Granule cell neuron-tropic JC virus variant

描述(申请人提供)：人类多瘤病毒JC(JCV)是进行性多灶性白质脑病(PML)的病原体，发生在免疫抑制的个体中。JCV可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一例HIV感染的PML患者的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局灶性丢失，导致小脑萎缩。这与临床上明显的小脑综合征有关，这与PML不同，因为典型的脱髓鞘病变只发现在大脑半球的白质，而不是在该患者的小脑。为了确定序列变异是否可能与该病毒的新嗜性有关，我们分析了这种颗粒细胞神经元相关JCV分离物(JCV[GCN])的全序列，并在VP1基因的羧基末端发现了一个独特的缺失，编码主要衣壳蛋白。这一缺失在从患者大脑半球白质分离的全长克隆(JCV[HWM])中不存在，该克隆包含典型的PML病变。因此，我们假设该突变有助于JCV进入颗粒细胞神经元。此外，我们有初步证据表明，这种突变并不是该患者独有的，而且存在于其他患者的血液和脑脊液中。具体地说，我们将：1)获得JCV[GCN]的全长感染性克隆；2)在体外表征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和其他HIV+患者尸检样本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.