Neural Stem Cells as Tools for Understanding Retroviral Neuropathogenesis

The discovery within the past decade that neural stem cells (NSCs) from the developing and adult mammalian brain can be propagated, cloned, and genetically manipulated ex vivo for ultimate transfer back into the CNS has opened the door to a novel means for modifying the CNS environment for experimental and therapeutic purposes. While a great deal of interest has been focused on the properties and promise of this new technology, especially in regard to cellular replacement and gene therapy, this minireview will focus on the recent use of NSCs to study the neuropathogenesis of the murine oncornaviruses. In brief, the use of this NSC-based approach has provided a means for selective reconstitution within the brain, of specific retroviral life cycle events, in order to consider their contribution to the induction of neurodegeneration. Furthermore, by virtue of their ability to disseminate virus within the brain, NSCs have provided a reliable means for assessing the true neurovirulence potential of murine oncornaviruses by directly circumventing a restriction to virus entry into the CNS. Importantly, these experiments have demonstrated that the neurovirulence of oncornaviruses requires late virus life cycle events occurring specifically within microglia, the resident macrophages of the brain. This initial application of NSC biology to the analysis of oncornavirus–CNS interactions may serve as an example for how other questions in viral neuropathogenesis might be addressed in the future.