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.
| Dang, Xin; Koralnik, Igor J (2013) Gone over to the dark side: Natalizumab-associated JC virus infection of neurons in cerebellar gray matter. Ann Neurol 74:503-5 |
| Wüthrich, Christian; Cheng, Yi Min; Joseph, Jeffrey T et al. (2009) Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 68:15-25 |
| Dang, Xin; Koralnik, Igor J (2006) A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol 87:2533-7 |
| Koralnik, Igor J (2006) Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 60:162-73 |
| Koralnik, Igor J; Wuthrich, Christian; Dang, Xin et al. (2005) JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 57:576-80 |
