Protection of Genital Mucosa and Ganglia Against HSV-2

描述（由申请人提供）：大约五分之一的美国人感染了2型单纯疱疹病毒（HSV-2），生殖器HSV疾病的直接成本大约每年超过2亿美元。除了新生儿中单纯疱疹病毒感染的破坏性影响外，由单纯疱疹病毒引起的生殖器病变是感染艾滋病毒的主要危险因素。对于许多免疫功能低下的患者来说，疾病复发频率的增加和口腔和肛门生殖器HSV病变的无法解决仍然是一个严重的并发症。目前还没有获得许可的预防单纯疱疹病毒疾病的疫苗。最近在临床试验中测试的疫苗引发了高滴度的特异性抗体，但并不能保护所有人群免受HSV-2感染。建议的研究将集中于特定T细胞亚群的保护反应，并检查它们在生殖上皮、感觉神经节和脊髓中作用以解决HSV感染的机制。

DESCRIPTION (provided by applicant): Approximately 1 in 5 Americans are infected with herpes simplex virus type 2 (HSV-2) and the approximate direct cost of genital HSV disease exceeds $200 million annually. In addition to the devastating effects of HSV infections in newborns, genital lesions caused by HSV represent a major risk factor for acquisition of HIV. The increased frequency of recurrent disease and the inability to resolve oral and anogenital HSV lesions remains a serious complication for many immunocompromised patients. There is no licensed vaccine for the prevention of HSV disease. Vaccines recently tested in clinical trial elicited high titers of specific antibody but did not protect all populations against HSV-2 infection. The proposed studies will focus on the protective responses by specific T cell subsets and examine the mechanisms by which they act in the genital epithelium, sensory ganglia, and spinal cord to resolve HSV infections. In Aim 1, we will transfer HSV-immune CD4+ and CD8+ T cell populations to bone marrow chimeric mice to examine the role of epithelial cells, innate immune cells, and IFN-gamma in clearance of HSV from the genital tract. We will determine if the cellular targets for IFN-gamma are hemopoietic or somatic cells and examine the molecular mechanisms of IFN-gamma -mediated protection of this site. HSV-1 is also emerging as an important genital pathogen. In Aim 2, we will identify the T cell subsets responsible for protection against genital HSV-1 infections. We will utilize ELISPOT and Tetramer staining to quantify recall T cell responses and assess their ability to protect the sensory ganglia following heterotypic genital HSV challenge. In Aim 3, we will analyze the protective role of CD4+ T cells in neuronal tissue. We will use cell depletion and adoptive transfer experiments to test the dependence of the HSV-specific recall antibody response and neuronal CD8+ T cell response on CD4+ T cells. Additionally, we will utilize adoptive transfer of immune CD4+ T cells to immunodeficient mice to determine if CD4+ T cells contribute to HSV clearance from neuronal tissue. The results of these studies should be important for the rational development of HSV vaccines as well as understanding the cellular interactions and specific molecular mechanisms required for resolution of HSV lesions.