Antibody-Mediated Neutralization of West Nile Virus: Factors that Govern Neutralization Potency

  • Christiane A. Jost
  • Theodore C. Pierson
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


Flaviviruses are complex immunogens that elicit antibodies of varying specificity and with a spectrum of functional properties. Flavivirus virions are covered by a dense array of envelope (E) proteins that mediate steps of the virus entry pathway and are a primary target of neutralizing antibodies. The development of virus-specific antibodies is a critical aspect of protection against flavivirus infection and a major goal of ongoing efforts to produce vaccines against flaviviruses of clinical importance, such as the West Nile virus. In this chapter, we will review current models that describe how antibodies engage flaviviruses and block infection. Recent insight into the relationships that govern where antibodies bind virions and how this impacts the potency and mechanisms of neutralization of antibodies have been driven in part by insights from the structural biology of flaviviruses. The factors that define antibody potency will be discussed with a focus on the stoichiometric requirements for neutralization.


West Nile Virus Japanese Encephalitis Virus DENV Infection West Nile Virus Infection Japanese Encephalitis Virus 


  1. Aasa-Chapman, M.M., Holuigue, S., Aubin, K., Wong, M., Jones, N.A., Cornforth, D., Pellegrino, P., Newton, P., Williams, I., Borrow, P., et al. (2005). Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection . J Virol 79, 2823–2830.PubMedGoogle Scholar
  2. AbuBakar S., Azmi, A., Mohamed-Saad, N., Shafee, N., and Chee, H.Y. (1997). Antibody responses of dengue fever patients to dengue 2 (New Guinea C strain) viral proteins .Malaysian J Pathol 19, 41–51.Google Scholar
  3. Agrawal, A.G., and Petersen, L.R. (2003). Human immunoglobulin as a treatment for West Nile virus infection. J Infect Dis 188, 1–4.PubMedGoogle Scholar
  4. Alcon-LePoder, S., Sivard, P., Drouet, M.T., Talarmin, A., Rice, C., and Flamand, M. (2006). Secretion of flaviviral non-structural protein NS1: from diagnosis to pathogenesis .Novartis Foundation Symposium 277, 233–247; discussion 247–253.PubMedGoogle Scholar
  5. Allison, S.L., Stiasny, K., Stadler, K., Mandl, C.W., and Heinz, F.X. (1999) . Mapping of functional elements in the stem-anchor region of tick-borne encephalitis virus envelope protein E. J Virol 73, 5605–5612.PubMedGoogle Scholar
  6. Allison, S.L., Schalich, J., Stiasny, K., Mandl, C.W., and Heinz, F.X. (2001). Mutational evidence for an internal fusion peptide in flavivirus envelope protein E . J Virol 75, 4268–4275.PubMedGoogle Scholar
  7. Alvarez, M., RodriguezRoche, R., Bernardo, L., Vazquez, S., Morier, L., Gonzalez, D., Castro, O., Kouri, G., Halstead, S.B., and Guzman, M.G. (2006). Dengue hemorrhagic fever caused by sequential dengue 1–3 virus infections over a long time interval: Havana epidemic, 2001–2002. Am J Trop Med Hyg 75, 1113–1117.PubMedGoogle Scholar
  8. Anderson, R. (2003). Manipulation of cell surface macromolecules by flaviviruses. Adv Virus Res 59, 229–274.PubMedGoogle Scholar
  9. Beasley, D.W., and Barrett, A.D. (2002). Identification of neutralizing epitopes within structural domain III of the West Nile virus envelope protein . J Virol 76, 13097–13100.PubMedGoogle Scholar
  10. Beebe, D.P., Schreiber, R.D., and Cooper, N.R. (1983). Neutralization of influenza virus by normal human sera: mechanisms involving antibody and complement . J Immunol 130, 1317–1322.PubMedGoogle Scholar
  11. Ben-Nathan, D., Lustig, S., Tam, G., Robinzon, S., Segal, S., and Rager-Zisman, B. (2003). Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice . J Infect Dis 188, 5–12.PubMedGoogle Scholar
  12. Berglund, P., Sjoberg, M., Garoff, H., Atkins, G.J., Sheahan, B.J., and Liljestrom, P. (1993). Semliki Forest virus expression system: production of conditionally infectious recom-binant particles. Bio/Technology 11, 916–920.PubMedGoogle Scholar
  13. Boonnak, K., Slike, B.M., Burgess, T.H., Mason, R.M., Wu, S.J., Sun, P., Porter, K., Rudiman, I.F., Yuwono, D., Puthavathana, P., et al. (2008). Role of dendritic cells in antibody dependent enhancement of dengue infection . J Virol 82, 3939–3951.PubMedGoogle Scholar
  14. Booy, F.P., Roden, R.B., Greenstone, H.L., Schiller, J.T., and Trus, B.L. (1998). Two antibodies that neutralize papillomavirus by different mechanisms show distinct binding patterns at 13 A resolution. J Mol Biol 281, 95–106.PubMedGoogle Scholar
  15. Bressanelli, S., Stiasny, K., Allison, S.L., Stura, E.A., Duquerroy, S., Lescar, J., Heinz, F.X., and Rey, F.A. (2004). Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J 23, 728–738.PubMedGoogle Scholar
