Granule cell neuron-tropic JC virus variant

描述（由申请方提供）：人多瘤病毒JC（JCV）是发生于免疫抑制个体的进行性多灶性白质脑病（PML）的病原体。JCV引起少突胶质细胞的裂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在一个HIV感染的PML患者中JCV对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，从而导致小脑萎缩。这与临床上明显的小脑综合征相关，该综合征与PML不同，因为仅在该患者的大脑半球白色物质中发现了典型的脱髓鞘病变，而在小脑中未发现。为了确定序列变异是否可能是该病毒新嗜性的原因，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，并发现编码主要衣壳蛋白的VP1基因的羧基末端存在独特缺失。从该患者（JCV[HWM]）大脑半球白色物质分离的全长克隆中不存在这种缺失，该克隆含有典型的PML病变。因此，我们推测，这种突变是有助于促进进入颗粒细胞神经元的JCV。此外，我们有初步证据表明，这种突变不是该患者独有的，也存在于其他患者的血液和CSF中。具体而言，我们将：1）获得以下的全长感染性克隆：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以及在来自其他HIV+个体的尸检样品中的颗粒细胞神经元中发现JCV[GCN]型突变。

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.