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，但这些感染没有治愈方法，目前的治疗方法与显著的毒性和/或免疫病理学有关。因此，开发治疗这些感染的新目标至关重要。有意义的是，我们的研究表明，功能活跃的PSGL-1与T细胞的连接可能是一个关键事件，它调节了导致功能障碍的T细胞反应的多个下游方面，而T细胞反应是慢性病毒感染的基础。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细胞的删除被削减，以及 持续的抗病毒T细胞不能发展出耗尽的表型，其特征是效应器功能的连续丧失。PSGL-1KO小鼠的病毒特异性T细胞表达的抑制性受体水平大大降低，这有助于在慢性感染期间抑制CD8+T细胞的反应。此外，PSGL-1的缺失支持增强病毒特异性的CD4+T细胞对LCMV Cl13的应答。最值得注意的是，T细胞功能的维持与病毒的清除有关。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。基于我们的发现，我们建议研究PSGL-1限制抗病毒免疫的机制，并探索靶向该受体以增强抗病毒效应器T细胞反应的治疗方法

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, there is no cure for these infections and current therapes are associated with significant toxicity and/or immunopathology. It is therefore critically important to develop new targets for treatment of these infections. Of significance, our studies suggest that ligation of functionally active PSGL-1 on T cells may be a pivotal event that regulates multiple downstream aspects that lead to dysfunctional T cell responses which 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 the inhibitory receptors, which contribute to dampening of the CD8+ T cell response during chronic infection. In addition, the absence of PSGL-1 supports enhanced virus-specific CD4+ T cell responses to LCMV Cl 13. Most notably, the maintenance of T cell functionality is associated with viral clearance. 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