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Transduction of Human Cells with Polymer-complexed Ecotropic Lentivirus for Enhanced Biosafety
Published on: July 24, 2011
Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus
Yuta Shirogane1, Hidetaka Harada1, Yuichi Hirai1
1Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract:
Measles virus (MeV), which is usually non-neurotropic, sometimes persists in the brain and causes subacute sclerosing panencephalitis (SSPE) several years after acute infection, serving as a model for persistent viral infections. The persisting MeVs have hyperfusogenic mutant fusion (F) proteins that likely enable cell-cell fusion at synapses and "en bloc transmission" between neurons. We here show that during persistence, F protein fusogenicity is generally enhanced by cumulative mutations, yet mutations paradoxically reducing the fusogenicity may be selected alongside the wild-type (non-neurotropic) MeV genome. A mutant F protein having SSPE-derived substitutions exhibits lower fusogenicity than the hyperfusogenic F protein containing some of those substitutions, but by the wild-type F protein coexpression, the fusogenicity of the former F protein is enhanced, while that of the latter is nearly abolished. These findings advance the understanding of the long-term process of MeV neuropathogenicity and provide critical insight into the genotype-phenotype relationships of en bloc transmitted viruses.
Insights
Measles virus (MeV) can persist in the brain, causing subacute sclerosing panencephalitis (SSPE). This study reveals complex mutations in MeV fusion (F) proteins that alter cell-cell fusion and viral transmission, impacting neuropathogenesis.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- Measles virus (MeV) typically does not infect the brain but can cause subacute sclerosing panencephalitis (SSPE) years after initial infection.
- Persistent MeV strains in the brain often possess hyperfusogenic mutant fusion (F) proteins, facilitating neuronal cell-cell fusion and 'en bloc' transmission.
- Understanding the viral mechanisms behind MeV neuropathogenicity is crucial for persistent viral infection research.
Purpose of the Study:
- To investigate the complex mutations affecting MeV fusion (F) protein fusogenicity during persistent infection.
- To elucidate the genotype-phenotype relationships of MeV F proteins in the context of neuropathogenesis.
- To understand how viral mutations influence cell-cell fusion and neuronal transmission in SSPE.
Main Methods:
- Analysis of cumulative mutations in MeV F proteins during persistent infection.
- Assessment of F protein fusogenicity in SSPE-derived MeV strains.
- Experimental coexpression of wild-type and mutant MeV F proteins to evaluate fusogenicity modulation.
Main Results:
- MeV F protein fusogenicity is generally enhanced by cumulative mutations during persistence.
- Paradoxically, mutations that reduce fusogenicity can be selected alongside wild-type MeV genomes.
- Coexpression with wild-type MeV F protein differentially affects the fusogenicity of SSPE-derived mutant F proteins.
Conclusions:
- Viral persistence and neuropathogenesis involve intricate modulation of MeV F protein fusogenicity.
- The interplay between wild-type and mutant F proteins is critical for understanding MeV transmission dynamics in the brain.
- These findings provide key insights into the long-term evolution of MeV and its neuropathogenic potential.
