DNA vaccine effiicacy in Herpes Simplex Virus type 2

描述：(改编自申请者摘要)单纯疱疹病毒2型 单纯疱疹病毒2型感染是最常见的性传播疾病之一。 生殖道急性感染后，病毒变得潜伏和 可以重新激活以导致复发或无症状地脱落。 因此，疫苗可以是预防性的，可以预防或改变 初次感染，或治疗，预防或减少复发疾病 在那些之前感染过HSV-2的人中。到目前为止，这两种疫苗策略都没有 很成功。最近的一种疫苗策略利用了DNA，但这种方法已经 没有经过优化。在本申请中，我们描述了旨在 提高单纯疱疹病毒DNA疫苗的效力。因为对两者的保护 急性和复发的单纯疱疹病毒病似乎是由T细胞介导的，最初的 目的是评估针对儿童的单纯疱疹病毒2型糖蛋白B(GB)DNA疫苗。 内酶体/溶酶体增加MHC II类递呈和CD4+反应 (目标1)。我们还将鉴定针对蛋白酶体的GB DNA疫苗 增加MHC I类递呈和CD8+T细胞反应(目标2)。我们 将验证靶向，评估T细胞反应，并在 我们具有良好特性的HSV-2感染的小动物模型。在目标3中，我们 将结合最好的MHC I类和MHC II类靶向疫苗 评估它们的联合疗效。在目标4中，我们将研究 与免疫归巢受体共表达gB。通过靶向抗原 将细胞呈现给淋巴结，我们假设我们将增加两个 单纯疱疹病毒特异性和先天免疫反应和保护。我们的经验是 小鼠和豚鼠模型以及病毒学、临床和 免疫学终点使这些模型成为检验策略的理想选择 建议。提出的实验将提高我们对 对急性和复发疾病的保护性免疫反应，增加我们的 了解HSV-2和其他病原体的靶向DNA载体，并应 导致改进的DNA疫苗。

DESCRIPTION: (Adapted from Applicant's Abstract) Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted diseases. Following acute infection of the genital tract, the virus becomes latent and can reactivate to cause recurrent disease or be shed asymptomatically. Therefore vaccines can either be prophylactic, preventing or modifying the initial infection, or therapeutic, preventing or minimizing recurrent disease in those previously infected with HSV-2. To date neither vaccine strategy has been successful. One recent vaccine strategy utilizes DNA but this approach has not been optimized. In this application, we describe experiments designed to increase the effectiveness of HSV DNA vaccines. Because protection from both acute and recurrent HSV disease appears to be mediated by T cells, the initial aims are to evaluate HSV-2 glycoprotein B (gB) DNA vaccines targeted to the endosome/lysosome to increase MHC class II presentation and the CD4+ response (Aim 1). We also will characterize gB DNA vaccines targeted to the proteasome to increase MHC Class I presentation and the CD8+ T cell response (Aim 2). We will verify targeting, evaluate T cell responses, and assess these vaccines in our well-characterized small animal models of HSV-2 infection. In Aim 3, we will combine the best MHC class I and MHC class II targeted vaccines and evaluate their combined efficacy. In Aim 4, we will examine the effects of co-expressing gB with immune homing receptors. By targeting the antigen presenting cells to the lymph nodes we hypothesize that we will increase both the HSV-specific and innate immune response and protection. Our experience with the murine and guinea pig models as well as the virologic, clinical and immunologic endpoints make these models ideal for examining the strategies proposed. The experiments proposed will improve our understanding of the protective immune response for acute and recurrent disease, increase our knowledge of targeted DNA vectors for HSV-2 and other pathogens, and should result in improved DNA vaccines.