Genetic Variability of Measles Virus in Acute and Persistent Infections

RNA viruses have high nucleotide substitution rates, and therefore the potential to mutate rapidly. In the case of vaccine preventable RNA viruses, this may potentially lead to emergence of vaccine escape mutants. The WHO has targeted measles virus (MV) for elimination in many regions, and its genetic variability is monitored to estimate appearance of such mutants. Phylogenetic analysis of partial N or H genes of 230 MV strains circulating in the UK over a 10-year period was performed. Substitution rates in three outbreaks were determined to be 3.9 x 10(-3) to 6.7 x 10(-3) per nucleotide per annum. This is an order of magnitude higher than previously reported for circulating MV. Analysis of virus detected sporadically in the UK between 1992 and 2000 lead to a slightly higher substitution rate of 7.8 x 10(-3) per site per year. Additionally, genetic variability of persistent MV, isolated from subacute sclerosing panencephalitis (SSPE) patients, was investigated and appeared more stable than circulating viruses. Profiles of nucleotide changes in acute and persistent virus were compared. In acute virus, 33% of all mutation events occurred from A-to-G, which contrasts the predominant U-to-C mutations found in persistent infections. Mutations do not seem to be driven by positive selection and no association with known biological functions could be found. We conclude that substitution rates in circulating virus may be higher than in persistent, hypermutated virus and that the high substitution rate of MV may allow evolution of escape. Diversity of circulating strains should be closely monitored in the future.