JC Virus Primary Infection, Latency, and Reactivation

描述（由申请人提供）：JC病毒（JCV）是一种多瘤病毒，感染86%的普通人群。无症状的原发性感染发生在儿童时期，病毒在健康个体中保持静止状态。在免疫抑制的情况下，JCV可以重新激活，导致大脑脱髓鞘疾病，称为进行性多灶性白质脑病（PML）。这种疾病无法治愈，通常发生在血液恶性肿瘤、实体器官和骨髓移植以及艾滋病毒/艾滋病患者身上。我们的初步研究已经确定骨髓是JCV的储存库，但尚未研究原发性感染的过程，感染细胞中JCV潜伏期的性质以及导致JCV在宿主中转化和再激活的机制。此外，艾滋病毒感染是PML发展的最大危险因素，与健康人相比，20%的艾滋病毒阳性患者血液中检测到JCV。因此，我们假设a) JCV的初次感染在肾脏和造血器官中建立病毒潜伏期，b)造血系统中HIV的共同存在诱导JCV向神经变性，以及c)细胞免疫应答调节JCV的再激活。为了验证这些假设，我们建议：1。在组织学样本和细胞培养模型中分析JCV和HIV在造血系统中的相互作用在人源化小鼠模型中建立JCV感染并表征HIV合并感染后影响JCV再激活的因素在她的导师、哈佛医学院神经学副教授Igor Koralnik博士的指导下，Tan博士将在贝斯以色列女执事医疗中心成为一名独立研究者。一个由杰出科学家组成的委员会将监督她走向独立的进程。Tan博士致力于在神经病毒学和免疫缺陷领域从事学术研究。

DESCRIPTION (provided by applicant): JC virus (JCV) is a polyomavirus which infects 86% of the general population. Asymptomatic primary infection occurs in childhood, and the virus remains quiescent in healthy individuals. In the context of immunosuppression, JCV can reactivate, causing a demyelinaing diseae of the brain called progressive multifocal leukoencephalopathy (PML). There is no cure for this disease, which classically occurs in patients with hematologic malignancies, solid organ and bone marrow transplants, and HIV/AIDS. Our preliminary studies have established bone marrow as a reservoir of JCV, but the course of primary infection, the nature of JCV latency in infected cells and the mechanisms that lead to JCV transformation and reactivation in the host have not been investigated. Furthermore, HIV infection is the largest risk factor for development of PML where, in contradistinction to healthy individuals, JCV is detected in the blood of 20% of HIV positive patients. Therefore, we hypothesize that a) primary Infection of JCV establishes viral latency In the kidney and the hematopoietic organs, b) the co-presence of HIV In the hematopoietic system Induces JCV neurotropic transformation, and c) reactivation of JCV is modulated by the cellular immune response. To test these hypotheses, we propose to: 1. Analyze JCV and HIV interactions in the hematopoietic system in histological samples and a cell culture model 2. Establish JCV Infection In the humanized mouse model and characterize factors that influence JCV reactivation after HIV co-infection 3. Decipher the impact of the cellular Immune response on JCV In Individuals undergoing allogeneic hematopoietic stem cell transplantation Dr. Tan's development as an independent investigator will be at the Beth Israel Deaconess Medical Center, guided by her mentor Dr. Igor Koralnik, Associate Professor of Neurology, Harvard Medical School. A committee of distinguished scientists will oversee her progress towards independence. Dr. Tan is committed to pursuing a career as an academic Investigator in the field of Neurovirology and Immunodeficiency. PUBLIC HEALTH RELEVANCE: JC virus causes progressive multifocal leukoencephalopathy (PML) In Immunocompromised Individuals, especially those with HIV Infection. The reservoir of JC virus is not known, but evidence points to the bone marrow. We propose to study JC virus reactivation and transformation in bone marrow of HIV positive and HIV negative patients. These studies may contribute to finding a cure for this deadly disease.