1887

Abstract

Despite a resurgence of flavivirus infections worldwide, no approved therapeutic agent exists for any member of the genus. While cross-reactive antibodies with therapeutic potential against flaviviruses have been generated, the majority of them are anti-E antibodies with the potential to cause antibody-dependent enhancement of flavivirus infection and disease. We described previously mAbs against the non-structural NS1 protein of the West Nile virus (WNV) that were protective in mice when administered pre- or post-infection of WNV. Here, we demonstrate that one of these mAbs (16NS1) cross-reacted with Japanese encephalitis virus (JEV) and exhibited protective activity against a lethal JEV infection. Overlapping peptide mapping analysis combined with site-specific mutations identified a novel epitope KAWGKSILFA and critical amino acid residues (W and I) for 16NS1 mAb binding. These results may facilitate the development of a broadly therapeutic mAb that lacks enhancing potential and/or subunit-based vaccine against flaviviruses that target the NS1 protein.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.036640-0
2012-01-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/1/20.html?itemId=/content/journal/jgv/10.1099/vir.0.036640-0&mimeType=html&fmt=ahah

References

  1. Avirutnan P., Zhang L., Punyadee N., Manuyakorn A., Puttikhunt C., Kasinrerk W., Malasit P., Atkinson J. P., Diamond M. S. 2007; Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E. PLoS Pathog 3:e183 [View Article][PubMed]
    [Google Scholar]
  2. Balsitis S. J., Williams K. L., Lachica R., Flores D., Kyle J. L., Mehlhop E., Johnson S., Diamond M. S., Beatty P. R., Harris E. 2010; Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6:e1000790 [View Article][PubMed]
    [Google Scholar]
  3. Beasley D. W., Aaskov J. G. 2001; Epitopes on the dengue 1 virus envelope protein recognized by neutralizing IgM monoclonal antibodies. Virology 279:447–458 [View Article][PubMed]
    [Google Scholar]
  4. Beasley D. W., Barrett A. D. 2002; Identification of neutralizing epitopes within structural domain III of the West Nile virus envelope protein. J Virol 76:13097–13100 [View Article][PubMed]
    [Google Scholar]
  5. Blitvich B. J., Scanlon D., Shiell B. J., Mackenzie J. S., Hall R. A. 1999; Identification and analysis of truncated and elongated species of the flavivirus NS1 protein. Virus Res 60:67–79 [View Article][PubMed]
    [Google Scholar]
  6. Cardosa M. J., Gordon S., Hirsch S., Springer T. A., Porterfield J. S. 1986; Interaction of West Nile virus with primary murine macrophages: role of cell activation and receptors for antibody and complement. J Virol 57:952–959[PubMed]
    [Google Scholar]
  7. Chung K. M., Liszewski M. K., Nybakken G., Davis A. E., Townsend R. R., Fremont D. H., Atkinson J. P., Diamond M. S. 2006a; West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Proc Natl Acad Sci U S A 103:19111–19116 [View Article][PubMed]
    [Google Scholar]
  8. Chung K. M., Nybakken G. E., Thompson B. S., Engle M. J., Marri A., Fremont D. H., Diamond M. S. 2006b; Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms. J Virol 80:1340–1351 [View Article][PubMed]
    [Google Scholar]
  9. Chung K. M., Thompson B. S., Fremont D. H., Diamond M. S. 2007; Antibody recognition of cell surface-associated NS1 triggers Fc-gamma receptor-mediated phagocytosis and clearance of West Nile virus-infected cells. J Virol 81:9551–9555 [View Article][PubMed]
    [Google Scholar]
  10. Crill W. D., Chang G. J. 2004; Localization and characterization of flavivirus envelope glycoprotein cross-reactive epitopes. J Virol 78:13975–13986 [View Article][PubMed]
    [Google Scholar]
  11. Crill W. D., Roehrig J. T. 2001; Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells. J Virol 75:7769–7773 [View Article][PubMed]
    [Google Scholar]
  12. Deng Y. Q., Dai J. X., Ji G. H., Jiang T., Wang H. J., Yang H. O., Tan W. L., Liu R., Yu M.other authors 2011; A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein. PLoS ONE 6:e16059 [View Article][PubMed]
    [Google Scholar]
  13. Desprès P., Dietrich J., Girard M., Bouloy M. 1991; Recombinant baculoviruses expressing yellow fever virus E and NS1 proteins elicit protective immunity in mice. J Gen Virol 72:2811–2816 [View Article][PubMed]
    [Google Scholar]
