Regulation of Chronic Viral Infections

描述(由申请人提供)：本项目的目标是确定黏附受体PSGL-1(P-选择素糖蛋白-1)调节慢性LCMV感染的机制，并评估以该受体为靶点是否代表了一种治疗慢性病毒感染的临床翻译方法。全球有超过5亿人感染艾滋病毒、丙型肝炎病毒和乙肝病毒，慢性病毒是一个主要的全球健康问题。小鼠慢性LCMV感染模型已被广泛证明与人类慢性感染具有临床相关性。虽然许多抗病毒化合物和生物制品可以抑制病毒复制，但目前的治疗方法与显著的毒性和/或免疫病理学有关。因此，开发治疗这些疾病的新靶点至关重要。 感染。有意义的是，我们的研究表明，连接T细胞上的PSGL-1可能是限制效应器T细胞聚集并导致病毒特异性T细胞功能障碍的关键事件 作为慢性病毒感染基础的反应。我们的数据表明，慢性LCMV病毒(Clone 13/Cl13)不能在PSGL-1基因缺陷的小鼠中建立慢性化，PSGL-1是黏附分子(P、E和L)选择素家族的主要受体。相反，病毒特异性CD8+T细胞的数量急剧增加，病毒特异性T细胞的缺失减少，持续存在的抗病毒T细胞未能发展出以连续丧失效应器功能为特征的耗尽表型。PSGL-1 KO小鼠的病毒特异性T细胞表达的免疫抑制受体水平显著降低，导致慢性感染期间CD8+T细胞功能反应增强。此外，PSGL-1的缺失还支持增强病毒特异性的CD4+T细胞对LCMV Cl13的反应。最值得注意的是，保存T细胞的功能与病毒清除和严重的免疫病理学有关，这突显了PSGL-1在慢性感染期间作为免疫调节器的关键功能。这些数据表明，PSGL-1对T细胞慢性抗病毒反应有广泛的影响，并支持PSGL-1是先前未知的T细胞免疫功能负调节的关键这一假说。根据我们的发现，我们建议研究PSGL-1限制抗病毒免疫的机制，并探索以该受体为靶点的治疗方法，以增强抗病毒效应器T细胞反应。

DESCRIPTION (provided by applicant): The goal of this project is to identify mechanisms by which the adhesion receptor, PSGL-1 (P-selectin glycoprotein-1) regulates the establishment of a chronic LCMV infection and to assess whether targeting this receptor represents a clinically translational approach to treating chronic viral infections. With more than 500 million people infected with HIV, HCV, and HBV worldwide, chronic viruses represent a major global health problem. The murine model of chronic LCMV infection has been widely demonstrated to have clinical relevance to human chronic infections. Although numerous anti-viral compounds and biologicals can inhibit viral replication, current therapies are associated with significant toxiciy and/or immunopathology. It is therefore critically important to develop new targets for treat these infections. Of significance, our studies suggest that ligation PSGL-1 on T cells may be a pivotal event that limits the effector T cell accumulation and leads to dysfunctional virus-specific T cell responses that underlie chronic viral infections. Our data show that the chronic LCMV virus (Clone 13/Cl 13) is unable to establish chronicity in mice that are genetically deficient in PSGL-1, a major receptor for the selectin family of adhesion molecules (P, E, and L). Instead, there are dramatic increases in the numbers of virus-specific CD8+ T cells, deletion of virus-specific T cells is curtailed, and persisting anti-viral T cells fail to develop the exhausted phenotype characterized by sequential loss of effector functions. Virus-specific T cells from PSGL-1 KO mice express greatly reduced levels of immune inhibitory receptors, resulting in enhanced CD8+ T cell functional responses during chronic infection. In addition, the absence of PSGL-1 also supports enhanced virus-specific CD4+ T cell responses to LCMV Cl 13. Most notably, the preservation T cell functionality is associated with viral clearance and severe immunopathology, highlighting a critical function for PSGL-1 as an immune regulator during chronic infection. The data show that there is a broad impact of PSGL-1 on T cell chronic anti-viral responses and support the hypothesis that PSGL-1 is a previously unknown key to negative regulation of T cell immune function. On the basis of our findings we propose to investigate the mechanisms engaged by PSGL-1 to limit anti-viral immunity and explore therapeutic approaches to target this receptor to enhance anti-viral effector T cell responses.