Roles of Nucleotide Metabolic Control in KSHV Persistence

卡波西肉瘤相关疱疹病毒（KSHV）属于淋巴性γ疱疹病毒科。在免疫功能低下的患者中，如器官移植受者和艾滋病患者，KSHV感染总是与卡波西肉瘤（一种皮肤血管生成肿瘤）相关。此外，KSHV是两种罕见淋巴增生性疾病的病因，原发性积液性淋巴瘤和多中心Castleman病。潜在的致癌性和相对普遍的感染对全世界的健康构成了严重威胁。了解基本病毒学和宿主免疫反应是KSHV感染的两个方面，将为治疗KSHV相关恶性肿瘤开辟新的途径。

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the lymphotropic gamma herpesviridae. In immunocompromised patients, such as organ transplant recipients and AIDS patients, KSHV infection is invariantly associated with Kaposi's sarcoma, a skin angiogenic neoplasm. Additionally, KSHV is the etiological agent for two rare lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease. The oncogenic potential and relatively ubiquitous infection imposes an eminent health threat worldwide. Understanding fundamental virology and host immune response are two sides of the same coins of KSHV infection and will pave new avenues to treat KSHV-associated malignancies. Innate immunity is the first line of defense against invading pathogens. Recent advances have outlined the framework of signal transduction in mounting host innate immune response. However, the specific functions of key innate immune components, e.g., the IKK-related kinase IKKe, remain contentious. We have recently discovered that the IKKs kinase restricts gamma herpesvirus lytic replication and enables latent/persistent infection. This study proposes to investigate the molecular mechanisms by which the IKKE kinase negates KSHV lytic replication, thereby enabling persistent infection! We will characterize virus-host interactions involving the IKKe kinase (Aim 1), define the regulatory action of IKKs on KSHV lytic replication (Aim 2), and finally assess the roles of IKKe and viral interactions thereof in KSHV persistent infection using a "humanized" mouse model. This proposal entails a powerful reverse genetic system to perturb virus-host interactions and investigate the roles of these interactions in KSHV lytic replication and persistent infection. The application of lytic replicating system and an animal model will identify key interactions and define mutual regulations of in vivo KSHV infection, instructing us on new ways to contain KSHV infection.