  16. Brinton , M.A. (2002) . The molecular biology of West Nile virus: a new invader of the western hemisphere. Annu Rev Microbiol 56, 371–402.PubMedGoogle Scholar
  17. Burnet, F.M., Keogh, E.V., and Lush, D. (1937). The immunological reactions of the filterable viruses. Aust J Exp Biol Med Sci 15, 227–368.Google Scholar
  18. Burrage, T., Kramer, E., and Brown, F. (2000). Structural differences between foot-and-mouth disease and poliomyelitis viruses influence their inactivation by aziridines . Vaccine 18, 2454–2461.PubMedGoogle Scholar
  19. Burton, D.R., Saphire, E.O., and Parren, P.W. (2001). A model for neutralization of viruses based on antibody coating of the virion surface . Curr Top Microbiol Immunol 260, 109–143.PubMedGoogle Scholar
  20. Calisher, C.H., Karabatsos, N., Dalrymple, J.M., Shope, R.E., Porterfield, J.S., Westaway, E.G., and Brandt, W.E. (1989). Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera . J Gen Virol 70(Pt 1), 37–43.PubMedGoogle Scholar
  21. Camenga, D.L., Nathanson, N., and Cole, G.A. (1974). Cyclophosphamide-potentiated West Nile viral encephalitis: relative influence of cellular and humoral factors . J Infect Dis 130, 634–641.PubMedGoogle Scholar
  22. Cardosa, M.J., Porterfield, J.S., and Gordon, S. (1983). Complement receptor mediates enhanced flavivirus replication in macrophages . J Exp Med 158, 258–263.PubMedGoogle Scholar
  23. Cardosa, M.J., Gordon, S., Hirsch, S., Springer, T.A., and 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.PubMedGoogle Scholar
  24. Cecilia, D., and Gould, E.A. (1991). Nucleotide changes responsible for loss of neuroinvasive-ness in Japanese encephalitis virus neutralization-resistant mutants . Virology 181, 70–77.PubMedGoogle Scholar
  25. Cecilia, D., Gadkari, D.A., Kedarnath, N., and Ghosh, S.N. (1988). Epitope mapping of Japanese encephalitis virus envelope protein using monoclonal antibodies against an Indian strain. J Gen Virol 69(Pt 11), 2741–2747.PubMedGoogle Scholar
  26. Chambers, T.J., Hahn, C.S., Galler, R., and Rice, C.M. (1990). Flavivirus genome organization, expression, and replication. Annu Rev Microbiol 44, 649–688.PubMedGoogle Scholar
  27. Chareonsirisuthigul, T., Kalayanarooj, S., and Ubol, S. (2007). Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells. J Gen Virol 88, 365–375.PubMedGoogle Scholar
  28. Che, Z., Olson, N.H., Leippe, D., Lee, W.M., Mosser, A.G., Rueckert, R.R., Baker, T.S., and Smith, T.J. (1998). Antibody-mediated neutralization of human rhinovirus 14 explored by means of cryoelectron microscopy and X-ray crystallography of virus-Fab complexes . J Virol 72, 4610–4622.PubMedGoogle Scholar
  29. Chu, J.J., and Ng, M.L. (2004). Infectious entry of West Nile virus occurs through a clathrin-mediated endocytic pathway. J Virol 78, 10543–10555.PubMedGoogle Scholar
  30. Chu, J.J., Rajamanonmani, R., Li, J., Bhuvanakantham, R., Lescar, J., and Ng, M.L. (2005). Inhibition of West Nile virus entry by using a recombinant domain III from the envelope glycoprotein. J Gen Virol 86, 405–412.PubMedGoogle Scholar
  31. Chung, K.M., Nybakken, G.E., Thompson, B.S., Engle, M.J., Marri, A., Fremont, D.H., and Diamond, M.S. (2006). Antibodies against West Nile virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms. J Virol 80, 1340–1351.PubMedGoogle Scholar
  32. Chung, K.M., Thompson, B.S., Fremont, D.H., and 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.PubMedGoogle Scholar
  33. Colman, P.M., and Lawrence, M.C. (2003). The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 4, 309–319.PubMedGoogle Scholar
  34. Colombage, G., Hall, R., Pavy, M., and Lobigs, M. (1998). DNA-based and alphavirus-vec-tored immunisation with prM and E proteins elicits long-lived and protective immunity against the flavivirus, Murray Valley encephalitis virus . Virology 250, 151–163.PubMedGoogle Scholar
  35. Colonno, R.J., Callahan, P.L., Leippe, D.M., Rueckert, R.R., and Tomassini, J.E. (1989). Inhibition of rhinovirus attachment by neutralizing monoclonal antibodies and their Fab fragments. J Virol 63, 36–42.PubMedGoogle Scholar
  36. Crill, W.D., and Chang, G.J. (2004). Localization and characterization of flavivirus envelope glycoprotein cross-reactive epitopes. J Virol 78, 13975–13986.PubMedGoogle Scholar
  37. Crill, W.D., and 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.PubMedGoogle Scholar
  38. Crill, W.D., Trainor, N.B., and Chang, G.J. (2007). A detailed mutagenesis study of flavivi-rus cross-reactive epitopes using West Nile virus-like particles . J Gen Virol 88, 1169–1174.PubMedGoogle Scholar
