Papillomavirus Host Interaction

描述（由申请方提供）：已证明乳头瘤病毒（PV）可导致宫颈癌、外阴癌、阴茎癌、口腔粘膜癌和皮肤癌的发病。对这些病毒感染的免疫力在疾病结果中起着重要作用，但用于预防感染和破坏体内活动性病变的免疫力的精确病毒靶点的特征很差。我们的长期目标是确定哪些病毒抗原和免疫效应细胞参与了对PV感染的成功免疫应答。本申请的目的是检测人乳头瘤病毒11型（HPV-11）、HPV-16、棉尾兔乳头瘤病毒（CRPV）和兔口腔乳头瘤病毒（ROPV）感染三个阶段的免疫力。第一阶段以抗体介导的病毒中和为代表，其靶向位于乳头瘤病毒蛋白的主要外壳蛋白（L1）的高变区中的表面构象型特异性表位和次要外壳蛋白（L2）上的线性表位。第二阶段是对感染上皮细胞中存在的加工和MHC相关早期病毒蛋白的（肽）表位的细胞介导的免疫。免疫的第三阶段将评估导致乳头状瘤自发消退的宿主细胞介导的反应。我们最近的研究清楚地表明，在这些不同的阶段中的每一个阶段都有不同的病毒靶蛋白和免疫效应物。待检验的中心假设是对PV蛋白的免疫可导致疾病的保护和消退。这项研究背后的基本原理是，对病毒免疫的研究将为HPV感染的保护性疫苗和免疫干预措施的设计提供必要的信息。为了实现本申请的目标，我们将追求两个具体目标：（1）定义参与对感染性病毒体的保护性免疫的乳头瘤病毒病毒体上的构象和线性中和表位的组分的性质，（2）确定天然和诱导的宿主细胞-使用具有遗传修饰的E6基因的CRPV基因组介导对CRPV的免疫，其遵循自然消退或持续存在的预测结果。在这项研究完成时，我们希望能够绘制出HPV-11、-16、CRPV和ROPV病毒体（L1和L2）上的关键氨基酸残基，这些残基可以被一组中和单克隆抗体（N-Mab）识别。此外，我们计划利用大量基因改变的CRPV基因组（E6基因中改变的氨基酸残基）来剖析导致CRPV诱导的感染消退和持续的宿主免疫应答。 在乳头瘤病毒感染的细胞中，确定乳头瘤病毒病毒粒子和早期病毒蛋白上的主要保护性病毒表位E6将是规划这种传染病的有效免疫管理的关键。

DESCRIPTION (provided by applicant): Papillomaviruses (PVs) have been shown to contribute to the pathogenesis of cancer of the cervix, vulva, penis, oral mucosal sites and skin. Immunity to these viral infections plays a significant role in disease outcome, but the precise viral targets of immunity for prevention of infection and destruction of active lesions in vivo are poorly characterized. Our long-range goal is to determine which viral antigens and immune effector cells are involved in a successful immune response to PV infection. The objective of this application is to examine immunity during three stages of human papillomavirus type 11 (HPV-11), HPV-16, cottontail rabbit papillomavirus (CRPV) and rabbit oral papillomavirus (ROPV) infection. The first stage is represented by antibody-mediated virus neutralization which targets surface conformational, type-specific epitopes located in the hypervariable regions of the major coat protein (L1) of papillomavirus proteins, and linear epitopes on the minor coat protein (L2). The second stage is cell-mediated immunity to (peptide) epitopes of processed and MHC-associated early viral proteins present in infected epithelial cells. The third stage of immunity will assess host cell-mediated responses that lead to spontaneous regression of papillomas. Our recent studies demonstrate clearly that there are different viral target proteins and immune effectors at each of these different stages. The central hypothesis to be tested is that immunity to PV proteins can lead to protection and resolution of the disease. The rationale behind the research is that studies on viral immunity will provide essential information for the design of protective vaccines and immunotherapeutic interventions for HPV infections. To accomplish the objectives of this application, we will pursue two Specific Aims: (1) define the nature of the components of conformational and linear neutralizing epitopes on papillomavirus virions involved in protective immunity to infectious virions, (2) determine the natural and induced host cell-mediated immunity to CRPV using CRPV genomes with genetically modified E6 genes that follow predicted outcomes of either natural regression or persistence. At the completion of this research, we expect to have mapped critical amino acid residues on HPV-11, -16, CRPV and ROPV virions (both L1 and L2) that are recognized by a panel of neutralizing monoclonal antibodies (N-Mabs). In addition, we plan to utilize a large number of genetically altered CRPV genomes (altered amino acid residues in the E6 gene) to dissect the host immune response leading to regression and persistence of CRPV-induced infections. Defining the major protective viral epitopes on papillomavirus virions and on the early viral protein, E6 in papillomavirusinfected cells will be key to planning effective immunotherapeutic management of this infectious disease.