IMMUNOBIOLOGY OF GENITAL HSV-2 INFECTION

急性和复发性生殖器疱疹仍然是一个主要的健康问题。 在本申请中，我们提出研究免疫应答， HSV-2多肽的数量。 然后我们将这些反应与 生殖器HSV-2疾病的自然史。 我们还将诱导免疫 在阴道内攻击之前，选择HSV-2蛋白，以检查 疾病自然史的后续变化，以及 在建立延迟后加强选定的响应，以确定 对复发性HSV-2感染的影响。 我们选择了表演 这些评估使用豚鼠模型的生殖器疱疹，因为 豚鼠的阴道内HSV-2接种产生自限性 生殖器疾病和神经组织潜伏感染。 不像其他 小动物模型，豚鼠，然而，也发生自发性， 临床上明显的复发，也可由紫外线暴露引起。 因此，这种在近交和远交动物中的独特模型可以用于 评估免疫干预对病毒学和临床的影响 表现为急性、复发和潜伏HSV-2感染。 我们将 开发表达选择的HSV-2多肽的牛痘重组体， 以诱导对所选HSV-2多肽的免疫应答。 我们 我选择牛痘是因为它有广泛的宿主范围， 在宿主细胞中正确加工的大片段外源DNA。 此外，接种牛痘可以诱导抗体和细胞介导的抗体， 免疫功能，包括细胞毒性T淋巴细胞，对外源基因 产品 我们将评估的多肽被选择，因为 疱疹病毒和其他病毒的初步证据表明， 这些可能是抗体，特别是细胞重要抗原 介导的免疫。 它们包括立即早期HSV-2蛋白、内部 结构蛋白、非结构蛋白和糖蛋白C。的 作为本申请的一部分开发的牛痘重组体也将 用于制备抗体介导的免疫的抗原和靶标，包括 免疫印迹、ELISA和抗体依赖性细胞毒性（ADCC）， 细胞介导的免疫，包括增殖和IL-2以及HSV 特异性MHC非限制性（NK）和MHC限制性（CTL）测定。 的 这项提案的总体目标是扩大我们对免疫的理解， 对所选HSV多肽的反应及其对急性和复发性HSV感染的影响， 生殖器疱疹的危害 这些知识最终将提供新的 解决这一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.