Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

JCV is a papovavirus which is widespread in the human population. The proto type Mad-1 variant of JCV induces a fatal demyelinating disease of the cent ral nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-l) to the CNS is attributed to the tissue-specific regulation of the viral early promoter which is responsible for the production of the viral regulatory p rotein, T-antigen, The archetype form of this virus, JCV(CY), which has bee n repeatedly isolated from the urine of PML and non-PML individuals, is dis tinct from JCV(Mad-1) in the structural organization of the regulatory sequ ence. To characterize the tissue specific expression of JCV(CY) and to inve stigate its potential in inducing disease, transgenic mice containing the e arly region of JCV(CY) were generated. Some of these mice between 9-13 mont hs of age exhibited signs of illness as manifested by paralysis of rear lim bs, hunched posture, and poor grooming. Neuropathological examination indic ated no sign of hypomyelination of the brain, but surprisingly, revealed th e presence of primitive tumors originating from the cerebellum and the surr ounding brain stem. The tumor masses also infiltrated the surrounding tissu e. Results from RNA and protein studies revealed a high level of T-antigen mRNA expression in hindbrains of clinically normal and affected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of J CV(CY) induced tumor in transgenic mice to the human medulloblastoma/primit ive neuroectodermal tumor (PNETs) in location, histologic appearance, and e xpression of marker proteins strongly suggests the utility of this novel an imal model for the study of human brain tumors.