Reactivated HSV-1 disease in immune compromised hosts

描述：（由申请人提供）疱疹病毒感染是一种非常严重的 人类常见的复发性健康问题，尤其是免疫抑制 个体原发感染消退后，出现潜伏状态 直到死亡。环境刺激，如紫外线，导致周期性 疾病复发。研究人员最近开发了一种强大的 由一种刺激的上皮再活化HSV疾病的鼠模型 最小紫外线暴露。这非常类似于人类的HSV上皮疾病， 允许在相关实验中研究皮肤HSV-1再活化 系统本申请中提出的研究将使用该模型来测试 HSV-1疾病的再活化是由于局部 细胞因子平衡和疾病的解决需要局部皮肤免疫学 变化他们建议研究HSV疾病再激活的免疫病理学 并提出新的治疗方法和疫苗策略。他们假设紫外线 暴露导致角质形成细胞分泌可溶性因子， 最终改变TH 1/TH 2平衡，诱导HSV再活化。缺乏 在CD 4耗竭的动物中， 疾病他们提出，包括IL-12在内的局部免疫因子的调节 和IFN-γ改变了再激活过程， 局部免疫系统的变化影响对HSV-1感染的易感性。研究 将在免疫活性小鼠和CD 4耗竭小鼠中进行， 以与HIV中的人类HSV疾病非常相似的方式重新激活HSV疾病 感染的宿主具体来说，他们将描述免疫反应的特征 局部皮肤水平的HSV-1并定义相互作用的背景 再活化皮肤HSV-1疾病期间的细胞因子和免疫细胞; 确定浸润性T淋巴细胞在原发性和再活化中的作用 在正常与免疫受损模型中的疾病;并确定 基因组疫苗候选物在预防原发性感染和 减少再活化的疾病。

DESCRIPTION: (Provided by the Applicant) Herpes virus infection is a very common recurrent health problem in humans, especially immuno suppressed individuals. After resolution of primary infection, a state of latency develops that persists until death. Environmental stimuli such as UV lead to periodic recrudescence of disease. The investigators have recently developed a powerful murine model of reactivated HSV disease of epithelium that is stimulated by a minimum UV exposure. This very closely mimics HSV epithelium disease in man, permitting study of cutaneous HSV-1 reactivation in a relevant experimental system. The studies proposed in this application will use this model to test the hypothesis that reactivated HSV-1 disease is due to a disruption in local cytokine balance, and disease resolution requires local cutaneous immunologic changes. They propose to study the immunopathology of HSV disease reactivation and suggest new treatments and vaccine strategies. They hypothesize that UV exposure results in secretion of soluble factors by keratinocytes that ultimately alter the TH1/TH2 balance which induces HSV from reactivation. Lack of CD4 responses in CD4 depleted animals then permit severe and prolonged disease. They propose that modulation of local immune factors including IL-12 and IFN-gamma alter the reactivation process and that differences of components of the local immune systems impact susceptibility to HSV-1 infection. Studies will be done in immune competent mice and in mice depleted of CD4 which yields reactivated HSV disease in a manner very similar to human HSV disease in HIV infected hosts. Specifically, they will characterize the immune response to HSV-1 at the local cutaneous level and to define the context of interplay of cytokines and immune cells during reactivated cutaneous HSV-1 disease; determine the role of infiltrating T lymphocytes in primary and reactivated disease in normal versus immune compromised models; and determine efficacy of genomic vaccine candidates in prevention of primary infection and in attenuation of reactivated disease.