  39. Davis, C.W., Nguyen, H.Y., Hanna, S.L., Sanchez, M.D., Doms, R.W., and Pierson, T.C. (2006) . West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol 80, 1290–1301.PubMedGoogle Scholar
  40. Della-Porta, A.J., and Westaway, E.G. (1978). A multi-hit model for the neutralization of animal viruses. J Gen Virol 38, 1–19.PubMedGoogle Scholar
  41. Diamond, M.S., Shrestha, B., Marri, A., Mahan, D., and Engle, M. (2003a) . B cells and antibody play critical roles in the immediate defense of disseminated infection by West Nile encephalitis virus. J Virol 77, 2578–2586.Google Scholar
  42. Diamond, M.S., Sitati, E.M., Friend, L.D., Higgs, S., Shrestha, B., and Engle, M. (2003b). A critical role for induced IgM in the protection against West Nile virus infection . J Exp Med 198, 1853–1862.Google Scholar
  43. Dulbecco, R., Vogt, M., and Strickland, A.G. (1956). A study of the basic aspects of neutralization of two animal viruses, western equine encephalitis virus and poliomyelitis virus . Virology 2, 162–205.PubMedGoogle Scholar
  44. Endy, T.P., Nisalak, A., Chunsuttitwat, S., Vaughn, D.W., Green, S., Ennis, F.A., Rothman, A.L., and Libraty, D.H. (2004). Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis 189, 990–1000.PubMedGoogle Scholar
  45. Engle, M.J., and Diamond, M.S. (2003). Antibody prophylaxis and therapy against West Nile virus infection in wild-type and immunodeficient mice . J Virol 77, 12941–12949.PubMedGoogle Scholar
  46. Falconar, A.K. (1999). Identification of an epitope on the dengue virus membrane (M) protein defined by cross-protective monoclonal antibodies: design of an improved epitope sequence based on common determinants present in both envelope (E and M) proteins . Arch Virol 144, 2313–2330.PubMedGoogle Scholar
  47. Feng, J.Q., Mozdzanowska, K., and Gerhard, W. (2002). Complement component C1q enhances the biological activity of influenza virus hemagglutinin-specific antibodies depending on their fine antigen specificity and heavy-chain isotype . J Virol 76, 1369–1378.PubMedGoogle Scholar
  48. Flamand, A., Raux, H., Gaudin, Y., and Ruigrok, R.W. (1993). Mechanisms of rabies virus neutralization. Virology 194, 302–313.PubMedGoogle Scholar
  49. Goldwasser, R.A., and Davies, A.M. (1953). Transmission of a West Nile-like virus by Aedes aegypti. Trans R Soc Trop Med Hyg 47, 336–337.PubMedGoogle Scholar
  50. Gollins, S.W., and Porterfield, J.S. (1984). Flavivirus infection enhancement in macrophages: radioactive and biological studies on the effect of antibody on viral fate . J Gen Virol 65(Pt 8), 1261–1272.PubMedGoogle Scholar
  51. Gollins, S.W., and Porterfield, J.S. (1985). Flavivirus infection enhancement in macrophages: an electron microscopic study of viral cellular entry . J Gen Virol 66(Pt 9), 1969–1982.PubMedGoogle Scholar
  52. Gollins, S.W., and Porterfield, J.S. (1986). A new mechanism for the neutralization of enveloped viruses by antiviral antibody. Nature 321, 244–246.PubMedGoogle Scholar
  53. Goncalvez, A.P., Men, R., Wernly, C., Purcell, R.H., and Lai, C.J. (2004). Chimpanzee Fab fragments and a derived humanized immunoglobulin G1 antibody that efficiently cross-neutralize dengue type 1 and type 2 viruses . J Virol 78, 12910–12918.PubMedGoogle Scholar
  54. Goncalvez, A.P., Engle, R.E., St Claire, M., Purcell, R.H., and Lai, C.J. (2007). Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention . Proc Natl Acad Sci USA 104, 9422–9427.PubMedGoogle Scholar
  55. Gromowski, G.D., and Barrett, A.D. (2007). Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus . Virology 366, 349–360.PubMedGoogle Scholar
  56. Guirakhoo, F., Heinz, F.X., Mandl, C.W., Holzmann, H., and Kunz, C. (1991). Fusion activity of flaviviruses: comparison of mature and immature (prM-containing) tick-borne encephalitis virions. J Gen Virol 72(Pt 6), 1323–1329.PubMedGoogle Scholar
  57. Guirakhoo, F., Bolin, R.A., and Roehrig, J.T. (1992). The Murray Valley encephalitis virus prM protein confers acid resistance to virus particles and alters the expression of epitopes within the R2 domain of E glycoprotein . Virology 191, 921–931.PubMedGoogle Scholar
  58. Halevy, M., Akov, Y., Ben-Nathan, D., Kobiler, D., Lachmi, B., and Lustig, S. (1994). Loss of active neuroinvasiveness in attenuated strains of West Nile virus: pathogenicity in immu-nocompetent and SCID mice. Arch Virol 137, 355–370.PubMedGoogle Scholar
  59. Haley, M., Retter, A.S., Fowler, D., Gea-Banacloche, J., and O'Grady, N.P. (2003). The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis . Clin Infect Dis 37, e88–e90.PubMedGoogle Scholar
  60. Hall, R.A., Kay, B.H., Burgess, G.W., Clancy, P., and Fanning, I.D. (1990). Epitope analysis of the envelope and non-structural glycoproteins of Murray Valley encephalitis virus . J Gen Virol 71(Pt 12), 2923–2930.PubMedGoogle Scholar
