Papillomavirus Host Interaction

描述(申请人提供)：乳头瘤病毒(PV)已被证明与宫颈癌、外阴、阴茎、口腔粘膜部位和皮肤癌的发病机制有关。对这些病毒感染的免疫在疾病转归中起着重要作用，但免疫在体内预防感染和破坏活动性病变的确切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感染的成功免疫反应。本应用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。第一阶段是抗体介导的病毒中和阶段，以位于乳头状瘤病毒蛋白主要外壳蛋白(L1)高变区的表面构象、类型特异性表位和次要外壳蛋白(L2)上的线性表位为目标。第二阶段是对感染的上皮细胞中存在的已加工的和MHC相关的早期病毒蛋白的(肽)表位的细胞介导性免疫。免疫的第三阶段将评估宿主细胞介导的导致乳头状瘤自发消退的反应。我们最近的研究清楚地表明，在这些不同的阶段中，都有不同的病毒靶蛋白和免疫效应器。需要检验的中心假设是，对PV蛋白的免疫可以导致疾病的保护和解决。这项研究背后的理论基础是，关于病毒免疫的研究将为设计保护性疫苗和针对HPV感染的免疫治疗干预措施提供重要信息。为了实现这一应用的目标，我们将追求两个特定的目标：(1)确定乳头瘤病毒病毒粒子上构象和线性中和表位的组成成分的性质，参与对感染性病毒粒子的保护性免疫；(2)使用带有转基因E6基因的CRPV基因组来确定对CRPV的自然和诱导宿主细胞介导的免疫，该基因组遵循自然回归或持续的预测结果。在这项研究完成后，我们希望绘制出一组中和单抗(N-MAb)识别的HPV-11、-16、CRPV和ROPV病毒粒子(L1和L2)上的关键氨基酸残基。此外，我们计划利用大量的基因改变的CRPV基因组(E6基因中改变的氨基酸残基)来剖析导致CRPV诱导的感染的消退和持续的宿主免疫反应。 确定乳头瘤病毒病毒粒子和早期病毒蛋白E6上的主要保护性病毒表位将是规划有效的免疫治疗措施的关键。

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.