Functional consequences of attenuating mutations in the haemagglutinin neuraminidase, fusion and polymerase proteins of a wild-type mumps virus strain.
Wild-type mumps viruses (MuVs) are highly neurotropic and, prior to widespread vaccination programmes, were a major cause of viral meningitis and encephalitis in most developed countries. At present, there are no markers for virus attenuation, apart from the failure of a passaged isolate to produce clinical symptoms in vaccinees. Indeed, some MuV vaccines have retained residual neurovirulence properties and have caused aseptic meningitis in vaccinees. Three amino acid changes associated with the neuroattenuation of a wild-type MuV strain were identified previously. This study evaluated the impact of these changes on the function of the respective proteins. The data demonstrated that the Ser-->Asp amino acid substitution at position 466 in the haemagglutinin-neuraminidase protein resulted in decreased receptor binding and neuraminidase activity, the Ala/Thr-->Thr selection in the fusion protein resulted in decreased fusion activity, and the Ile-->Val substitution in the polymerase resulted in increased replicative/transcriptional activity. These data suggest a polygenic component (i.e. specific and inter-related roles of these amino acid changes) to MuV neuroattenuation.
Malik
Tahir
T
DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Wolbert
Candie
C
DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Mauldin
Jeremy
J
Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Sauder
Christian
C
DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Carbone
Kathryn M
KM
DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Rubin
Steven A
SA
DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D050939:Gene Fusion; D015707:HN Protein / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D009109:Mumps virus / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013912:Threonine; D014760:Viral Fusion Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
D017931:DNA Primers; D015707:HN Protein; D012367:RNA, Viral; D014760:Viral Fusion Proteins; D014764:Viral Proteins; D013912:Threonine; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase; D009439:Neuraminidase