Immune surveillance in murine gammaherpesvirus infection

持续性病毒感染的复发会给艾滋病患者和其他艾滋病患者带来严重的健康问题。 严重的免疫抑制对于疱疹病毒家族尤其如此，其中几个成员是 在大多数人群中以潜伏形式存在。两种人类伽玛疱疹病毒，爱泼斯坦病毒- 巴尔病毒和人类疱疹病毒-8都能引起免疫抑制者的恶性肿瘤，包括非免疫抑制者。 霍奇金淋巴瘤、中枢神经系统淋巴瘤、卡波西肉瘤和原发性渗出性淋巴瘤。 然而，在健康患者中，T细胞应答非常有效地控制潜伏性γ疱疹病毒感染。 目前，还不完全清楚T细胞应答的哪些组分需要缺乏，以便 伽马疱疹病毒突破并导致疾病。也不知道免疫疗法是否可以 开发了一种可以恢复免疫监视和预防病毒相关疾病的疫苗。 在这项应用中，我们研究了小鼠γ疱疹病毒（MHV-68）感染，一个公认的和有价值的 用于γ疱疹病毒发病机制和免疫学的小动物模型。而正常小鼠控制潜伏期 感染MHV-68后，在缺乏CD 4 T细胞的小鼠中发生自发的病毒再活化。病毒 因此，在缺乏CD 4 T细胞的情况下的再活化提供了类似于复发性γ疱疹病毒的模型- 在艾滋病患者中发生的相关疾病，也缺乏CD 4 T细胞。我们的研究，以及其他 实验室的研究表明，MHV-68特异性CD 8 T细胞在没有CD 4 T细胞的情况下仍然存在， 表面上是有功能的，但却不能抑制病毒复制。在初步数据中， 在本申请中，我们描述了对抗病毒T细胞应答产生负面影响的因子，从而 使病毒重新激活。在具体目标1中，我们确定了导致这种效应的机制， 以及它的阻断如何部分恢复对病毒再激活的控制。我们的初步数据也描述了一个 免疫疗法可以增强CD 8 T细胞应答，非常有效地克服这种负面影响 恢复病毒控制，该疗法的作用机制在具体目标2中阐明。鉴于 本提案中描述的两种免疫方法的成功，具体目标3测试是否 这两种疗法可通过与治疗性疫苗组合或通过两者的共同施用而得到改善 治疗该具体目标还描述了使用新开发的γ疱疹病毒模型- 相关的肿瘤发展，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，可以恢复控制， γ疱疹病毒感染后免疫功能受到抑制。目前，治疗选择非常有限， 而那些可用的方法，如过继免疫疗法，非常昂贵且难以实施， 在专科中心之外。有一个很好的可能性，类似于我们所描述的治疗将是 对人类有效，我们的研究提供了有关其作用方法的重要信息。

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.