  61. Halstead, S.B. (1979). In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. J Infect Dis 140, 527–533.PubMedGoogle Scholar
  62. Halstead, S.B. (2003). Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 60, 421–467.PubMedGoogle Scholar
  63. Halstead, S.B., and O'Rourke, E.J. (1977). Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody . J Exp Med 146, 201–217.PubMedGoogle Scholar
  64. Hamdan, A., Green, P., Mendelson, E., Kramer, M.R., Pitlik, S., and Weinberger, M. (2002). Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis . Transpl Infect Dis 4, 160–162.PubMedGoogle Scholar
  65. Hayes, E.B., Sejvar, J.J., Zaki, S.R., Lanciotti, R.S., Bode, A.V., and Campbell, G.L. (2005). Virology, pathology, and clinical manifestations of West Nile virus disease . Emerg Infect Dis 11, 1174–1179.PubMedGoogle Scholar
  66. Heinz, F.X., and Allison, S.L. (2000). Structures and mechanisms in flavivirus fusion. Adv Virus Res 55, 231–269.PubMedGoogle Scholar
  67. Heinz, F.X., Berger, R., Tuma, W., and Kunz, C. (1983). A topological and functional model of epitopes on the structural glycoprotein of tick-borne encephalitis virus defined by monoclonal antibodies. Virology 126, 525–537.PubMedGoogle Scholar
  68. Heinz, F.X., Stiasny, K., Puschner-Auer, G., Holzmann, H., Allison, S.L., Mandl, C.W., and Kunz, C. (1994). Structural changes and functional control of the tick-borne encephalitis virus glycoprotein E by the heterodimeric association with protein prM . Virology 198, 109–117.PubMedGoogle Scholar
  69. Henchal, E.A., Henchal, L.S., and 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(Pt 8), 2101–2107.PubMedGoogle Scholar
  70. He, R.T., Innis, B.L., Nisalak, A., Usawattanakul, W., Wang, S., Kalayanarooj, S., and Anderson, R. (1995). Antibodies that block virus attachment to Vero cells are a major component of the human neutralizing antibody response against dengue virus type 2 . J Med Virol 45, 451–461.PubMedGoogle Scholar
  71. Hiramatsu, K., Tadano, M., Men, R., and Lai, C.J. (1996). Mutational analysis of a neutralization epitope on the dengue type 2 virus (DEN2) envelope protein: monoclonal antibody resistant DEN2/DEN4 chimeras exhibit reduced mouse neurovirulence . Virology 224, 437–445.PubMedGoogle Scholar
  72. Holzmann, H., Heinz, F.X., Mandl, C.W., Guirakhoo, F., and Kunz, C. (1990). A single amino acid substitution in envelope protein E of tick-borne encephalitis virus leads to attenuation in the mouse model. J Virol 64, 5156–5159.PubMedGoogle Scholar
  73. Iankov, I.D., Pandey, M., Harvey, M., Griesmann, G.E., Federspiel, M.J., and Russell, S.J. (2006) . Immunoglobulin g antibody-mediated enhancement of measles virus infection can bypass the protective antiviral immune response . J Virol 80, 8530–8540.PubMedGoogle Scholar
  74. Icenogle, J., Shiwen, H., Duke, G., Gilbert, S., Rueckert, R., and Anderegg, J. (1983). Neutralization of poliovirus by a monoclonal antibody: kinetics and stoichiometry .Virology 127, 412–425.PubMedGoogle Scholar
  75. Jennings, A.D., Gibson, C.A., Miller, B.R., Mathews, J.H., Mitchell, C.J., Roehrig, J.T., Wood, D.J., Taffs, F., Sil, B.K., Whitby, S.N., et-al. (1994). Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis . J Infect Dis 169, 512–518.PubMedGoogle Scholar
  76. Jiang, W.R., Lowe, A., Higgs, S., Reid, H., and Gould, E.A. (1993). Single amino acid codon changes detected in louping ill virus antibody-resistant mutants with reduced neuroviru-lence. J Gen Virol 74(Pt 5), 931–935.PubMedGoogle Scholar
  77. Kanai, R., Kar, K., Anthony, K., Gould, L.H., Ledizet, M., Fikrig, E., Marasco, W.A., Koski, R.A., and Modis, Y. (2006). Crystal structure of west nile virus envelope glycoprotein reveals viral surface epitopes. J Virol 80, 11000–11008.PubMedGoogle Scholar
  78. Kaufmann, B., Nybakken, G.E., Chipman, P.R., Zhang, W., Diamond, M.S., Fremont, D.H., Kuhn, R.J., and Rossmann, M.G. (2006). West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody . Proc Natl Acad Sci USA 103, 12400–12404.PubMedGoogle Scholar
  79. Klasse, P.J., and Burton, D.R. (2007). Antibodies to West Nile virus: a double-edged sword. Cell Host Microbe 1, 87–89.PubMedGoogle Scholar
  80. Klasse, P.J., and Moore, J.P. (1996). Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1. J Virol 70, 3668–3677.PubMedGoogle Scholar
  81. Klasse, P.J., and Sattentau, Q.J. (2002). Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J Gen Virol 83, 2091–2108.PubMedGoogle Scholar
  82. Kliks, S.C., Nimmanitya, S., Nisalak, A., and Burke, D.S. (1988). Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants .Am J Trop Med Hyg 38, 411–419.PubMedGoogle Scholar
