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）：人多瘤病毒 JC (JCV) 是进行性多灶性白质脑病 (PML) 的病原体，该病发生在免疫抑制个体中。 JCV 引起少突胶质细胞的溶解性感染和星形胶质细胞的限制性感染。我们最近首次描述了感染 HIV 的 PML 患者中 JCV 对小脑颗粒细胞神经元的有效感染。这种神经元感染导致颗粒细胞神经元局部丧失，导致小脑萎缩。这与临床上明显的小脑综合征有关，该综合征与 PML 不同，因为经典脱髓鞘病变仅在大脑半球白质中发现，但在该患者的小脑中没有发现。为了确定序列变异是否可能导致该病毒的新趋向性，我们分析了该颗粒细胞神经元相关 JCV 分离株 (JCV[GCN]) 的完整序列，并发现了该病毒的羧基末端的独特缺失。 VP1基因，编码主要衣壳蛋白。从该患者的大脑半球白质 (JCV[HWM]) 分离的全长克隆中不存在这种缺失，该患者含有典型的 PML 病变。因此，我们假设这种突变有助于促进 JCV 进入颗粒细胞神经元。此外，我们有初步证据表明这种突变并非该患者独有，也存在于其他患者的血液和脑脊液中。具体来说，我们将： 1) 获得全长感染性克隆 2) 体外表征 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中发现 JCV[GCN] 型突变以及其他 HIV+ 个体尸检样本中的颗粒细胞神经元。

项目成果

A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene.

颗粒细胞神经元相关 JC 病毒变种的 VP1 基因有一个独特的缺失。

• 发表时间: 2006-09
• 作者: Dang, Xin;Koralnik, Igor J
• 通讯作者: Koralnik, Igor J