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Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection

  • Theodore C. Pierson (a1) and Michael S. Diamond (a2)

Abstract

Flaviviruses are a group of positive-stranded RNA viruses that cause a spectrum of severe illnesses globally in more than 50 million individuals each year. While effective vaccines exist for three members of this group (yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses), safe and effective vaccines for several other flaviviruses of clinical importance, including West Nile and dengue viruses, remain in development. An effective humoral immune response is critical for protection against flaviviruses and an essential goal of vaccine development. The effectiveness of virus-specific antibodies in vivo reflects their capacity to inhibit virus entry and spread through several mechanisms, including the direct neutralisation of virus infection. Recent advances in our understanding of the structural biology of flaviviruses, coupled with the use of small-animal models of flavivirus infection, have promoted significant advances in our appreciation of the factors that govern antibody recognition and inhibition of flaviviruses in vitro and in vivo. In this review, we discuss the properties that define the potency of neutralising antibodies and the molecular mechanisms by which they inhibit virus infection. How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed.

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Corresponding author

*Corresponding author: Theodore C. Pierson, Laboratory of Viral Diseases, NIAID, NIH, 33 North Drive, Room 1E19A.2, Bethesda, MD 20814, USA. Tel: +1 301 451 7977; Fax: 1 301 451 7978; E-mail: piersontc@mail.nih.gov

References

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Excellent general reviews on flaviviruses:

Whitehead, S.S. et al. (2007) Prospects for a dengue virus vaccine. Nat Rev Microbiol 5, 518-528
Mukhopadhyay, S., Kuhn, R.J. and Rossmann, M.G. (2005) A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3, 13-22
Stiasny, K. and Heinz, F.X. (2006) Flavivirus membrane fusion. J Gen Virol 87, 2755-2766
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, S98-109
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
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
Klasse, P.J. and Sattentau, Q.J. (2002) Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J Gen Virol 83, 2091-2108
Smith, T.J. (2003) Structural studies on antibody-virus complexes. Adv Protein Chem 64, 409-453
Dimmock, N.J. (1993) Neutralization of animal viruses. Curr Top Microbiol Immunol 183, 1-149
Hangartner, L., Zinkernagel, R.M. and Hengartner, H. (2006) Antiviral antibody responses: the two extremes of a wide spectrum. Nat Rev Immunol 6, 231-243

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