  14. Douglas K. O., Kilpatrick A. M., Levett P. N., Lavoie M. C. 2007; A quantitative risk assessment of West Nile virus introduction into Barbados. West Indian Med J 56:394–397[PubMed]
    [Google Scholar]
  15. Falconar A. K. 2007; Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. Clin Vaccine Immunol 14:493–504 [View Article][PubMed]
    [Google Scholar]
  16. Falconar A. K., Young P. R., Miles M. A. 1994; Precise location of sequential dengue virus subcomplex and complex B cell epitopes on the nonstructural-1 glycoprotein. Arch Virol 137:315–326 [View Article][PubMed]
    [Google Scholar]
  17. Gould E. A., Solomon T. 2008; Pathogenic flaviviruses. Lancet 371:500–509 [View Article][PubMed]
    [Google Scholar]
  18. Gould E. A., Buckley A., Barrett A. D., Cammack N. 1986; Neutralizing (54K) and non-neutralizing (54K and 48K) monoclonal antibodies against structural and non-structural yellow fever virus proteins confer immunity in mice. J Gen Virol 67:591–595 [View Article][PubMed]
    [Google Scholar]
  19. Henchal E. A., Henchal L. S., Thaisomboonsuk B. K. 1987; Topological mapping of unique epitopes on the dengue-2 virus NS1 protein using monoclonal antibodies. J Gen Virol 68:845–851 [View Article][PubMed]
    [Google Scholar]
  20. Henchal E. A., Henchal L. S., Schlesinger J. J. 1988; Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. J Gen Virol 69:2101–2107 [View Article][PubMed]
    [Google Scholar]
  21. Hubálek Z., Halouzka J. 1999; West Nile fever – a reemerging mosquito-borne viral disease in Europe. Emerg Infect Dis 5:643–650 [View Article][PubMed]
    [Google Scholar]
  22. Jia X. Y., Briese T., Jordan I., Rambaut A., Chi H. C., Mackenzie J. S., Hall R. A., Scherret J., Lipkin W. I. 1999; Genetic analysis of West Nile New York 1999 encephalitis virus. Lancet 354:1971–1972 [View Article][PubMed]
    [Google Scholar]
  23. Jupp P. G. 2001; The ecology of West Nile virus in South Africa and the occurrence of outbreaks in humans. Ann N Y Acad Sci 951:143–152 [View Article][PubMed]
    [Google Scholar]
  24. Krishna V. D., Rangappa M., Satchidanandam V. 2009; Virus-specific cytolytic antibodies to nonstructural protein 1 of Japanese encephalitis virus effect reduction of virus output from infected cells. J Virol 83:4766–4777 [View Article][PubMed]
    [Google Scholar]
  25. Lanciotti R. S., Roehrig J. T., Deubel V., Smith J., Parker M., Steele K., Crise B., Volpe K. E., Crabtree M. B.other authors 1999; Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286:2333–2337 [View Article][PubMed]
    [Google Scholar]
  26. Lanciotti R. S., Ebel G. D., Deubel V., Kerst A. J., Murri S., Meyer R., Bowen M., McKinney N., Morrill W. E.other authors 2002; Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States, Europe, and the Middle East. Virology 298:96–105 [View Article][PubMed]
    [Google Scholar]
  27. Lok S. M., Kostyuchenko V., Nybakken G. E., Holdaway H. A., Battisti A. J., Sukupolvi-Petty S., Sedlak D., Fremont D. H., Chipman P. R.other authors 2008; Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Nat Struct Mol Biol 15:312–317 [View Article][PubMed]
    [Google Scholar]
  28. Mackenzie J. S., Barrett A. D., Deubel V. 2002a; The Japanese encephalitis serological group of flaviviruses: a brief introduction to the group. Curr Top Microbiol Immunol 267:1–10 [View Article][PubMed]
    [Google Scholar]
  29. Mackenzie J. S., Johansen C. A., Ritchie S. A., van den Hurk A. F., Hall R. A. 2002b; Japanese encephalitis as an emerging virus: the emergence and spread of Japanese encephalitis virus in Australasia. Curr Top Microbiol Immunol 267:49–73 [View Article][PubMed]
    [Google Scholar]
  30. Mackenzie J. S., Gubler D. J., Petersen L. R. 2004; Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 10:Suppl.S98–S109 [View Article][PubMed]
    [Google Scholar]
  31. Mason P. W. 1989; Maturation of Japanese encephalitis virus glycoproteins produced by infected mammalian and mosquito cells. Virology 169:354–364 [View Article][PubMed]
    [Google Scholar]
  32. Mehlhop E., Ansarah-Sobrinho C., Johnson S., Engle M., Fremont D. H., Pierson T. C., Diamond M. S. 2007; Complement protein C1q inhibits antibody-dependent enhancement of flavivirus infection in an IgG subclass-specific manner. Cell Host Microbe 2:417–426 [View Article][PubMed]
    [Google Scholar]
