous-tropic cottontail rabbit PV (CRPV) and the mucosotropic rabbit oral PV (ROPV). We have recently developed a novel HLA-A2.1 transgenic rabbit model to assist our studies on key HPV and CRPV epitopes that trigger CD8 T-cell-mediated immunity. We will pursue 3 critical aims in this renewal application as follows: 1) Assess the role of therapeutic and protective CMI-induced immunity to papillomaviral tumor antigens in a rabbit papillomavirus tumor model. 2) Determine the role of HLA-A2.1 restricted papillomaviral antigen epitopes that trigger CD8 T-cell protective and therapeutic anti-tumor immunity, and 3) Determine the mechanism of immunological responses to viral tumor antigens that lead to therapeutic resolution and/or enhancement of papillomaviral tumors and cancers. Upon conclusion of these experiments, it is our expectation that the combination of work proposed in aims 1, 2 and 3 will translate directly into the design of improved therapeutic vaccines for HPV infections in patient populations.