The Analysis Of The Dynamic Variation Of The Neutralization Antigen Genes And Antigenic Epitopes Of The H1 Genotype Measles Viruses Circulating In Mainland China

Measeles is a highly contagious infection caused by the measles virus; symptoms typically include fever and erythematous rash. Despite the existence of an effective vaccine,Measles still has been a serious threat to infant and child health in the worldwide. Measles virus (MV), a member of the genus Morbillivirus of the family Paramyxoviridae, is an enveloped virus with a nonsegmented negative-sense RNA genome. Despite the variety of measles genotype, there is only one measles serotype. Up to now, 24 measles genotypes have been found in the world. According to the previously study, the H1 genoytpe measles viruses have been circulating in mainland China at least 20 years,it's very strange because here the only one genotype persistent has been circulating in one country. It's very important to disclose the evolutionary laws of the pathogen so as to take effective measures to control and prevent diseases. This study focuses on clarifying the dynamic variation of the neutralization antigen genes and antigenic epitopes of the H1 genotype measles viruses circulating in mainland China. In addition, combined with the phenomenon of the change of the patient age(the number of patients those who less than 8 months are increasing due to down regulation of maternal transferred antibody; primary, second immune failure or declining immune persistence lead to the increase of the number of adult cases), so it's urgent to assess the protection efficiency of the Chinese vaccines.This study selected the 86 H1 genotype representative viral strains based on the distributions of the chronology, geography and the phylogenetic relationship of N-COOH terminal 450 nuleotide, analysed the variation laws of the two main neutralization antigens of the measles virus by using the virus isolation, RT-PCR, sequencing and bioinformatics technology, with the purpose of disclosing the viral origin, evolution, genetic diversity,phylogenetic relationship and stability analysis of the key amino acids (receptor binding sites and antigenic epitopes) based on the 3D crystal structure of the HA protein. The results showed that the trend of the topological structure based on the polygenetic tree of N, H and F genes is consistent, the H1 genotype is further divided into H1a, H1b and H1c, the H1c were dispeared since 1994, the H1b were dispeared since 2000, the H1a has been continuous circulating in China, the circulation of the endemic measles virus didn't follow the regular pattern, the same or multiple measles virus(es) caused the circulation and co-circulation within one province or between provinces in recent years; the result of the selection pressure showed that the H gene belongs to the negative selection pressure, there is no the phenomenon of the accumulation mutation and the antigenic drift; the result of the homology analysis of the amino acid and nucleotide of H and F genes showed the H1 genotype bear the minimize homology among all the genotypes when comparing with the Chinese vaccine strains; there are 15 and 13 amino acids variation on the H and F genes between the H1 genotype measle viruses and Chinese vaccine strains, the 211 and 303 amino acids of the H gene is also the antigenic epitopes, the 481 amino acids is the binding site of the CD46 receptor; there are 10 highly variation sites within the H1 genotype measles viruses (the conservation rate less than 90%); the evolutionary rate of the nucleotide of the H,N and F genes are respectively 0.75 X 10-3/per site/per year, 1.65 X 10-3/per site/per year ,1.07 X 10-3/per site/per year; the fifth glycosylation site was disappeared because of the mutation of the 238th amino acid of the H gene; the time of most recent common ancestor(TMRC) for the Hlgenotype measle viruses was estimated as approximately 1985, the genetic diversity of the measles viruses decreased from 2005 to 2012, this trend was coincident with the trend of a substantial decrease of measles cases; the analysis of the dynamic stability of the receptor binding sites and antigenic sites revealed they were conserved and located in the lateral of the protein based on the 3D crystal structure of the HA protein (expect previously variations sites).This study clarified the variation laws of the H and F genes of H1 genotype measles viruses circulating in mainland China at least 20 years, disclosed the viral origin, evolutionary pattern, the genetic diversity, and the dynamic antigenic stability based on the 3D crystal structure of the HA protein. The conclusions were that the H1 genotype measles viruses is relative conserved, there aren't the phenomenon of the accumulation mutation and antigenic drift, the current measles viruses could infect mankind effectively and the Chinese vaccines could prevent against the H1 genotype measles viruses, but the mutations of the amino acids on the neutralization genes might well lead to the change of the immunization efficiency and persistence of the vaccines, so it's urgent to scientific assess the performance of the Chinese vaccines in the near future.