  83. Krishnan, M.N., Sukumaran, B., Pal, U., Agaisse, H., Murray, J.L., Hodge, T.W., and Fikrig, E. (2007) . Rab 5 is required for the cellular entry of dengue and West Nile viruses . J Virol 81, 4881–4885.PubMedGoogle Scholar
  84. Kuhn, R.J., Zhang, W., Rossmann, M.G., Pletnev, S.V., Corver, J., Lenches, E., Jones, C.T., Mukhopadhyay, S., Chipman, P.R., Strauss, E.G., et-al. (2002). Structure of dengue virus: implications for flavivirus organization, maturation, and fusion . Cell 108, 717–725.PubMedGoogle Scholar
  85. Lai, C.J., Goncalvez, A.P., Men, R., Wernly, C., Donau, O., Engle, R.E., and Purcell, R.H. (2007) . Epitope determinants of a chimpanzee dengue virus type 4 (DENV-4)-neutralizing antibody and protection against DENV-4 challenge in mice and rhesus monkeys by passively transferred humanized antibody. J Virol 81, 12766–12774.PubMedGoogle Scholar
  86. Lewis, J.K., Bothner, B., Smith, T.J., and Siuzdak, G. (1998). Antiviral agent blocks breathing of the common cold virus . Proc Natl Acad Sci USA 95, 6774–6778.PubMedGoogle Scholar
  87. Li, Q., Yafal, A.G., Lee, Y.M., Hogle, J., and Chow, M. (1994). Poliovirus neutralization by antibodies to internal epitopes of VP4 and VP1 results from reversible exposure of these sequences at physiological temperature. J Virol 68, 3965–3970.PubMedGoogle Scholar
  88. Lobigs M., Pavy, M., and Hall, R. (2003). Cross-protective and infection-enhancing immunity in mice vaccinated against flaviviruses belonging to the Japanese encephalitis virus sero-complex. Vaccine 21, 1572–1579.PubMedGoogle Scholar
  89. 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., Roehrig, J.T., et-al. (2008). Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycopro-teins. Nat Struct Mol Biol 15, 312–317.PubMedGoogle Scholar
  90. Mackenzie, J.M., and Westaway, E.G. (2001). Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. J Virol 75, 10787–10799.PubMedGoogle Scholar
  91. Mackenzie , J.S. , Gubler , D.J. , and Petersen , L.R. (2004) . Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses . Nat Med 10, S98–S109.PubMedGoogle Scholar
  92. Mahalingam, S., and Lidbury, B.A. (2002). Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus . Proc Natl Acad Sci USA 99, 13819–13824.PubMedGoogle Scholar
  93. Mandl, C.W., Guirakhoo, F., Holzmann, H., Heinz, F.X., and Kunz, C. (1989). Antigenic structure of the flavivirus envelope protein E at the molecular level, using tick-borne encephalitis virus as a model. J Virol 63, 564–571.PubMedGoogle Scholar
  94. Mandl, C.W., Allison, S.L., Holzmann, H., Meixner, T., and Heinz, F.X. (2000). Attenuation of tick-borne encephalitis virus by structure-based site-specific mutagenesis of a putative flavivirus receptor binding site. J Virol 74, 9601–9609.PubMedGoogle Scholar
  95. Mehlhop, E., and Diamond, M.S. (2006). Protective immune responses against West Nile virus are primed by distinct complement activation pathways . J Exp Med 203, 1371–1381.PubMedGoogle Scholar
  96. Mehlhop, E., Whitby, K., Oliphant, T., Marri, A., Engle, M., and Diamond, M.S. (2005). Complement activation is required for induction of a protective antibody response against West Nile virus infection. J Virol 79, 7466–7477.PubMedGoogle Scholar
  97. Mehlhop, E., Ansarah-Sobrinho, C., Johnson, S., Engle, M., Fremont, D.H., Pierson, T.C., and 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.PubMedGoogle Scholar
  98. Meyer, K., Basu, A., Przysiecki, C.T., Lagging, L.M., Di Bisceglie, A.M., Conley, A.J., and Ray, R. (2002) . Complement-mediated enhancement of antibody function for neutralization of pseu-dotype virus containing hepatitis C virus E2 chimeric glycoprotein . J Virol 76, 2150–2158.PubMedGoogle Scholar
  99. Modis, Y., Ogata, S., Clements, D., and Harrison, S.C. (2003). A ligand-binding pocket in the dengue virus envelope glycoprotein . Proc Natl Acad Sci USA 100, 6986–6991.PubMedGoogle Scholar
  100. Modis, Y., Ogata, S., Clements, D., and Harrison, S.C. (2004). Structure of the dengue virus envelope protein after membrane fusion. Nature 427, 313–319.PubMedGoogle Scholar
  101. Morrey, J.D., Siddharthan, V., Olsen, A.L., Roper, G.Y., Wang, H., Baldwin, T.J., Koenig, S.,Johnson, S., Nordstrom, J.L., and Diamond, M.S. (2006). Humanized monoclonal antibody against West Nile virus envelope protein administered after neuronal infection protects against lethal encephalitis in hamsters . J Infect Dis 194, 1300–1308.PubMedGoogle Scholar
  102. Morrey, J.D., Siddharthan, V., Olsen, A.L., Wang, H., Julander, J.G., Hall, J.O., Li, H., Nordstrom, J.L., Koenig, S., Johnson, S., et-al. (2007). Defining limits of treatment with humanized neutralizing monoclonal antibody for West Nile virus neurological infection in a hamster model. Antimicrob Agents Chemother 51, 2396–2402.PubMedGoogle Scholar
