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Mutated and hypermutated genes of persistent measles viruses which caused lethal human brain diseases
R Cattaneo1, A Schmid, P Spielhofer
1Institut für Molekularbiologie I, Universität Zürich, Hönggerberg, Switzerland.
Abstract:
Persistent measles viruses (MVs) causing lethal human brain diseases are defective, and the structure of several mutated matrix genes has been elucidated previously. The present study of four persistent MVs revealed a high number of differences from a consensus sequence also in other genes. Amino acid changes accumulated in the carboxyl terminus of the nucleocapsid protein and in the amino terminus of the phosphoprotein, but did not significantly alter these products, which are implicated in viral replication and transcription. The contrary is true for the envelope glycoproteins: In three of four cases, mutations caused partial deletion of the short intracellular domain of the fusion protein, most likely compromising efficient viral budding. Moreover, in the hemagglutinin gene of a strain showing strongly reduced hemadsorption, 20 clustered A to G mutations, resulting in 16 amino acid changes, were detected. This hypermutation might be due to unwinding modification of a part of the MV RNA genome accidentally present in a double-stranded form. Finally, we classified four lytic and seven persistent MV strains on the basis of their sequences. Surprisingly, the four lytic viruses considered belong to the same class. The persistent viruses form more loosely defined groups, which all differ from the vaccine strain Edmonston.
Insights
Persistent measles viruses (MVs) show significant genetic mutations, particularly in envelope glycoproteins, impacting viral budding and disease. These genetic differences help classify lytic and persistent MV strains.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Persistent measles viruses (MVs) are linked to lethal human brain diseases.
- Previous studies identified mutations in the matrix genes of defective MVs.
Purpose of the Study:
- To investigate genetic differences in persistent MV strains beyond the matrix gene.
- To understand the impact of mutations on viral proteins and function.
- To classify MV strains based on sequence data.
Main Methods:
- Sequence analysis of four persistent MV strains.
- Comparison with consensus sequences and identification of amino acid changes.
- Classification of lytic and persistent MV strains.
Main Results:
- Significant genetic variations were found in multiple MV genes, not just the matrix gene.
- Mutations in envelope glycoproteins, including the fusion protein, likely impair viral budding.
- A specific strain exhibited hypermutation in the hemagglutinin gene, possibly due to RNA modification.
- Lytic MV strains clustered together, while persistent strains formed looser groups, distinct from the vaccine strain.
Conclusions:
- Genetic mutations in persistent MVs affect viral structure and function, particularly envelope glycoproteins.
- Sequence-based classification reveals distinct groupings for lytic and persistent measles viruses.
- Understanding these genetic alterations is crucial for comprehending MV pathogenesis and developing antivirals.