Role of gammaHV68 M1 antigen in Vbeta4+ T cell expansion and fibrosis

描述(申请人提供)：疱疹病毒病的发病机制与宿主免疫状态密切相关。小鼠伽马疱疹病毒68(？hv68)为研究免疫活性宿主和免疫缺陷宿主慢性感染伽马疱疹病毒的结局提供了模型。？野生型小鼠感染HV68会在接种部位引起有限的急性感染，然后是各种组织和细胞类型的潜伏播散性感染。虽然野生型小鼠很少表现出任何与病毒相关的病理，但干扰素-γ受体缺陷宿主(干扰素？r-/-)会发展成潜在的致命性全身炎症。这种免疫介导的病理包括多器官纤维化组织损伤和血管炎，与潜伏病毒的慢性重新激活和持续复制有关。有趣的是，在缺乏M1开放阅读框(ORF)编码抗原的？HV68突变体的慢性感染期间，这种疾病的许多特征都缺失--尽管这种突变病毒对急性复制或建立潜伏感染没有损害。M1抗原与一些痘病毒蛇蛋白(尽管缺少关键的催化残基)和分泌的高亲和力趋化因子结合蛋白M3具有序列同源性，已被证明从潜伏期调节？HV68的重新激活。M1发挥这种作用的机制以及免疫系统参与的程度尚不清楚。在潜伏期的整个过程中，除了V24+CD8+T细胞的显著扩张外，？HV68抗病毒反应并没有明显的刺激。我们最近发现，这种反应需要M1抗原的表达。本应用旨在研究hv68M1基因产物诱导V24+T细胞活性的潜在新机制(S)，可能是通过表达干扰素来自我限制潜伏期的重新激活，以及这种T细胞在免疫受损宿主中可能在介导慢性病中所起的作用。目标1：研究M1转录本结构(S)及其对M1基因表达的调控。目的：明确M1诱导V24+T细胞活化的机制及其对T细胞功能的影响。目的3：明确M1和V24+T细胞在调节？HV68重新激活、潜伏期和病毒诱导的全身炎性疾病中的作用。

DESCRIPTION (provided by applicant): Herpesvirus disease pathogenesis is closely linked to host immune status. Murine gammaherpesvirus 68 (?HV68) provides a model for studying the outcome of chronic gammaherpesvirus infection in the immunocompetent versus immunodeficient host. ?HV68 infection of a wild-type mouse results in a limited, acute infection at the site of inoculation, followed by latent, disseminated infection in a variety of tissues and cell types. Although wild-type mice rarely display any virus-related pathology, interferon-gamma receptor- deficient hosts (IFN?R-/-) develop potentially lethal, systemic inflammatory disease. This immune-mediated pathology consists of multi-organ fibrotic tissue damage and vasculitis, associated with chronic reactivation of latent virus and persistent replication. Interestingly, many features of this disease are absent during chronic infection with a ?HV68 mutant lacking the antigen encoded by the M1 open reading frame (ORF) - even though this mutant virus is not impaired for either acute replication or establishment of a latent infection. The M1 antigen, which bears sequence homology to some pox virus serpins (although it lacks critical catalytic residues) and to the ?HV68 secreted high affinity chemokine binding protein M3, has been shown to regulate ?HV68 reactivation from latency. The mechanism by which M1 exerts this effect, and the extent of immune system involvement, is unknown. Throughout the course of latency, the ?HV68 antiviral response is not appreciably stimulated with one notable exception - the significant expansion of V24+ CD8+ T cells. We have recently shown that expression of the M1 antigen is required for this response. This application aims to study the potentially novel mechanism(s) by which the ?HV68 M1 gene product induces V24+ T cell activity, perhaps to self-limit reactivation from latency through expression of IFN-?, and the role such T cells might play in mediating chronic disease in an immunocompromised host. The following 3 aims are proposed: Aim 1: Characterize M1 transcript structure(s) and regulation of M1 gene expression. Aim 2: Define the mechanism of M1-induced V24+ T cell activation and its influence on T cell function. Aim 3: Define the role of M1 and V24+ T cells in regulating ?HV68 reactivation, latency, and virus-induced systemic inflammatory disease.