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.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/005199-0
2008-12-01
2021-03-03
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/12/3113.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/005199-0&mimeType=html&fmt=ahah

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]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.2008/005199-0
Loading
/content/journal/jgv/10.1099/vir.0.2008/005199-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error