JC virus inclusions in progressive multifocal leukoencephalopathy: scaffolding promyelocytic leukemia nuclear bodies grow with cell cycle transition through an S-to-G2-like state in enlarging oligodendrocyte nuclei.
In progressive multifocal leukoencephalopathy, JC virus-infected oligodendroglia display 2 distinct patterns of intranuclear viral inclusions: full inclusions in which progeny virions are present throughout enlarged nuclei and dot-shaped inclusions in which virions are clustered in subnuclear domains termed "promyelocytic leukemia nuclear bodies" (PML-NBs). Promyelocytic leukemia nuclear bodies may serve a scaffolding role in viral progeny production. We analyzed the formation process of intranuclear viral inclusions by morphometry and assessed PML-NB alterations in the brains of 2 patients with progressive multifocal leukoencephalopathy. By immunohistochemistry, proliferating cell nuclear antigen was most frequently detected in smaller nuclei; cyclin A was detected in larger nuclei. This suggests an S-to-G2 cell cycle transition in infected cells associated with nuclear enlargement. Sizes of PML-NBs were variable, but they were usually either small speckles 200 to 400 nm in diameter or distinct spherical shells with a diameter of 1 μm or more. By confocal microscopy, JC virus capsid proteins were associated with both small and large PML-NBs, but disruption of large PML-NBs was observed by ground-state depletion fluorescence nanoscopy. Clusters of progeny virions were also detected by electron microscopy. Our data suggest that, in progressive multifocal leukoencephalopathy, JC virus produces progeny virions in enlarging oligodendrocyte nuclei in association with growing PML-NBs and with cell cycle transition through an S-to-G2-like state.
From the Departments of Pathology (YS-H, TY, HK) and Neurosurgery (MN), Kyorin University School of Medicine, Shinkawa, Mitaka; Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute for Medical Science, Kamikitazawa, Setagaya-ku (YS-H, TU); Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku (SA-S, Mku, MKi), Tokyo; and Section of Pathology, Aizawa Hospital, Honjo, Matsumoto, Nagano (KH), Japan.
Yukiko
Y
Shishido-Hara
Takuya
T
Yazawa
Motoo
M
Nagane
Kayoko
K
Higuchi
Shiho
S
Abe-Suzuki
Morito
M
Kurata
Masanobu
M
Kitagawa
Hiroshi
H
Kamma
Toshiki
T
Uchihara
D000368:Aged; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000473:pathology / Q000648:ultrastructure / Q000821:virology; D005260:Female; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000473:pathology* / Q000648:ultrastructure / Q000821:virology; D007577:JC Virus / Q000648:ultrastructure; D007968:Leukoencephalopathy, Progressive Multifocal / Q000473:pathology* / Q000821:virology; D009836:Oligodendroglia / Q000473:pathology* / Q000648:ultrastructure / Q000821:virology; D016196:S Phase / Q000502:physiology