The Stoichiometry of Antibody-Mediated Neutralization and Enhancement of West Nile Virus Infection

Theodore C. Pierson; Qing Xu; Steevenson Nelson; Theodore Oliphant; Grant E. Nybakken; Daved H H. Fremont; Michael S. Diamond

doi:10.1016/j.chom.2007.03.002

The Stoichiometry of Antibody-Mediated Neutralization and Enhancement of West Nile Virus Infection

Theodore C. Pierson, Qing Xu, Steevenson Nelson, Theodore Oliphant, Grant E. Nybakken, Daved H H. Fremont, Michael S. Diamond

Research output: Contribution to journal › Article › peer-review

254 Scopus citations

Abstract

Antibody binding to the icosahedral arrangement of envelope proteins on the surface of flaviviruses can result in neutralization or enhancement of infection. We evaluated how many antibodies must bind to a given epitope on West Nile virus (WNV) to achieve neutralization. The most potent monoclonal antibodies (mAbs) block infection at concentrations that result in low occupancy of accessible sites on the virion, with neutralization occurring when as few as 30 of 180 envelope proteins are bound. In contrast, weakly neutralizing mAbs recognize fewer sites on the virion and require almost complete occupancy to inhibit WNV infection. For all mAbs studied, enhancement of infection is possible in cells bearing activating Fc-γ receptors when the number of mAbs docked to the virion is not sufficient for neutralization. Thus, neutralization is best described by a model requiring "multiple hits" with the cumulative functional outcome determined by interplay between antibody affinity and epitope accessibility.

Original language	English
Pages (from-to)	135-145
Number of pages	11
Journal	Cell Host and Microbe
Volume	1
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2007.03.002
State	Published - Apr 19 2007

Keywords

MICROBIO
MOLIMMUNO

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10.1016/j.chom.2007.03.002

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title = "The Stoichiometry of Antibody-Mediated Neutralization and Enhancement of West Nile Virus Infection",

abstract = "Antibody binding to the icosahedral arrangement of envelope proteins on the surface of flaviviruses can result in neutralization or enhancement of infection. We evaluated how many antibodies must bind to a given epitope on West Nile virus (WNV) to achieve neutralization. The most potent monoclonal antibodies (mAbs) block infection at concentrations that result in low occupancy of accessible sites on the virion, with neutralization occurring when as few as 30 of 180 envelope proteins are bound. In contrast, weakly neutralizing mAbs recognize fewer sites on the virion and require almost complete occupancy to inhibit WNV infection. For all mAbs studied, enhancement of infection is possible in cells bearing activating Fc-γ receptors when the number of mAbs docked to the virion is not sufficient for neutralization. Thus, neutralization is best described by a model requiring {"}multiple hits{"} with the cumulative functional outcome determined by interplay between antibody affinity and epitope accessibility.",

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author = "Pierson, {Theodore C.} and Qing Xu and Steevenson Nelson and Theodore Oliphant and Nybakken, {Grant E.} and Fremont, {Daved H H.} and Diamond, {Michael S.}",

note = "Funding Information: This work was supported by the Intramural Research Program of the NIH, National Institutes of Allergy and Infectious Diseases (NIAID). Additional support was provided by grants NIH F31 RR05074 and NIH U01 AI061373 (M.S.D.), and the Pediatric Dengue Vaccine Initiative (T.C.P., M.S.D., and D.H.F.). We thank S. Johnson for providing the N297Q form of chimeric E16. M.S.D. is a consultant for MacroGenics, Inc., which has licensed the E16 antibody for commercial use.",

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AU - Fremont, Daved H H.

AU - Diamond, Michael S.

N1 - Funding Information: This work was supported by the Intramural Research Program of the NIH, National Institutes of Allergy and Infectious Diseases (NIAID). Additional support was provided by grants NIH F31 RR05074 and NIH U01 AI061373 (M.S.D.), and the Pediatric Dengue Vaccine Initiative (T.C.P., M.S.D., and D.H.F.). We thank S. Johnson for providing the N297Q form of chimeric E16. M.S.D. is a consultant for MacroGenics, Inc., which has licensed the E16 antibody for commercial use.

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The Stoichiometry of Antibody-Mediated Neutralization and Enhancement of West Nile Virus Infection

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