Regulation of Chronic Viral Infections

描述（由申请人提供）：该项目的目标是确定粘附受体PSGL-1 （p -选择素糖蛋白-1）调节慢性LCMV感染的机制，并评估靶向该受体是否代表治疗慢性病毒感染的临床转化方法。全世界有超过5亿人感染艾滋病毒、丙型肝炎病毒和乙型肝炎病毒，慢性病毒是一个重大的全球卫生问题。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。尽管许多抗病毒化合物和生物制剂可以抑制病毒复制，但目前还没有治愈这些感染的方法，目前的治疗方法与显著的毒性和/或免疫病理有关。因此，开发治疗这些感染的新靶点至关重要。重要的是，我们的研究表明，T细胞上功能活跃的PSGL-1的结联可能是调节导致慢性病毒感染基础上功能失调的T细胞反应的多个下游方面的关键事件。我们的数据显示，慢性LCMV病毒（克隆13/ cl13）无法在PSGL-1基因缺陷的小鼠中建立慢性，PSGL-1是粘附分子选择素家族（P、E和L）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细胞的删除被减少，并且

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