1887

Abstract

Human metapneumovirus (hMPV) is genetically related to respiratory syncytial virus (RSV); both cause respiratory tract illnesses ranging from a mild cough to bronchiolitis and pneumonia. The F protein-directed monoclonal antibody (mAb) palivizumab has been shown to prevent severe lower respiratory tract RSV infection in animals and humans. We have previously reported on a panel of mAbs against the hMPV F protein that neutralize hMPV and, in two cases, . Here we describe the generation of hMPV mAb-resistant mutants (MARMs) to these neutralizing antibodies. Sequencing the F proteins of the hMPV MARMs identified several neutralizing epitopes. Interestingly, some of the epitopes mapped on the hMPV F protein coincide with homologous regions mapped previously on the RSV F protein, including the site against which the broadly protective mAb palivizumab is directed. This suggests that these homologous regions play important, conserved functions in both viruses.

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2008-12-01
2019-11-16
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References

  1. Arbiza, J., Taylor, G., Lopez, J. A., Furze, J., Wyld, S., Whyte, P., Stott, E. J., Wertz, G., Sullender, W. & Trudel, M. ( 1992; ). Characterization of two antigenic sites recognized by neutralizing monoclonal antibodies directed against the fusion glycoprotein of human respiratory syncytial virus. J Gen Virol 73, 2225–2234.[CrossRef]
    [Google Scholar]
  2. Beeler, J. A. & van Wyke Coelingh, K. ( 1989; ). Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol 63, 2941–2950.
    [Google Scholar]
  3. Corvaisier, C., Bourgeois, C. & Pothier, P. ( 1997; ). Cross-reactive and group-specific immune responses to a neutralizing epitope of the human respiratory syncytial virus fusion protein. Arch Virol 142, 1073–1086.[CrossRef]
    [Google Scholar]
  4. Crowe, J. E., Firestone, C. Y., Crim, R., Beeler, J. A., Coelingh, K. L., Barbas, C. F., Burton, D. R., Chanock, R. M. & Murphy, B. R. ( 1998; ). Monoclonal antibody-resistant mutants selected with a respiratory syncytial virus-neutralizing human antibody fab fragment (fab 19) define a unique epitope on the fusion (F) glycoprotein. Virology 252, 373–375.[CrossRef]
    [Google Scholar]
  5. Cseke, G., Wright, D. W., Tollefson, S. J., Johnson, J. E., Crowe, J. E., Jr & Williams, J. V. ( 2007; ). Human metapneumovirus fusion protein vaccines that are immunogenic and protective in cotton rats. J Virol 81, 698–707.[CrossRef]
    [Google Scholar]
  6. Easton, A. J., Domachowske, J. B. & Rosenberg, H. F. ( 2004; ). Animal pneumoviruses: molecular genetics and pathogenesis. Clin Microbiol Rev 17, 390–412.[CrossRef]
    [Google Scholar]
  7. Herfst, S., de Graaf, M., Schrauwen, E. J. A., Ulbrandt, N. D., Barnes, A. S., Senthil, K., Osterhaus, A. D. M. E., Fouchier, R. A. M. & van den Hoogen, B. G. ( 2007; ). Immunization of syrian golden hamsters with F subunit vaccine of human metapneumovirus induces protection against challenge with homologous or heterologous strains. J Gen Virol 88, 2702–2709.[CrossRef]
    [Google Scholar]
  8. Impact-RSV Study Group ( 1998; ). Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102, 531–537.[CrossRef]
    [Google Scholar]
  9. Johnson, S., Oliver, C., Prince, G. A., Hemming, V. G., Pfarr, D. S., Wang, S. C., Dormitzer, M., O'Grady, J., Koenig, S. & other authors ( 1997; ). Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 176, 1215–1224.[CrossRef]
    [Google Scholar]
  10. Lamb, R. A., Paterson, R. G. & Jardetzky, T. S. ( 2006; ). Paramyxovirus membrane fusion: lessons from the F and HN atomic structures. Virology 344, 30–37.[CrossRef]
    [Google Scholar]
  11. Langedijk, J. P., Meloen, R. H. & van Oirschot, J. T. ( 1998; ). Identification of a conserved neutralization site in the first heptad repeat of the fusion protein of respiratory syncytial virus. Arch Virol 143, 313–320.[CrossRef]
    [Google Scholar]
  12. Lopez, J. A., Andreu, D., Carreno, C., Whyte, P., Taylor, G. & Melero, J. A. ( 1993; ). Conformational constraints of conserved neutralizing epitopes from a major antigenic area of human respiratory syncytial virus fusion glycoprotein. J Gen Virol 74, 2567–2577.[CrossRef]
    [Google Scholar]
  13. Lopez, J. A., Bustos, R., Orvell, C., Berois, M., Arbiza, J., Garcia-Barreno, B. & Melero, J. A. ( 1998; ). Antigenic structure of human respiratory syncytial virus fusion glycoprotein. J Virol 72, 6922–6928.
    [Google Scholar]
  14. Lounsbach, G. R., Bourgeois, C., West, W. H., Robinson, J. W., Carter, M. J. & Toms, G. L. ( 1993; ). Binding of neutralizing monoclonal antibodies to regions of the fusion protein of respiratory syncytial virus expressed in Escherichia coli. J Gen Virol 74, 2559–2565.[CrossRef]
    [Google Scholar]
