Virus-Host Cell Interactions in AIDS-Associated PML

描述（由申请人提供）：进行性多灶性脑白质病（PML）是潜在免疫抑制疾病（如艾滋病）患者和接受免疫治疗的自身免疫性疾病（如多发性硬化症、克罗恩病、严重斑块性牛皮癣、系统性狼疮红斑病、血液恶性肿瘤和类风湿性关节炎）患者的主要危及生命的并发症。这种疾病是由一种常见的人类多瘤病毒从潜伏期激活到生长裂解期引起的。在我们对PML基本生物学的理解中有几个关键的空白。首先，病毒潜伏的解剖位置尚不清楚，但肾脏、扁桃体、骨髓和大脑都被认为与之有关。其次，控制病毒潜伏期和裂解性生长的机制尚不清楚。第三，病毒向中枢神经系统和中枢神经系统内部传播的机制尚不清楚。我们假设病毒诱导的信号重编程细胞环境以促进复制和传播，并且表观遗传学在控制潜伏期和激活之间的平衡中起作用。这里提出的实验将定义这些信号和参与病毒发病的分子途径。这些机制和途径可能适用于药物干预。

DESCRIPTION (provided by applicant): Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with underlying immunosuppressive disorders (e.g. AIDS) and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following activation from a latent to a lytic phase of growth. There are several critical gaps in our understanding of the basic biology of PML. First, the anatomical site of virus latency is not known but kidney, tonsil, bone marrow, and brain have all been postulated to be involved. Second, the mechanisms that govern latency versus lytic growth of the virus are not well understood. Third, the mechanisms of viral spread to the CNS and within the CNS are not known. We hypothesize that virus induced signals reprogram the cellular environment to promote replication and spread and that epigenetics plays a role in governing the balance between latency and activation. The experiments proposed here will define these signals and the molecular pathways involved in viral pathogenesis. These mechanisms and pathways may be amenable to pharmacological intervention.