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Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein.

ABSTRACT: Effective vaccination programs have dramatically reduced the number of measles-related deaths globally. Although all the available data suggest that measles eradication is biologically feasible, a structural and biochemical basis for the single serotype nature of measles virus (MV) remains to be provided. The hemagglutinin (H) protein, which binds to two discrete proteinaceous receptors, is the major neutralizing target. Monoclonal antibodies (MAbs) recognizing distinct epitopes on the H protein were characterized using recombinant MVs encoding the H gene from different MV genotypes. The effects of various mutations on neutralization by MAbs and virus fitness were also analyzed, identifying the location of five epitopes on the H protein structure. Our data in the present study demonstrated that the H protein of MV possesses at least two conserved effective neutralizing epitopes. One, which is a previously recognized epitope, is located near the receptor-binding site (RBS), and thus MAbs that recognize this epitope blocked the receptor binding of the H protein, whereas the other epitope is located at the position distant from the RBS. Thus, a MAb that recognizes this epitope did not inhibit the receptor binding of the H protein, rather interfered with the hemagglutinin-fusion (H-F) interaction. This epitope was suggested to play a key role for formation of a higher order of an H-F protein oligomeric structure. Our data also identified one nonconserved effective neutralizing epitope. The epitope has been masked by an N-linked sugar modification in some genotype MV strains. These data would contribute to our understanding of the antigenicity of MV and support the global elimination program of measles.

SUBMITTER: Tahara M

PROVIDER: S-EPMC3536376 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein.

Tahara Maino M Ito Yuri Y Brindley Melinda A MA Ma Xuemin X He Jilan J Xu Songtao S Fukuhara Hideo H Sakai Kouji K Komase Katsuhiro K Rota Paul A PA Plemper Richard K RK Maenaka Katsumi K Takeda Makoto M

Journal of virology 20121031 1

Effective vaccination programs have dramatically reduced the number of measles-related deaths globally. Although all the available data suggest that measles eradication is biologically feasible, a structural and biochemical basis for the single serotype nature of measles virus (MV) remains to be provided. The hemagglutinin (H) protein, which binds to two discrete proteinaceous receptors, is the major neutralizing target. Monoclonal antibodies (MAbs) recognizing distinct epitopes on the H protein ...[more]

PMID: 23115278

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Project description:We analyzed the roles of the individual measles virus (MV) surface glycoproteins in mediating functional and structural interactions with human CD46, the primary MV receptor. On one cell population, recombinant vaccinia virus vectors were used to produce the MV hemagglutinin (H) and fusion (F) glycoproteins. As fusion partner cells, various cell types were examined, without or with human CD46 (endogenous or recombinant vaccinia virus encoded). Fusion between the two cell populations was monitored by a quantitative reporter gene activation assay and by syncytium formation. MV glycoproteins promoted fusion with primate cells but not with nonprimate cells; recombinant CD46 rendered nonprimate cells competent for MV glycoprotein-mediated fusion. Markedly different fusion specificity was observed for another morbillivirus, canine distemper virus (CDV): recombinant CDV glycoproteins promoted fusion with primate and nonprimate cells independently of CD46. Fusion by the recombinant MV and CDV glycoproteins required coexpression of H plus F in either homologous or heterologous combinations. To assess the role of H versus F in determining the CD46 dependence of MV fusion, we examined the fusion specificities of cells producing heterologous glycoprotein combinations. The specificity of HMV plus FCDV paralleled that observed for the homologous MV glycoproteins: fusion occurred with primate cells but not with nonprimate cells unless they produced recombinant CD46. By contrast, the specificity of HCDV plus FMV paralleled that for the homologous CDV glycoproteins: fusion occurred with either primate or nonprimate cells with no dependence on CD46. Thus, for both MV and CDV, fusion specificity was determined by H. In particular, the results demonstrate a functional interaction between HMV and CD46. Flow cytometry and antibody coprecipitation studies provided a structural correlate to this functional interaction: CD46 formed a molecular complex with HMV but not with FMV or with either CDV glycoprotein. These results highlight the critical role of the H glycoprotein in determining MV specificity for CD46-positive cells.

Dataset Information

Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein.

Publications

Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein.

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