Successful archetype JC polyomavirus infection in hiPSC-derived neural culture of astrocytes and neurons.

BACKGROUND: JC polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal neurodegenerative disease in immunocompromised individuals. JCPyV is a strictly human pathogen, and animal models are inappropriate to fully reproduce human disease. PML is often associated with neurotropic JCPyV variants harboring rearrangements within the non-coding regulatory region (NCCR) and VP1 capsid protein gene. However, archetype virus has also been identified in the brain and its association with PML cannot be excluded. METHODS: To assess the ability of archetype virus to infect neural cells and to explore the cellular effects of JCPyV infection, we performed experimental 35-day infections in neural cell cultures consisting of astrocytes and neurons derived from human induced pluripotent stem cells (hiPSC). RESULTS: Archetype JCPyV infection was successfully established in both astrocytes and neurons at comparable rates. Infection in neurons supports our previous observations from brain tissue of PML patients, suggesting that neurons are also true target cells of JCPyV infection. Minor neurotropic variants emerged in the course of infection. RNA sequencing revealed significant regulation of genes implicated in cell cycle, DNA replication and repair, and cell division. The observed remarkable regulation of gene expression was proposedly driven by viral large T antigen, pRb and E2F family transcription factors, with consequent enhancement of JCPyV replication. CONCLUSIONS: Our neural cell model reproduced many observations from PML brain tissue, suggesting that the model is appropriate to study key cellular events and the pathogenesis of JCPyV in neurodegeneration.