ANALYSIS OF PAPILLOMAVIRUS

乳头瘤病毒（PV）感染动物和人的上皮，其中它们通常在感染部位诱导良性增殖。然而，人类生殖器病变的恶性进展与某些HPV类型（最常见的是HPV 16）之间存在很强的相关性。我们已经产生了HPV 16和其他PV的病毒样颗粒（VLP），这些颗粒由L1主要衣壳蛋白或L1加L2次要衣壳蛋白组成。在动物模型中，经纯化的VLP的胃肠外注射诱导高滴度的中和抗体和对实验攻击的保护。基于这些结果，我们已经验证了GMP级VLP，并于最近完成了HPV 16 VLP疫苗的1期临床试验。疫苗接种者，即使是在没有佐剂的情况下接种的疫苗，也会产生高滴度的HPV 16假病毒中和抗体，并且仅报告轻微的副作用。目前正在进行第二阶段试验，我们也在开发替代疫苗。为了增加基于VLP的疫苗的治疗潜力，我们将非结构HPV蛋白作为L2融合蛋白掺入VLP中。用HPV 16 E7嵌合VLP接种产生了CD 8限制性T细胞应答，其保护小鼠免受使用表达E7的肿瘤系的肿瘤攻击，并且还诱导了已建立的肿瘤的消退。为了增加粘膜抗体应答，我们已经测试了在小鼠中鼻内滴注纯化的VLP。与VLP的肠胃外接种相反，该方案引起女性生殖道中的分泌型伊加和漏出型IgG。中和抗体在鼻内接种疫苗的小鼠的整个发情周期中检测到，但不是在那些接种parenterals.To打破B细胞的耐受性和诱导抗体反应的自身蛋白质，我们取代了一个免疫优势表位的VLP与自我多肽。具体来说，我们设计了一种L1蛋白，它在颗粒表面展示了小鼠CCR 5的第一个外环。用这些颗粒接种的小鼠诱导了高滴度的抗体，这些抗体结合细胞表面CCR 5并阻断培养细胞的HIV感染。用展示猕猴/人CCR 5肽的类似颗粒接种的猕猴也产生抗CCR 5 IgG。这些发现表明了诱导自身抗体的一般方法，具有许多基本和应用的再研究应用。 - 癌症预防，免疫反应，乳头瘤病毒，疫苗设计，病毒-细胞相互作用，艾滋病，抗体，自身抗体，癌症疫苗，CCR 5，宫颈癌，宫颈发育不良，HIV，HPV，人类逆转录病毒疫苗，-人体受试者&人体组织，液体，细胞等。

Papillomaviruses (PVs) infect the epithelia of animals and man where they generally induce benign proliferation at the site of infection. However, there is a strong association between malignant progression of human genital lesions and certain HPV types, most frequently HPV 16. We have generated virus-like particles (VLPs) for HPV 16 and other PVs that consist of the L1 major capsid protein or L1 plus L2, the minor capsid protein. Parenteral injection of purifed VLPs induced high titers of neutralizing antibodies and protection from experimental challenge in animal models. Based upon these results, we have validated GMP grade VLPs and have recently completed a phase 1 clinical trial of an HPV16 VLP vaccine. Vaccinees, even those vaccinated in the absence of adjuvant, produced high titers of HPV16 psuedovirion neutralizing antibodies and reported only minor side effects. A phase 2 trial is currently in progress.We are also developing alternative vaccine candidates. To increase the therapeutic potential of a VLP-based vaccine, we have incorporated non-structural HPV proteins into the VLPs as L2 fusion proteins. Vaccination with an HPV16 E7 chimeric VLP generated a CD8 restricted T cell response that protected mice from tumor challenge using an E7 expressing tumor line and also induced regression of established tumors. To increase mucosal antibody responses, we have tested intranasal instillation of purified VLPs in mice. In contrast to parenteral inoculation of VLPs, this protocol elicited both secretory IgA and transudated IgG in the female genital tract. Neutralizing antibodies were detected throughout the estus cycle in intranasally vaccinated mice, but not in those vaccinated parenterally.To break B-cell tolerance and induce antibody responses to a self-protein, we replaced an immunodominant epitope of a VLP with a self polypeptide. Specifically, we engineered a L1 protein that displayed the first external loop of mouse CCR5 on the surface of particles. Mice vaccinated with these particles induced high titers of antibodies that bound cell surface CCR5 and blocked HIV infection of culutred cells. Macaques vaccinated with similar particles displaying macaque/human CCR5 peptide also produced anti-CCR5 IgG. These findings suggest a general method for inducing auto-antibodies, with many basic and applied reasearch applications. - Cancer Prevention, immune response, Papillomaviruses, vaccine design, Virus-Cell Interactions, AIDS, Antibody, autoantibodies, Cancer vaccines, CCR5, cervical cancer, cervical dysplasia, HIV, HPV, vaccine against human retroviruses, - Human Subjects & Human Tissues, Fluids, Cells, etc.