JC Virus Primary Infection, Latency, and Reactivation

描述(申请人提供)：JC病毒(JCV)是一种多瘤病毒，感染86%的普通人群。无症状的原发感染发生在儿童时期，在健康人中病毒处于静止状态。在免疫抑制的情况下，JCV可以重新激活，导致大脑的一种脱髓鞘疾病，称为进行性多灶性白质脑病(PML)。这种疾病没有治愈的方法，这种疾病通常发生在恶性血液病、实体器官和骨髓移植以及艾滋病毒/艾滋病患者中。我们的初步研究已经建立了骨髓作为JCV的储存库，但尚未对JCV的原发感染过程、感染细胞中JCV潜伏的性质以及导致JCV在宿主中转化和重新激活的机制进行研究。此外，艾滋病毒感染是PML发生的最大风险因素，与健康人不同，在20%的艾滋病毒阳性患者的血液中检测到JCV。因此，我们假设a)JCV的原发感染在肾脏和造血器官建立了病毒潜伏期，b)HIV在造血系统中的共存诱导了JCV的趋神经转化，c)JCV的重新激活受到细胞免疫反应的调节。为了验证这些假说，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2.在人源化的小鼠模型中建立JCV感染，并表征在HIV合并感染后影响JCV重新激活的因素3.破译细胞免疫反应对接受异基因造血干细胞移植的个体JCV的影响Tan博士作为独立研究员将在她的导师、哈佛医学院神经病学副教授Igor Koralnik博士的指导下在Beth以色列女执事医学中心发展。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。谭博士致力于神经病毒学和免疫缺陷领域的学术研究。 公共卫生相关性：JC病毒会在免疫功能低下的人中引起进行性多灶性白质脑病(PML)，特别是那些感染了艾滋病毒的人。JC病毒的宿主尚不清楚，但有证据表明是骨髓。我们建议研究JC病毒在HIV阳性和HIV阴性患者骨髓中的激活和转化。这些研究可能有助于找到治疗这种致命疾病的方法。

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.