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Animal Models for Progressive Multifocal Leukoencephalopathy
Martyn K White1, Jennifer Gordon1, Joseph R Berger2
1Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania.
Abstract:
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS caused by the human polyomavirus JC (JCV). JCV replication occurs only in human cells and investigation of PML has been severely hampered by the lack of an animal model. The common feature of PML is impairment of the immune system. The key to understanding PML is working out the complex mechanisms that underlie viral entry and replication within the CNS and the immunosurveillance that suppresses the virus or allows it to reactivate. Early models involved the simple inoculation of JCV into animals such as monkeys, hamsters, and mice. More recently, mouse models transgenic for the gene encoding the JCV early protein, T-antigen, a protein thought to be involved in the disruption of myelin seen in PML, have been employed. These animal models resulted in tumorigenesis rather than demyelination. Another approach is to use animal polyomaviruses that are closely related to JCV but able to replicate in the animal such as mouse polyomavirus and SV40. More recently, novel models have been developed that involve the engraftment of human cells into the animal. Here, we review progress that has been made to establish an animal model for PML, the advances and limitations of different models and weigh future prospects.
Insights
Developing an animal model for progressive multifocal leukoencephalopathy (PML) is crucial for understanding JC virus (JCV) pathogenesis. This review examines various animal models, highlighting their successes and limitations in studying this severe CNS demyelinating disease.
Area of Science:
- Neurovirology
- Immunology
- Animal Models
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS).
- PML is caused by the human polyomavirus JC (JCV), which replicates exclusively in human cells.
- The lack of a suitable animal model has significantly hindered PML research.
Purpose of the Study:
- To review the progress in establishing an animal model for PML.
- To analyze the advancements and limitations of different existing animal models.
- To discuss future prospects for PML research through animal models.
Main Methods:
- Review of historical and recent animal models for PML.
- Analysis of models involving direct JCV inoculation, transgenic approaches, and use of related animal polyomaviruses.
- Evaluation of novel models utilizing engraftment of human cells into animals.
Main Results:
- Early models (e.g., JCV inoculation in monkeys) had limited success in replicating PML.
- Transgenic mouse models targeting JCV T-antigen led to tumorigenesis, not demyelination.
- Models using animal polyomaviruses (e.g., mouse polyomavirus, SV40) or human cell engraftment show promise but require further development.
Conclusions:
- Establishing a faithful animal model for PML remains a significant challenge.
- Continued development and refinement of existing and novel models are essential for understanding JCV pathogenesis and developing therapies.
- Future research should focus on models that accurately recapitulate CNS demyelination and viral replication.
