JC polyomavirus (JCPyV) is a ubiquitous human virus isolated in 1971 from the brain of a patient with Hodgkin disease (Padgett et al.
1971). It is the etiological agent of the progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, caused by lytic infection of oligodendrocytes upon viral reactivation (Pietropaolo et al.
2018). The viral genome comprises the early and late gene region and the non-coding control region (NCCR). The early region encodes for nonstructural proteins, large T antigen (LTAg), small t antigen (stAg), and T’135, T’136, and T’165 proteins involved in the regulation of the virus cycle and in cell transformation (Frisque et al.
1984; Khalili
2001). The N-terminal region of LTAg can interact with members of the retinoblastoma (Rb) protein family, whereas the C-terminal domain can bind p53 (Zheng et al.
2022). The interaction with these tumor suppressors induces progression of the cell cycle and is a major feature of the oncogenic properties (Del Valle et al.
2001). The late region encodes for the capsid proteins VP1, VP2, and VP3, for the agnoprotein (Frisque et al.
1984), and for two mature microRNAs (miRNAs), miR-J1-3p and miR-J1-5p, which can modulate viral replication by downregulating LTAg expression (Giovannelli et al.
2015). The NCCR, encompassing the origin of replication and transcription control sequences, has a hypervariable structure that contributes to neurotropism and neurovirulent properties of JCPyV (Pietropaolo et al.
2018). The archetype NCCR structure has been isolated in the kidney and urine from healthy subjects (Yogo et al.
1990) whereas the rearranged or “prototype” strain is frequently disease-associated (Frisque et al.
1984). JCPyV-mediated oncogenesis has been described both in in vitro and in vivo studies (White and Khalili
2005). Inoculation of JCPyV into rodents, owl, or squirrel monkeys produces central nervous system (CNS) tumors including medulloblastoma, astrocytoma, glioblastoma, and neuroblastoma
(Khalili
2001; Del Valle and Khalili
2021). JCPyV DNA was also detected in human brain tumors such as glioblastomas, astrocytomas, and medulloblastomas (Ahye et al.
2020).