Regulation of Chronic Viral Infections

描述（由申请方提供）：本项目的目的是确定粘附受体PSGL-1（P-选择素糖蛋白-1）调节慢性LCMV感染建立的机制，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HIV、HCV和HBV，慢性病毒是一个主要的全球健康问题。慢性LCMV感染的鼠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，但目前的治疗与显著的毒性和/或免疫病理学相关。因此，开发治疗这些疾病的新靶点至关重要 感染.重要的是，我们的研究表明，T细胞上的PSGL-1连接可能是限制效应T细胞积聚并导致功能失调的病毒特异性T细胞的关键事件。 慢性病毒感染的基础反应。我们的数据表明，慢性LCMV病毒（克隆13/C113）不能在PSGL-1基因缺陷的小鼠中建立慢性，PSGL-1是粘附分子（P、E和L）选择素家族的主要受体。相反，病毒特异性CD 8 + T细胞的数量急剧增加，病毒特异性T细胞的缺失减少，并且持续的抗病毒T细胞不能发展出以效应子功能的顺序丧失为特征的衰竭表型。来自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大大降低，导致慢性感染期间CD 8 + T细胞功能应答增强。此外，PSGL-1的不存在也支持增强的对LCMV C113的病毒特异性CD 4 + T细胞应答。最值得注意的是，保存T细胞功能与病毒清除和严重的免疫病理学有关，突出了PSGL-1在慢性感染期间作为免疫调节剂的关键功能。数据显示，PSGL-1对T细胞慢性抗病毒应答具有广泛的影响，并支持PSGL-1是T细胞免疫功能负调节的先前未知关键的假设。基于我们的研究结果，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T细胞应答的治疗方法。

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, 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.