Immune surveillance in murine gammaherpesvirus infection

描述(申请人提供)：持续病毒感染的复发对艾滋病患者和其他严重免疫抑制的人造成了严重的健康问题。疱疹病毒家族尤其如此，其中几个成员在大多数人口中以潜伏形式存在。这两种人类伽马疱疹病毒，爱泼斯坦-巴尔病毒和人类疱疹病毒-8都会导致免疫抑制者的恶性肿瘤，包括非霍奇金淋巴瘤、中枢神经系统淋巴瘤、卡波西肉瘤和原发渗出性淋巴瘤。然而，在健康患者中，T细胞反应非常有效地控制了潜在的伽马疱疹病毒感染。目前还不完全了解，为了使伽马疱疹病毒突破并导致疾病，T细胞反应中需要缺少哪些成分。目前也不清楚是否可以开发出能够恢复免疫监视和预防病毒相关疾病的免疫疗法。在这一应用中，我们研究了小鼠伽马疱疹病毒(MHV-68)感染，这是一种公认的、有价值的伽马疱疹病毒发病机制和免疫学的小动物模型。虽然正常小鼠控制着MHV-68的潜伏感染，但在缺乏CD4T细胞的小鼠中会发生自发的病毒重新激活。因此，在没有CD4T细胞的情况下，病毒的重新激活提供了一种类似于艾滋病患者中反复发生的伽马疱疹病毒相关疾病的模型，艾滋病患者也缺乏CD4T细胞。我们和其他实验室的研究表明，在没有CD4T细胞的情况下，MHV-68特异性CD8T细胞仍然存在，表面上有功能，但仍然无法抑制病毒复制。在这项应用的初步数据中，我们描述了一种对抗病毒T细胞反应产生负面影响的因素，从而允许病毒重新激活。在特定的目标1中，我们确定了造成这种效果的机制，以及它的阻断如何部分恢复对病毒重新激活的控制。我们的初步数据还描述了一种免疫疗法，它可以增强CD8 T细胞反应以克服这种负面影响，非常有效地恢复病毒控制，这种疗法的作用机制在特定目标2中阐明。鉴于本提案中描述的两种免疫治疗方法的成功，特定目标3测试了这两种疗法是否可以通过联合治疗性疫苗或两种疗法的联合应用而得到改善。这一特定目的还描述了一种新开发的用于伽马疱疹病毒相关肿瘤发展的模型的使用，并在该模型中测试这些免疫疗法的有效性。总之，迫切需要新的治疗方法来恢复对免疫受抑患者的伽马疱疹病毒感染的控制。目前的治疗选择非常有限，而那些可用的治疗方法，如过继免疫疗法，都非常昂贵，而且很难在专家中心外进行。与我们描述的疗法类似的疗法很有可能对人类有效，我们的研究提供了关于它们的作用方法的基本信息。 公共卫生相关性：伽马疱疹病毒感染大多数人类人口，但受到免疫反应的很好控制。在患有艾滋病或其他免疫抑制疾病的患者中，这些病毒可能会重新出现，并导致严重的医疗问题，包括淋巴瘤。这项应用研究的是免疫疗法，可以防止小鼠伽马疱疹病毒模型中的病毒复发。

DESCRIPTION (provided by applicant): Recurrence of persistent virus infections causes major health problems for AIDS patients and others who are severely immunosuppressed. This is particularly true for the herpesvirus family, several members of which are present in a latent form in the majority of the population. The two human gammaherpesviruses, the Epstein- Barr virus and Human Herpesvirus-8 both cause malignancies in the immunosuppressed, including non- Hodgkin's lymphoma, central nervous system lymphomas, Kaposi's sarcoma and primary effusion lymphomas. However in healthy patients, the T cell response controls latent gammaherpesvirus infection very efficiently. Currently it is not fully understood what components of the T cell response need to be lacking in order for gammaherpesviruses to break through and cause disease. Nor is it known whether immune therapies can be developed which can restore immune surveillance and prevent virus-associated disease. In this application we study murine gammaherpesvirus (MHV-68) infection, an accepted and valuable small animal model for gammaherpesvirus pathogenesis and immunology. While normal mice control latent infection with MHV-68, spontaneous virus reactivation occurs in mice that are deficient in CD4 T cells. Virus reactivation in the absence of CD4 T cells therefore provides a model similar to recurrent gammaherpesvirus- associated disease that occurs in AIDS patients, who also lack CD4 T cells. Our research, and that of other labs, has shown that MHV-68-specific CD8 T cells are still present in the absence of CD4 T cells, and are ostensibly functional, but nevertheless unable to contain virus replication. In the preliminary data for this application we describe a factor that exerts a negative influence on the antiviral T cell response, thereby allowing virus reactivation to occur. In Specific Aim 1 we determine the mechanism responsible for this effect, and how its blockade can partly restore control over virus reactivation. Our preliminary data also describe an immunotherapy that can enhance the CD8 T cell response to overcome this negative influence, very efficiently restoring viral control, and the mechanism of action of this therapy is elucidated in Specific Aim 2. Given the success of the two immunotherapeutic approaches described in this proposal, Specific Aim 3 tests whether these two therapies can be improved by combination with a therapeutic vaccine or by co-administration of both therapies. This Specific aim also describes the use of a newly developed model for gammaherpesvirus- associated tumor development, and tests the effectiveness of these immunotherapies in this model. In conclusion, there is a pressing need for novel therapies that can restore control of gammaherpesvirus infection in the immune suppressed. At present there are very limited treatment options, and those that are available, such as adoptive immunotherapy, are very expensive and difficult to perform outside of specialist centers. There is a good likelihood that therapies similar to those we describe will be effective in humans, and our studies provide essential information concerning their method of action. PUBLIC HEALTH RELEVANCE: Gammaherpesviruses infect the majority of the human population but are well controlled by the immune response. In patients with AIDS or other immunosuppressive conditions, these viruses can re-emerge and cause serious medical problems, including lymphomas. This application studies immunotherapies that can prevent virus recurrence in a mouse gammaherpesvirus model.