  33. Melian E. B., Hinzman E., Nagasaki T., Firth A. E., Wills N. M., Nouwens A. S., Blitvich B. J., Leung J., Funk A.other authors 2010; NS1′ of flaviviruses in the Japanese encephalitis virus serogroup is a product of ribosomal frameshifting and plays a role in viral neuroinvasiveness. J Virol 84:1641–1647 [View Article][PubMed]
    [Google Scholar]
  34. Nybakken G. E., Oliphant T., Johnson S., Burke S., Diamond M. S., Fremont D. H. 2005; Structural basis of West Nile virus neutralization by a therapeutic antibody. Nature 437:764–769 [View Article][PubMed]
    [Google Scholar]
  35. Oliphant T., Engle M., Nybakken G. E., Doane C., Johnson S., Huang L., Gorlatov S., Mehlhop E., Marri A.other authors 2005; Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med 11:522–530 [View Article][PubMed]
    [Google Scholar]
  36. Peiris J. S., Gordon S., Unkeless J. C., Porterfield J. S. 1981; Monoclonal anti-Fc receptor IgG blocks antibody enhancement of viral replication in macrophages. Nature 289:189–191 [View Article][PubMed]
    [Google Scholar]
  37. Petersen L. R., Marfin A. A., Gubler D. J. 2003; West Nile virus. JAMA 290:524–528 [View Article][PubMed]
    [Google Scholar]
  38. Pierson T. C., Xu Q., Nelson S., Oliphant T., Nybakken G. E., Fremont D. H., Diamond M. S. 2007; The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe 1:135–145 [View Article][PubMed]
    [Google Scholar]
  39. Putnak J. R., Charles P. C., Padmanabhan R., Irie K., Hoke C. H., Burke D. S. 1988; Functional and antigenic domains of the dengue-2 virus nonstructural glycoprotein NS-1. Virology 163:93–103 [View Article][PubMed]
    [Google Scholar]
  40. Rodenhuis-Zybert I. A., Wilschut J., Smit J. M. 2011; Partial maturation: an immune-evasion strategy of dengue virus?. Trends Microbiol 19:248–254 [View Article][PubMed]
    [Google Scholar]
  41. Roehrig J. T., Staudinger L. A., Hunt A. R., Mathews J. H., Blair C. D. 2001; Antibody prophylaxis and therapy for flavivirus encephalitis infections. Ann N Y Acad Sci 951:286–297 [View Article][PubMed]
    [Google Scholar]
  42. Schlesinger J. J., Brandriss M. W., Walsh E. E. 1985; Protection against 17D yellow fever encephalitis in mice by passive transfer of monoclonal antibodies to the nonstructural glycoprotein gp48 and by active immunization with gp48. J Immunol 135:2805–2809[PubMed]
    [Google Scholar]
  43. Schlesinger J. J., Foltzer M., Chapman S. 1993; The Fc portion of antibody to yellow fever virus NS1 is a determinant of protection against YF encephalitis in mice. Virology 192:132–141 [View Article][PubMed]
    [Google Scholar]
  44. Serafin I. L., Aaskov J. G. 2001; Identification of epitopes on the envelope (E) protein of dengue 2 and dengue 3 viruses using monoclonal antibodies. Arch Virol 146:2469–2479 [View Article][PubMed]
    [Google Scholar]
  45. Shrestha B., Brien J. D., Sukupolvi-Petty S., Austin S. K., Edeling M. A., Kim T., O’Brien K. M., Nelson C. A., Johnson S.other authors 2010; The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1. PLoS Pathog 6:e1000823 [View Article][PubMed]
    [Google Scholar]
  46. Sukupolvi-Petty S., Austin S. K., Purtha W. E., Oliphant T., Nybakken G. E., Schlesinger J. J., Roehrig J. T., Gromowski G. D., Barrett A. D.other authors 2007; Type- and subcomplex-specific neutralizing antibodies against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 81:12816–12826 [View Article][PubMed]
    [Google Scholar]
  47. Sukupolvi-Petty S., Austin S. K., Engle M., Brien J. D., Dowd K. A., Williams K. L., Johnson S., Rico-Hesse R., Harris E.other authors 2010; Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. J Virol 84:9227–9239 [View Article][PubMed]
    [Google Scholar]
  48. Youn S., Cho H., Fremont D. H., Diamond M. S. 2010; A short N-terminal peptide motif on flavivirus nonstructural protein NS1 modulates cellular targeting and immune recognition. J Virol 84:9516–9532 [View Article][PubMed]
    [Google Scholar]
  49. Young P. R. 1990; Antigenic analysis of dengue virus using monoclonal antibodies. Southeast Asian J Trop Med Public Health 21:646–651[PubMed]
    [Google Scholar]
  50. Yun S. I., Kim S. Y., Choi W. Y., Nam J. H., Ju Y. R., Park K. Y., Cho H. W., Lee Y. M. 2003; Molecular characterization of the full-length genome of the Japanese encephalitis viral strain K87P39. Virus Res 96:129–140 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.036640-0
Loading
/content/journal/jgv/10.1099/vir.0.036640-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
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