Spontaneous mutation rate of measles virus: Direct estimation based on mutations conferring monoclonal antibody resistance

High mutation rates typical of RNA viruses often generate a unique viral po pulation structure consisting of a large number of genetic microvariants. I n the case of viral pathogens, this can result in rapid evolution of antivi ral resistance or vaccine-escape mutants. We determined a direct estimate o f the mutation rate of measles virus, the next likely target for global eli mination following poliovirus. In a laboratory tissue culture system, we us ed the fluctuation test method of estimating mutation rate, which involves screening a large number of independent populations initiated by a small nu mber of viruses each for the presence or absence of a particular single poi nt mutation. The mutation we focused on, which can be screened for phenotyp ically, confers resistance to a monoclonal antibody (MAb 80-III-B2), The en tire H gene of a subset of mutants was sequenced to verify that the resista nce phenotype was associated with single point mutations. The epitope confe rring MAb resistance was further characterized by Western blot analysis. Ba sed on this approach, measles virus was estimated to have a mutation rate o f 9 x 10(-5) per base per replication and a genomic mutation rate of 1.43 p er replication. The mutation rates we estimated for measles virus are compa rable to recent in vitro estimates for both poliovirus and vesicular stomat itis virus. In the field, however, measles virus shows marked genetic stabi lity. We briefly discuss the evolutionary implications of these results.