  15. Ma, X., Endo, R., Ebihara, T., Ishiguro, N., Ishiko, H. & Kikuta, H. ( 2005; ). Production and characterization of neutralizing monoclonal antibodies against human metapneumovirus F protein. Hybridoma (Larchmt) 24, 201–205.[CrossRef]
    [Google Scholar]
  16. MacPhail, M., Schickli, J. H., Tang, R. S., Kaur, J., Robinson, C., Fouchier, R. A., Osterhaus, A. D., Spaete, R. R. & Haller, A. A. ( 2004; ). Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hMPV) and implications for hMPV vaccine design. J Gen Virol 85, 1655–1663.[CrossRef]
    [Google Scholar]
  17. Miller, S. A., Tollefson, S., Crowe, J. E., Jr, Williams, J. V. & Wright, D. W. ( 2007; ). Examination of a fusogenic hexameric core from human metapneumovirus and identification of a potent synthetic peptide inhibitor from the heptad repeat 1 region. J Virol 81, 141–149.[CrossRef]
    [Google Scholar]
  18. Morton, C. J., Cameron, R., Lawrence, L. J., Lin, B., Lowe, M., Luttick, A., Mason, A., McKimm-Breschkin, J., Parker, M. W. & other authors ( 2003; ). Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay. Virology 311, 275–288.[CrossRef]
    [Google Scholar]
  19. Peret, T. C., Boivin, G., Li, Y., Couillard, M., Humphrey, C., Osterhaus, A. D., Erdman, D. D. & Anderson, L. J. ( 2002; ). Characterization of human metapneumoviruses isolated from patients in North America. J Infect Dis 185, 1660–1663.[CrossRef]
    [Google Scholar]
  20. Skiadopoulos, M. H., Biacchesi, S., Buchholz, U. J., Riggs, J. M., Surman, S. R., Amaro-Carambot, E., McAuliffe, J. M., Elkins, W. R., St Claire, M. & other authors ( 2004; ). The two major human metapneumovirus genetic lineages are highly related antigenically, and the fusion (F) protein is a major contributor to this antigenic relatedness. J Virol 78, 6927–6937.[CrossRef]
    [Google Scholar]
  21. Skiadopoulos, M. H., Biacchesi, S., Buchholz, U. J., Amaro-Carambot, E., Surman, S. R., Collins, P. L. & Murphy, B. R. ( 2006; ). Individual contributions of the human metapneumovirus F, G, and SH surface glycoproteins to the induction of neutralizing antibodies and protective immunity. Virology 345, 492–501.[CrossRef]
    [Google Scholar]
  22. Smith, B. J., Lawrence, M. C. & Colman, P. M. ( 2002; ). Modelling the structure of the fusion protein from human respiratory syncytial virus. Protein Eng 15, 365–371.[CrossRef]
    [Google Scholar]
  23. Tang, R. S., Mahmood, K., Macphail, M., Guzzetta, J. M., Haller, A. A., Liu, H., Kaur, J., Lawlor, H. A. & Stillman, E. A. ( 2005; ). A host-range restricted parainfluenza virus type 3 (PIV3) expressing the human metapneumovirus (hMPV) fusion protein elicits protective immunity in African green monkeys. Vaccine 23, 1657–1667.[CrossRef]
    [Google Scholar]
  24. Ulbrandt, N. D., Ji, H., Patel, N. K., Riggs, J. M., Brewah, Y. A., Ready, S., Donacki, N. E., Folliot, K., Barnes, A. S. & other authors ( 2006; ). Isolation and characterization of monoclonal antibodies which neutralize human metapneumovirus in vitro and in vivo. J Virol 80, 7799–7806.[CrossRef]
    [Google Scholar]
  25. van den Hoogen, B. G., de Jong, J. C., Groen, J., Kuiken, T., de Groot, R., Fouchier, R. A. & Osterhaus, A. D. ( 2001; ). A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 7, 719–724.[CrossRef]
    [Google Scholar]
  26. van den Hoogen, B. G., Bestebroer, T. M., Osterhaus, A. D. & Fouchier, R. A. ( 2002; ). Analysis of the genomic sequence of a human metapneumovirus. Virology 295, 119–132.[CrossRef]
    [Google Scholar]
  27. van den Hoogen, B. G., Herfst, S., Sprong, L., Cane, P. A., Forleo-Neto, E., de Swart, R. L., Osterhaus, A. D. & Fouchier, R. A. ( 2004; ). Antigenic and genetic variablility of human metapneumoviruses. Emerg Infect Dis 10, 658–666.[CrossRef]
    [Google Scholar]
  28. Williams, J. V., Wang, C. K., Yang, C. F., Tollefson, S J., House, F S., Heck, J. M., Chu, M., Brown, J. B., Lintao, L. D. & other authors ( 2006; ). The role of human metapneumovirus in upper respiratory tract infections in children: a 20-year experience. J Infect Dis 193, 387–395.[CrossRef]
    [Google Scholar]
  29. Wu, H., Pfarr, D. S., Tang, Y., An, L. L., Patel, N. K., Watkins, J. D., Huse, W. D., Kiener, P. A. & Young, J. F. ( 2005; ). Ultra-potent antibodies against respiratory syncytial virus: effects of binding kinetics and binding valence on viral neutralization. J Mol Biol 350, 126–144.[CrossRef]
    [Google Scholar]
  30. Zhao, X., Singh, M., Malashkevich, V. N. & Kim, P. S. ( 2000; ). Structural characterization of the human respiratory syncytial virus fusion protein core. Proc Natl Acad Sci U S A 97, 14172–14177.[CrossRef]
    [Google Scholar]
  31. Zhao, X., Chen, F. P., Megaw, A. G. & Sullender, W. M. ( 2004; ). Variable resistance to palivizumab in cotton rats by respiratory syncytial virus mutants. J Infect Dis 190, 1941–1946.[CrossRef]
    [Google Scholar]
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