JC polyomavirus neuroinvasion across the blood-brain barrier: Current understanding and emerging perspectives.

JC Polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), an often-fatal demyelinating disease. Unfortunately, a diagnosis of PML occurs only after patients have suffered irreversible neuropathologies. One requirement for the development of PML is for JCPyV to enter the brain, but the mechanisms responsible for neuroinvasion have not been well established. The blood-brain barrier (BBB) is a potential site for JCPyV neuroinvasion. JCPyV DNA is found in the vascular endothelium in postmortem brain tissue from PML patients, and demyelinating lesions commonly emerge around vascularized sites. This review explores three potential pathways that may underlie JCPyV traversal across the BBB: diapedesis ("Trojan Horse") via JCPyV-associated B cells, paracellular passage, and transcytosis. Elucidating the route and mechanism of JCPyV neuroinvasion will deepen our understanding of how the virus enters the brain before the manifestation of PML neuropathologies. Additionally, we discuss current limitations of in vitro BBB modeling and propose future approaches to more accurately capture the physiological dynamics underlying JCPyV neuroinvasion.