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Published on: February 17, 2016
Human iPS cell-derived astrocytes support efficient replication of progressive multifocal leukoencephalopathy-type JC
Emiko Shimbo1, Souichi Nukuzuma2, Yoh-Ichi Tagawa1
1Tokyo Institute of Technology School of Life Science and Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan.
Abstract:
JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system, in immunocompromised patients. Although PML used to be rare, recently the incidence of PML has risen due to an increase in immunosuppressive therapy. An in vitro JCPyV infection system could be used for anti-drug screening and investigation of tropism changes, but study of JCPyV in vitro has been limited due to the difficulty of efficiently propagating the virus in cultured cells. PML-type JCPyV efficiently propagates in primary human fetal and progenitor cell-derived astrocytes, but the preparation of cells from human fetuses is associated with severe ethical problems. In this study, human iPS cell-derived astrocytes were exposed to PML-type JCPyV. Infection, replication, and VP1 and T antigens of JCPyV were detected and confirmed in this culture. The non-coding control region (NCCR) of M1-IMRb was conserved in infected cells without point mutations. In addition, PML-type JCPyV genomic DNA in infected cells was detected as a single band of approximately 5.1 kbp, with no deletions. This is the first demonstration that human iPS cell-derived astrocytes efficiently support replication of PML-type JCPyV without production of defective interfering particles. These findings indicated that a culture system using human iPS cell-derived astrocyte would be useful for studies of PML, especially for screening anti-JCPyV drugs.
Insights
Human induced pluripotent stem cell-derived astrocytes efficiently support JC polyomavirus (JCPyV) replication. This breakthrough enables new in vitro studies for progressive multifocal leukoencephalopathy (PML) and anti-JCPyV drug screening.
Area of Science:
- Neurovirology
- Stem Cell Biology
- Infectious Diseases
Background:
- JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a serious CNS demyelinating disease.
- PML incidence is rising due to increased immunosuppressive therapies.
- Studying JCPyV in vitro is challenging due to difficulties in viral propagation.
Purpose of the Study:
- To establish a novel in vitro system for JCPyV propagation using human induced pluripotent stem cell (hiPSC)-derived astrocytes.
- To investigate the efficiency of JCPyV replication in hiPSC-derived astrocytes.
- To provide a new platform for anti-JCPyV drug screening and tropism studies.
Main Methods:
- Exposure of hiPSC-derived astrocytes to PML-type JCPyV.
- Detection and confirmation of JCPyV infection, replication, and antigen expression (VP1, T antigens).
- Analysis of JCPyV non-coding control region (NCCR) and genomic DNA integrity.
Main Results:
- JCPyV infection and replication were successfully confirmed in hiPSC-derived astrocytes.
- Viral VP1 and T antigens were detected, indicating active viral processes.
- Conserved NCCR and intact JCPyV genomic DNA (approx. 5.1 kbp) were observed without defective interfering particles.
Conclusions:
- hiPSC-derived astrocytes efficiently support PML-type JCPyV replication.
- This system represents the first demonstration of efficient JCPyV propagation in hiPSC-derived astrocytes without defective interfering particles.
- The developed culture system is valuable for PML research and anti-JCPyV drug development.
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