IMMUNITY TO HSV-1 INFECTION IN THE NERVOUS SYSTEM

HSV-1感染可在初始感染部位产生复发性病毒病变，并有能力引起严重疾病。疱疹性基质角膜炎（HSK）是由HSV-1感染引起的一种此类疾病，并且是美国境内人类角膜失明的主要原因。 这种疾病被认为是免疫介导的，一些研究人员已经开始剖析涉及的潜在机制。 虽然这些研究中的许多都集中在免疫机制上，例如细胞因子对疾病进展的存在或不存在，但很少有人确定这些免疫因子对已知潜伏HSV-1的感觉神经元内的病毒基因调控或复制的影响。控制HSV-1潜伏状态的机制仍然难以捉摸。 利用体外神经元模型，在本实验室开发的，允许直接检查的神经元，并用于确定哪些免疫因子有助于HSV-1潜伏感染的神经元的维持或再激活。 免疫调节和HSV-1感染对神经元基因调节的影响也可以使用该系统进行检查。HSK小鼠模型将用于研究体内HSV-1感染。 免疫缺陷小鼠将用于确定在我们的研究中发现的对体外神经元HSV-1潜伏期模型中的维持或再活化具有影响的免疫组分是否参与体内HSV- 1感染的建立、维持或再活化。了解HSV潜伏期和再活化的建立所涉及的事件将可以想象地导致免疫抑制技术的发展，该免疫抑制技术可能潜在地改善破坏性免疫应答或增强针对HSV-1感染的保护性免疫应答。

HSV-1 infections can produce recurrent viral lesions at the site of initial infection and has the ability to cause severe disease. Herpetic stromal keratitis (HSK) is one such disease caused by HSV-1 infection and is the leading cause of corneal blindness in humans within the United States. This disease is thought to be immune-mediated and several investigators have started to dissect the potential mechanisms involved. While many of these investigations have focused on immune mechanisms such as the presence or absence of cytokines on disease progression, very little has been done to determine the effects of these immune factors on viral gene regulation or replication within the sensory neuron which is known to harbor latent HSV-1. The mechanisms that control the latent state of HSV-1 remain elusive. The utilization of an in vitro neuronal model, developed in this laboratory, allows for the direct examination of the neuron and is useful for determining which immune factors contribute to the maintenance or reactivation of HSV-1 latently infected neurons. The effects of immune modulation and HSV-1 infection on the regulation of neuronal genes can also be examined using this system. The HSK mouse model will be used to stud) HSV-1 infection in vivo. Immune deficient mice will be used to determine if immune components, which are discovered in our studies to have an effect on maintenance or reactivation in the in vitro neuronal HSV-1 latency model are involved in the establishment, maintenance or reactivation of HSV- 1 infection in vivo. Understanding the events involved in the establishment of HSV latency and reactivation will conceivably lead to the development of immunotherapeutic techniques which may potentially ameliorate damaging immune responses or enhance the protective immune responses against infection with HSV-1.