Papillomavirus Host Interation

描述（由申请方提供）：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）感染仍将在患者人群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+ HPV类型中的4种，仅对疫苗相关类型提供保护，对相关类型的交叉保护最小。HPV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，其中宫颈癌占主导地位，全世界每年有500，000人死亡。因此，激活T细胞介导的免疫的感染后治疗性疫苗将是控制现有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）哪些病毒抗原可以诱导HPV感染的最有效的免疫介导的清除;（ii）哪些病毒表位产生对乳头瘤病毒感染和相关癌症的最有效的保护性和治疗性免疫;（iii）CD 8 + T细胞在控制和清除HPV感染中起什么作用，以及（iv）为什么自然发展的对持续性乳头瘤病毒感染的CMI反应不能清除这些病毒相关的肿瘤和癌症。我们的研究计划的长期目标是回答这些问题。为了更好地了解宿主对乳头瘤病毒（PV）的免疫反应，我们需要有效的天然乳头瘤病毒（PV）感染的临床前模型，随后进展为PV相关的恶性肿瘤。不幸的是，不存在用于免疫学和病毒学研究的PV感染的小型近交啮齿动物模型。在缺乏小鼠和大鼠PV模型系统的情况下，最有效的小型实验室动物模型是对亲皮肤棉尾兔PV（CRPV）和亲粘膜兔口服PV（ROPV）感染易感的家兔。我们最近开发了一种新的HLA-A2.1转基因兔模型，以协助我们对触发CD 8 T细胞介导的免疫的关键HPV和CRPV表位的研究。我们将在该更新申请中追求3个关键目标，如下所示：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)确定触发CD 8 T细胞保护性和治疗性抗肿瘤免疫的HLA-A2.1限制性乳头瘤病毒抗原表位的作用，和3）确定导致乳头瘤病毒肿瘤和癌症的治疗性消退和/或增强的对病毒肿瘤抗原的免疫应答的机制。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针对患者群体中HPV感染的改进治疗性疫苗的设计。 公共卫生相关性：持续性人乳头瘤病毒（HPV）感染可导致宫颈癌，每年全球有多达50万妇女死亡。目前的疫苗将提供保护，但不能治愈这些持续感染的妇女。该研究项目的目标是优化诱导免疫性T细胞免疫反应的方法，以消除现有的HPV感染和相关癌症。

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. PUBLIC HEALTH RELEVANCE: Persistent Human papillomavirus (HPV) infections can lead to cervical cancer and up to 500,000 deaths in women each year world-wide. Current vaccines will provide protection, but not cures for women with these persistent infections. The goal of this research project is to optimize approaches to induce immunotherapeutic T-cell immune responses that can eliminate existing HPV infections and associated cancers.