IMMUNOBIOLOGY OF GENITAL HSV-2 INFECTION IN GUINEA PIGS

急性和复发性生殖器疱疹仍然是一个主要的健康问题。 在本应用程序中，我们建议研究对 HSV-2多肽的数量。然后，我们会将这些响应与 生殖器单纯疱疹病毒2型疾病的自然病史。我们还将诱导免疫力 在阴道内激发前选择HSV-2蛋白以检查 疾病自然病史的后续变化以及对 在确定延迟后提升选定的响应以确定 对HSV-2复发感染的影响。我们选择了表演 这些评估使用了豚鼠生殖器疱疹模型，因为 豚鼠经阴道接种HSV-2后产生的自限性 生殖器疾病和神经组织的潜伏感染。不同于其他 然而，小动物模型，即豚鼠，也会自发发展。 临床上明显的复发，也可以由紫外线照射引起。 因此，近交系和远交系动物的这种独特模式可以用来 评价免疫干预对病毒学和临床的影响 急性、复发性和潜伏性HSV-2感染的表现。我们会 表达HSV-2多肽的重组痘苗疫苗的构建 以诱导对所选HSV-2多肽的免疫应答。我们 选择了牛痘，因为它的宿主范围很广，可以将 在宿主细胞中被正确处理的外来DNA的大片段。 此外，接种牛痘疫苗可以诱导抗体和细胞介导的 外源基因的免疫功能，包括细胞毒性T淋巴细胞 产品。我们将评估的多肽之所以被选择是因为 关于疱疹病毒和其他病毒的初步证据表明 这些可能是抗体，特别是细胞的重要抗原 中介免疫。它们包括即刻早期HSV-2蛋白，内部 结构蛋白、非结构蛋白和糖蛋白C 作为这一应用程序的一部分开发的牛痘重组体也将 用于制造抗原和抗体介导的免疫靶点，包括 免疫印迹、ELISA和抗体依赖的细胞毒性(ADCC)和 包括增殖、IL-2和HSV在内的细胞免疫 特异性MHC非限制性(NK)和MHC限制性(CTL)检测。这个 这项建议的总体目标是扩大我们对免疫的理解 选择的HSV多肽的应答及其对急性和复发的影响 租生殖器疱疹。这一知识最终应该会提供新的 控制这一常见公共卫生问题的方法。

Acute and recurrent genital herpes remains a major health concern. In this application we propose to investigate the immune response to a number of HSV-2 polypeptides. We will then correlate these responses to the natural history of genital HSV-2 disease. We will also induce immunity to selected HSV-2 proteins prior to intravaginal challenge to examine the subsequent alterations in the natural history of the disease and also to boost selected responses after latency has been established to determine the consequences on recurrent HSV-2 infection. We have chosen to perform these evaluations using the guinea pig model of genital herpes because intravaginal HSV-2 inoculation of guinea pigs produces a self-limited genital disease and a latent infection in neural tissues. Unlike other small animal models, guinea pigs, however, also develop spontaneous clinically apparent recurrences that can also be induced by UV exposure. This unique model in inbred and outbred animals can, therefore, be used to evaluate the effects of immune intervention on virological and clinical manifestations of acute, recurrent and latent HSV-2 infections. We will develop vaccinia recombinants expressing selected HSV-2 polypeptides in order to induce immune responses to the selected HSV-2 polypeptides. We have chosen vaccinia because it has a wide host range and can incorporate large fragments of foreign DNA which are correctly processed in host cells. Further, inoculation with vaccinia can induce antibody and cell mediated immune functions, including cytotoxic T lymphocytes, to the foreign gene product. The polypeptides we will evaluate were selected because preliminary evidence with herpes viruses as well as other viruses suggests that these may be important antigens for antibody and especially cell mediated immunity. They include immediate early HSV-2 proteins, internal structural proteins, nonstructural proteins and glycoprotein C. The vaccinia recombinants developed as part of this application will also be used to make antigen and targets for antibody mediated immunity including immunoblot, ELISA and antibody dependent cellular cytotoxicity (ADCC) and cell mediated immunity including proliferation, and IL-2 as well as HSV specific MHC unrestricted (NK) and MHC restricted (CTL) assays. The overall goal of this proposal is to expand our understanding of the immune response to selected HSV polypeptides and their effects on acute and recur- rent genital herpes. This knowledge should ultimately provide new approaches to the control of this common public health problem.