  103. Mozdzanowska, K., Feng, J., Eid, M., Zharikova, D., and Gerhard, W. (2006). Enhancement of neutralizing activity of influenza virus-specific antibodies by serum components .Virology 352, 418–426.PubMedGoogle Scholar
  104. Mukhopadhyay, S., Kim, B.S., Chipman, P.R., Rossmann, M.G., and Kuhn, R.J. (2003). Structure of West Nile virus. Science 302, 248.PubMedGoogle Scholar
  105. Mukhopadhyay, S., Kuhn, R.J., and Rossmann, M.G. (2005). A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3, 13–22.PubMedGoogle Scholar
  106. Nguyen, T.H., Lei, H.Y., Nguyen, T.L., Lin, Y.S., Huang, K.J., Le, B.L., Lin, C.F., Yeh, T.M., Do , Q.H. , Vu , T.Q. , et-al. (2004) . Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J Infect Dis 189, 221–232.PubMedGoogle Scholar
  107. Nimmerjahn, F., and Ravetch, J.V. (2008). Fcgamma receptors as regulators of immune responses. Nat Rev 8, 34–47.Google Scholar
  108. Nybakken, G.E., Oliphant, T., Johnson, S., Burke, S., Diamond, M.S., and Fremont, D.H. (2005) . Structural basis of West Nile virus neutralization by a therapeutic antibody .Nature 437, 764–769.PubMedGoogle Scholar
  109. Nybakken, G.E., Nelson, C.A., Chen, B.R., Diamond, M.S., and Fremont, D.H. (2006). Crystal structure of the West Nile virus envelope glycoprotein . J Virol 80, 11467–11474.PubMedGoogle Scholar
  110. Oliphant, T., and Diamond, M.S. (2007). The molecular basis of antibody-mediated neutralization of West Nile virus . Expert Opin Biol Ther 7, 885–892.PubMedGoogle Scholar
  111. Oliphant, T., Engle, M., Nybakken, G.E., Doane, C., Johnson, S., Huang, L., Gorlatov, S., Mehlhop, E., Marri, A., Chung, K.M., et-al. (2005). Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus . Nat Med 11, 522–530.PubMedGoogle Scholar
  112. Oliphant, T., Nybakken, G.E., Engle, M., Xu, Q., Nelson, C.A., Sukupolvi-Petty, S., Marri, A., Lachmi, B.E., Olshevsky, U., Fremont, D.H., et-al. (2006). Antibody recognition and neutralization determinants on domains I and II of West Nile virus envelope protein .J V i r o l 80, 12149–12159.PubMedGoogle Scholar
  113. Oliphant, T., Nybakken, G.E., Austin, S.K., Xu, Q., Bramson, J., Loeb, M., Throsby, M., Fremont, D.H., Pierson, T.C., and Diamond, M.S. (2007). Induction of epitope-specific neutralizing antibodies against West Nile virus . J Virol 81, 11828–11839.PubMedGoogle Scholar
  114. Pantophlet, R., and Burton, D.R. (2006). GP120: target for neutralizing HIV-1 antibodies. Annu Rev Immunol 24, 739–769.PubMedGoogle Scholar
  115. Peiris, J.S., and Porterfield, J.S. (1979). Antibody-mediated enhancement of Flavivirus replication in macrophage-like cell lines. Nature 282, 509–511.PubMedGoogle Scholar
  116. Peiris, J.S., Gordon, S., Unkeless, J.C., and Porterfield, J.S. (1981). Monoclonal anti-Fc receptor IgG blocks antibody enhancement of viral replication in macrophages . Nature 289, 189–191.PubMedGoogle Scholar
  117. Pierson, T.C., Xu, Q., Nelson, S., Oliphant, T., Nybakken, G.E., Fremont, D.H., and Diamond, M.S. (2007). The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe 1, 135–145.PubMedGoogle Scholar
  118. Pincus, S., Mason, P.W., Konishi, E., Fonseca, B.A., Shope, R.E., Rice, C.M., and Paoletti, E. (1992) . Recombinant vaccinia virus producing the prM and E proteins of yellow fever virus protects mice from lethal yellow fever encephalitis . Virology 187, 290–297.PubMedGoogle Scholar
  119. Randolph, V.B., and Stollar, V. (1990). Low pH-induced cell fusion in flavivirus-infected Aedes albopictuscell cultures. J Gen Virol 71(Pt 8), 1845–1850.PubMedGoogle Scholar
  120. Randolph, V.B., Winkler, G., and Stollar, V. (1990). Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology 174, 450–458.PubMedGoogle Scholar
  121. Reisdorph, N., Thomas, J.J., Katpally, U., Chase, E., Harris, K., Siuzdak, G., and Smith, T.J. (2003). Human rhinovirus capsid dynamics is controlled by canyon flexibility. Virology 314, 34–44.PubMedGoogle Scholar
  122. Rey, F.A., Heinz, F.X., Mandl, C., Kunz, C., and Harrison, S.C. (1995). The envelope glyco-protein from tick-borne encephalitis virus at 2 A resolution . Nature 375, 291–298.PubMedGoogle Scholar
  123. Rice, C.M. (1996). Flaviviridae: the viruses and their replication. In Fields Virology, B.N. Fields, P.M. Knipe, and P.M. Howley, eds. (Philadelphia, Lippincott-Raven), pp.931–959.Google Scholar
  124. Roden, R.B., Weissinger, E.M., Henderson, D.W., Booy, F., Kirnbauer, R., Mushinski, J.F., Lowy, D.R., and Schiller, J.T. (1994). Neutralization of bovine papillomavirus by antibodies to L1 and L2 capsid proteins . J Virol 68, 7570–7574.PubMedGoogle Scholar
