Neural stem cells as tools for understanding retroviral neuropathogenesis.
Animals; Humans; Membrane Fusion/physiology; Microglia/virology; Neurons/*virology; Retroviridae Infections/virology; Retroviridae Proteins/metabolism; Retroviridae/*pathogenicity; Stem Cells/*virology; Viral Envelope Proteins/metabolism; Virulence
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.
Lynch W P; Portis J L
Virology
2000
2000-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1006/viro.2000.0338" target="_blank" rel="noreferrer noopener">10.1006/viro.2000.0338</a>
Strain-dependent structural variants of herpes simplex virus type 1 ICP34.5 determine viral plaque size, efficiency of glycoprotein processing, and viral release and neuroinvasive disease potential.
*Genetic Variation; Animals; Cercopithecus aethiops; Cultured; Encephalitis; Genetic; Herpes Simplex/*physiopathology/virology; Herpesvirus 1; Human/*classification/genetics/*pathogenicity; Inbred BALB C; Male; Mice; Recombination; Transfection; Tumor Cells; Vero Cells; Viral Envelope Proteins/metabolism; Viral Plaque Assay; Viral Proteins/*chemistry/*genetics/metabolism
The ability of certain strains of herpes simplex virus type 1 (HSV-1) to cause encephalitis or neuroinvasive disease in the mouse upon peripheral infection is dependent on a combination of activities of specific forms of viral proteins. The importance of specific variants of ICP34.5 to neuroinvasive disease potential and its correlation with small-plaque production, inefficient glycoprotein processing, and virus release were suggested by comparison of ICP34.5 from the SP7 virus, originally obtained from the brain of a neonate with disseminated disease, and the tissue culture-passaged progeny of SP7 (SLP5 and SLP10) and the KOS321 virus. SLP5, SLP10, and KOS321 are attenuated and exhibit a large-plaque phenotype, including efficient glycoprotein processing and viral release. We show that expression of the KOS321 ICP34.5 protein in cells infected with SP7 or ICP34.5 deletion mutants promotes large plaque formation and efficient viral glycoprotein processing, while expression of the SP7 ICP34.5 protein decreases efficiency of viral glycoprotein processing. In addition, a recombinant virus, 4hS1, with the SP7 ICP34.5 gene replacing the KOS321-like ICP34.5 gene in the SLP10a background, rescues the small-plaque phenotype and neuroinvasive disease. The major difference in the ICP34.5 gene product is the number of Pro-Ala-Thr repeats in the middle region of the protein, with 18 for SP7 and 3 for KOS321. Strain-dependent differences in the ICP34.5 protein can therefore alter the tissue culture behavior and the virulence of HSV-1.
Mao Hanwen; Rosenthal Ken S
Journal of virology
2003
2003-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1128/jvi.77.6.3409-3417.2003" target="_blank" rel="noreferrer noopener">10.1128/jvi.77.6.3409-3417.2003</a>