Granule cell neuron-tropic JC virus variant

颗粒细胞嗜神经元JC病毒变种

• 批准号: 7001270
• 负责人: Igor J Koralnik
• 金额: $ 19.19万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001270
• 关键词: DNA replication; HIV infections; Polyomavirus hominis 2; atrophy; capsid; cerebellar disorders; cerebellum; clinical research; comorbidity; gene expression; gene mutation; granule cell; human tissue; laser capture microdissection; molecular cloning; mutant; neurotropic virus; postmortem; progressive multifocal leukoencephalopathy; tissue /cell culture; tissue resource /registry; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): The human polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML), which occurs in immunosuppressed individuals. JCV causes a lytic infection of oligodendrocytes, and a restrictive infection of astrocytes. We have recently described for the first time a productive infection of cerebellar granule cell neurons by JCV in an HIV- Infected patient with PML. This neuronal infection resulted in focal loss of granule cell neurons leading to cerebellar atrophy. This was associated with a clinically apparent cerebellar syndrome which was distinct from PML since classical demyelinating lesions were found only in the hemispheric white matter of the cerebrum, but not of the cerebellum of this patient. To determine if sequence variations could be responsible for the novel tropism of this virus, we have analyzed the complete sequence of this granule cell neuron-associated JCV isolate (JCV[GCN]), and have found a unique deletion in the carboxy terminus of the VP1 gene, coding for the major capsid protein. This deletion was not present in the full length clone isolated from the cerebral hemispheric white matter of this patient (JCV[HWM]), which contained classical PML lesions. We therefore hypothesize that this mutation was instrumental in facilitating entry of JCV into granule cell neurons. Moreover, we have preliminary evidence that this mutation is not unique to this patient, and is present in the blood and CSF of other patients. Specifically we will: 1) Obtain a full length infectious clone of 2) Characterize the host cell range of JCV[GCN] in vitro -, 3) Determine whether a JCV[GCN]-type mutation can be found in other organs of this patient and in granule cell neurons in autopsy samples from other HIV+ individuals.

描述（由申请人提供）：人类多瘤病毒JC（JCV）是进行性多焦点白细胞术（PML）的病因，它发生在免疫抑制的个体中。 JCV引起少突胶质细胞的裂解感染，并引起星形胶质细胞的限制性感染。我们最近首次通过JCV在患有PML的HIV感染患者中首次描述了小脑颗粒细胞神经元的生产性感染。这种神经元感染导致颗粒细胞神经元的局灶性丧失导致小脑萎缩。这与临床明显的小脑综合征有关，该综合征与PML不同，因为仅在大脑的半球白质中发现了经典的脱髓鞘病变，但没有该患者的小脑。为了确定序列变化是否可能导致该病毒的新型向潮流，我们分析了该颗粒细胞神经元相关的JCV分离株（JCV [GCN]）的完整序列，并在VP1基因的Carboxy Terminus中发现了独特的缺失，用于编码主要的Capsid蛋白质。这种缺失不存在于该患者的脑半球白质（JCV [HWM]）中分离出的全长克隆，其中包含经典的PML病变。因此，我们假设该突变有助于促进JCV进入颗粒细胞神经元。此外，我们有初步证据表明该突变不是该患者独有的，并且存在于其他患者的血液和CSF中。具体而言，我们将：1）获得全长感染性克隆2）2）在体外的JCV [GCN]的宿主细胞范围 - ，3）确定是否可以在该患者的其他器官和其他HIV+个体中的尸体性细胞神经元中的其他器官中找到JCV [GCN]型突变。