  125. Rodrigo, W.W., Jin, X., Blackley, S.D., Rose, R.C., and Schlesinger, J.J. (2006). Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32) . J Virol 80, 10128–10138.PubMedGoogle Scholar
  126. Roehrig, J.T. (2003). Antigenic structure of flavivirus proteins. Adv Virus Res 59, 141–175.PubMedGoogle Scholar
  127. Roehrig, J.T., Mathews, J.H., and Trent, D.W. (1983). Identification of epitopes on the E glyco-protein of Saint Louis encephalitis virus using monoclonal antibodies . Virology 128, 118–126.PubMedGoogle Scholar
  128. Roehrig, J.T., Bolin, R.A., and Kelly, R.G. (1998). Monoclonal antibody mapping of the envelope glycoprotein of the dengue 2 virus, Jamaica . Virology 246, 317–328.PubMedGoogle Scholar
  129. Roehrig, J.T., Staudinger, L.A., Hunt, A.R., Mathews, J.H., and Blair, C.D. (2001). Antibody prophylaxis and therapy for flavivirus encephalitis infections . Ann N Y Acad Sci 951, 286–297.PubMedGoogle Scholar
  130. Ryman, K.D., Ledger, T.N., Campbell, G.A., Watowich, S.J., and Barrett, A.D. (1998). Mutation in a 17D-204 vaccine substrain-specific envelope protein epitope alters the pathogenesis of yellow fever virus in mice . Virology 244, 59–65.PubMedGoogle Scholar
  131. Salminen, A., Wahlberg, J.M., Lobigs, M., Liljestrom, P., and Garoff, H. (1992). Membrane fusion process of Semliki Forest virus . II: Cleavage-dependent reorganization of the spike protein complex controls virus entry. J Cell Biol 116, 349–357.PubMedGoogle Scholar
  132. Samuel, M.A., and Diamond, M.S. (2006). Pathogenesis of West Nile virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion . J Virol 80, 9349–9360.PubMedGoogle Scholar
  133. Sanchez, M.D., Pierson, T.C., McAllister, D., Hanna, S.L., Puffer, B.A., Valentine, L.E., Murtadha, M.M., Hoxie, J.A., and Doms, R.W. (2005). Characterization of neutralizing antibodies to West Nile virus. Virology 336, 70–82.PubMedGoogle Scholar
  134. Schonning, K., Lund, O., Lund, O.S., and Hansen, J.E. (1999). Stoichiometry of monoclonal antibody neutralization of T-cell line-adapted human immunodeficiency virus type 1 .J Virol 73, 8364–8370.PubMedGoogle Scholar
  135. Sejvar, J.J. (2007). The long-term outcomes of human West Nile virus infection. Clin Infect Dis 44, 1617–1624.PubMedGoogle Scholar
  136. Serafin, I.L., and 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.PubMedGoogle Scholar
  137. Shepherd, C.M., Borelli, I.A., Lander, G., Natarajan, P., Siddavanahalli, V., Bajaj, C., Johnson, J.E., BrooksIII, C.L., , and Reddy, V.S. (2006). VIPERdb: a relational database for structural virology. Nucleic Acids Res 34, D386–D389.PubMedGoogle Scholar
  138. Shimoni, Z., Niven, M.J., Pitlick, S., and Bulvik, S. (2001). Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis 7, 759.PubMedGoogle Scholar
  139. Shu, P.Y., Chen, L.K., Chang, S.F., Yueh, Y.Y., Chow, L., Chien, L.J., Chin, C., Lin, T.H., and Huang, J.H. (2000). Dengue NS1-specific antibody responses: isotype distribution and serotyping in patients with dengue fever and dengue hemorrhagic fever . J Med Virol 62, 224–232.PubMedGoogle Scholar
  140. Simmons, C.P., Chau, T.N., Thuy, T.T., Tuan, N.M., Hoang, D.M., Thien, N.T., Lien le, B., Quy, N.T., Hieu, N.T., Hien, T.T., et-al. (2007). Maternal antibody and viral factors in the pathogenesis of dengue virus in infants . J Infect Dis 196, 416–424.PubMedGoogle Scholar
  141. Spector, S.L., and Tauraso, N.M. (1969). Yellow fever virus. II. Factors affecting the plaque neutralization test. Appl Microbiol 18, 736–743.PubMedGoogle Scholar
  142. Stadler, K., Allison, S.L., Schalich, J., and Heinz, F.X. (1997). Proteolytic activation of tick-borne encephalitis virus by furin. J Virol 71, 8475–8481.PubMedGoogle Scholar
  143. Stephens, H.A., Klaythong, R., Sirikong, M., Vaughn, D.W., Green, S., Kalayanarooj, S., Endy, T.P., Libraty, D.H., Nisalak, A., Innis, B.L., et-al. (2002). HLA-A and -B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais . Tissue Antigens 60, 309–318.PubMedGoogle Scholar
  144. Stiasny, K., and Heinz, F.X. (2006). Flavivirus membrane fusion. J Gen Virol 87, 2755–2766.PubMedGoogle Scholar
  145. Stiasny, K., Kiermayr, S., Holzmann, H., and Heinz, F.X. (2006). Cryptic properties of a cluster of dominant flavivirus cross-reactive antigenic sites . J Virol 80, 9557–9568.PubMedGoogle Scholar
  146. Stiasny, K., Brandler, S., Kossl, C., and Heinz, F.X. (2007a). Probing the flavivirus membrane fusion mechanism by using monoclonal antibodies . J Virol 81, 11526–11531.Google Scholar
  147. Stiasny, K., Kossl, C., Lepault, J., Rey, F.A., and Heinz, F.X. (2007b). Characterization of a structural intermediate of flavivirus membrane fusion . PLoS Pathog 3, e20.Google Scholar
