Immune surveillance in murine gammaherpesvirus infection

描述（由申请人提供）：持续病毒感染的复发会给艾滋病患者和其他严重免疫抑制的人带来严重的健康问题。疱疹病毒家族尤其如此，其中一些成员在大多数人群中以潜伏形式存在。两种人类伽玛疱疹病毒，爱泼斯坦-巴尔病毒和人类疱疹病毒-8都能在免疫抑制中引起恶性肿瘤，包括非霍奇金淋巴瘤、中枢神经系统淋巴瘤、卡波西肉瘤和原发性积液淋巴瘤。然而，在健康患者中，T细胞反应非常有效地控制潜伏的伽玛疱疹病毒感染。目前还不完全清楚需要缺少T细胞反应的哪些成分才能使γ疱疹病毒突破并引起疾病。也不知道是否可以开发免疫疗法来恢复免疫监视和预防病毒相关疾病。在这个应用程序中，我们研究了小鼠γ疱疹病毒（MHV-68）感染，这是一个公认的和有价值的γ疱疹病毒发病机制和免疫学的小动物模型。虽然正常小鼠可以控制MHV-68的潜伏感染，但在CD4 T细胞缺乏的小鼠中会发生自发的病毒再激活。因此，在缺乏CD4 T细胞的情况下，病毒再激活提供了一种类似于艾滋病患者复发性γ疱疹病毒相关疾病的模型，这些患者也缺乏CD4 T细胞。我们和其他实验室的研究表明，在没有CD4 T细胞的情况下，mhv -68特异性CD8 T细胞仍然存在，并且表面上具有功能，但却无法抑制病毒复制。在该应用的初步数据中，我们描述了一个对抗病毒T细胞反应产生负面影响的因素，从而允许病毒再激活发生。在特异性目标1中，我们确定了这种作用的机制，以及它的阻断如何在一定程度上恢复对病毒再激活的控制。我们的初步数据还描述了一种可以增强CD8 T细胞反应以克服这种负面影响的免疫疗法，非常有效地恢复病毒控制，这种疗法的作用机制在Specific Aim 2中得到阐明。鉴于本提案中描述的两种免疫治疗方法的成功，特异性目标3测试了这两种疗法是否可以通过与治疗性疫苗联合使用或两种疗法共同使用来改善。本文还介绍了一种新开发的伽玛疱疹病毒相关肿瘤发展模型的使用，并在该模型中测试了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免疫抑制的γ疱疹病毒感染的控制。目前有非常有限的治疗选择，而那些可用的治疗，如过继免疫治疗，非常昂贵，而且很难在专科中心之外进行。与我们所描述的类似的治疗方法很有可能对人类有效，我们的研究提供了有关其作用方法的基本信息。

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.