Related Experiment Videos
Multiple viral mutations rather than host factors cause defective measles virus gene expression in a subacute
R Cattaneo1, A Schmid, M A Billeter
1Institut für Molekularbiologie I, Universität Zürich, Switzerland.
Abstract:
A measles virus (MV) genome originally derived from brain cells of a subacute sclerosing panencephalitis patient expressed in IP-3-Ca cells an unstable MV matrix protein and was unable to produce virus particles. Transfection of this MV genome into other cell lines did not relieve these defects, showing that they are ultimately encoded by viral mutations. However, these defects were partially relieved in a weakly infectious virus which emerged from IP-3-Ca cells and which produced a matrix protein of intermediate stability. The sequences of several cDNAs related to the unstable and intermediately stable matrix proteins showed many differences in comparison with a stable matrix protein sequence and even appreciable heterogeneity among themselves. Nevertheless, partial restoration of matrix protein stability could be ascribed to a single additional amino acid change. From an examination of additional genes, we estimated that, on average, each MV genome in IP-3-Ca cells differs from the others in 30 to 40 of its 16,000 bases. The role of extreme variability of RNA virus genomes in persistent viral infections is discussed in the context of the pathogenesis of subacute sclerosing panencephalitis and of other human diseases of suspected viral etiology.
Insights
Measles virus (MV) mutations cause an unstable matrix protein, hindering virus particle production. Genetic analysis revealed significant viral genome variability in persistent infections, impacting subacute sclerosing panencephalitis pathogenesis.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Subacute sclerosing panencephalitis (SSPE) is a severe neurological complication of measles virus (MV) infection.
- Persistent MV infections are characterized by significant viral genetic diversity.
- Understanding MV genome variability is crucial for deciphering SSPE pathogenesis.
Purpose of the Study:
- To investigate the genetic basis of defects in MV replication and matrix protein stability.
- To analyze the extent of MV genome heterogeneity in persistent infections.
- To explore the role of viral variability in SSPE pathogenesis.
Main Methods:
- Expression of an SSPE-derived MV genome in IP-3-Ca cells.
- Transfection of MV genome into various cell lines.
- Analysis of MV matrix protein stability and viral particle production.
- Sequencing of MV matrix protein cDNAs.
- Estimation of MV genome sequence variation.
Main Results:
- An MV genome from SSPE patient brain cells produced an unstable matrix protein and failed to form virus particles.
- These defects were linked to viral mutations and partially rescued by a weakly infectious MV with an intermediately stable matrix protein.
- Sequencing revealed significant differences and heterogeneity in matrix protein genes, with a single amino acid change potentially restoring stability.
- MV genomes in IP-3-Ca cells showed an average of 30-40 base differences per 16,000 bases.
Conclusions:
- Extreme genetic variability of MV genomes is a key feature of persistent infections.
- Viral mutations affecting matrix protein stability contribute to the defects observed in SSPE.
- Understanding MV genome evolution is essential for addressing SSPE and other suspected viral diseases.