  148. Sukupolvi-Petty , S., Austin, S.K., Purtha, W.E., Oliphant, T., Nybakken, G.E., Schlesinger, J.J., Roehrig, J.T., .). Type- and sub-complex-specific neutralizing antibodies against domain III of dengue virus type-2 envelope protein recognize adjacent epitopes. J Virol.Google Scholar
  149. Takada, A., and Kawaoka, Y. (2003). Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications . Rev Med Virol 13, 387–398.PubMedGoogle Scholar
  150. Tassaneetrithep, B., Burgess, T.H., Granelli-Piperno, A., Trumpfheller, C., Finke, J., Sun, W., Eller, M.A., Pattanapanyasat, K., Sarasombath, S., Birx, D.L., et-al. (2003). DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells . J Exp Med 197, 823–829.PubMedGoogle Scholar
  151. Taylor, H.P., Armstrong, S.J., and Dimmock, N.J. (1987). Quantitative relationships between an influenza virus and neutralizing antibody. Virology 159, 288–298.PubMedGoogle Scholar
  152. Tesh, R.B., Arroyo, J., Travassos Da Rosa, A.P., Guzman, H., Xiao, S.Y., and Monath, T.P. (2002) . Efficacy of killed virus vaccine, live attenuated chimeric virus vaccine, and passive immunization for prevention of West Nile virus encephalitis in hamster model . Emerg Infect Dis 8, 1392–1397.PubMedGoogle Scholar
  153. Throsby, M., Geuijen, C., Goudsmit, J., Bakker, A.Q., Korimbocus, J., Kramer, R.A., Clijsters-van der Horst, M., de Jong, M., Jongeneelen, M., Thijsse, S., et-al. (2006). Isolation and characterization of human monoclonal antibodies from individuals infected with West Nile Virus. J Virol 80, 6982–6992.PubMedGoogle Scholar
  154. Thullier, P., Demangel, C., Bedouelle, H., Megret, F., Jouan, A., Deubel, V., Mazie, J.C., and Lafaye, P. (2001). Mapping of a dengue virus neutralizing epitope critical for the infectiv-ity of all serotypes: insight into the neutralization mechanism . J Gen Virol 82, 1885–1892.PubMedGoogle Scholar
  155. van der Schaar, H.M., Rust, M.J., Waarts, B.L., van der Ende-Metselaar, H., Kuhn, R.J., Wilschut, J., Zhuang, X., and Smit, J.M. (2007). Characterization of the early events in dengue virus cell entry by biochemical assays and single-virus tracking . J Virol 81, 12019–12028.PubMedGoogle Scholar
  156. Vaughn, D.W., Green, S., Kalayanarooj, S., Innis, B.L., Nimmannitya, S., Suntayakorn, S., Endy, T.P., Raengsakulrach, B., Rothman, A.L., Ennis, F.A., et-al. (2000). Dengue viremiatiter, antibody response pattern, and virus serotype correlate with disease severity . J Infect Dis 181, 2–9.PubMedGoogle Scholar
  157. Volanakis, J.E. (2002). The role of complement in innate and adaptive immunity. Curr Top Microbiol Immunol 266, 41–56.PubMedGoogle Scholar
  158. Volk, D.E., Beasley, D.W., Kallick, D.A., Holbrook, M.R., Barrett, A.D., and Gorenstein, D.G. (2004). Solution structure and antibody binding studies of the envelope protein domain III from the New York strain of West Nile virus . J Biol Chem 279, 38755–38761.PubMedGoogle Scholar
  159. Wang, T., Anderson, J.F., Magnarelli, L.A., Wong, S.J., Koski, R.A., and Fikrig, E. (2001). Immunization of mice against West Nile virus with recombinant envelope protein . J Immunol 167, 5273–5277.PubMedGoogle Scholar
  160. Yamanaka, A., Kosugi, S., and Konishi, E. (2008). Infection-enhancing and -neutralizing activities of mouse monoclonal antibodies against dengue type 2 and 4 viruses are controlled by complement levels. J Virol 82, 927–937.PubMedGoogle Scholar
  161. Yang, K.D., Yeh, W.T., Yang, M.Y., Chen, R.F., and Shaio, M.F. (2001). Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFNgamma production. J Med Virol 63, 150–157.PubMedGoogle Scholar
  162. Yang, X., Kurteva, S., Lee, S., and Sodroski, J. (2005). Stoichiometry of antibody neutralization of human immunodeficiency virus type 1 . J Virol 79, 3500–3508.PubMedGoogle Scholar
  163. Zhang, Y., Corver, J., Chipman, P.R., Zhang, W., Pletnev, S.V., Sedlak, D., Baker, T.S., Strauss, J.H., Kuhn, R.J., and Rossmann, M.G. (2003). Structures of immature flavivirus particles. EMBO J 22, 2604–2613.PubMedGoogle Scholar
  164. Zhang, Y., Zhang, W., Ogata, S., Clements, D., Strauss, J.H., Baker, T.S., Kuhn, R.J., and Rossmann, M.G. (2004). Conformational changes of the flavivirus E glycoprotein. Structure 12, 1607–1618.PubMedGoogle Scholar
  165. Zhang, Y., Kaufmann, B., Chipman, P.R., Kuhn, R.J., and Rossmann, M.G. (2007). Structure of immature West Nile virus. J Virol 81, 6141–6145.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Christiane A. Jost
    • 1
  • Theodore C. Pierson
    • 1
  1. 1.Laboratory of Viral Diseases Viral Pathogenesis SectionNational Institutes of HealthBethesdaUSA

Personalised recommendations