@article{ccb9d9d437de4cb9a9ed807b85a6ba48,
title = "Complement Protein C1q Reduces the Stoichiometric Threshold for Antibody-Mediated Neutralization of West Nile Virus",
abstract = "Virus neutralization is governed by the number of antibodies that bind a virion during the cellular entry process. Cellular and serum factors that interact with antibodies have the potential to modulate neutralization potency. Although the addition of serum complement can increase the neutralizing activity of antiviral antibodies in vitro, the mechanism and significance of this augmented potency in vivo remain uncertain. Herein, we show that the complement component C1q increases the potency of antibodies against West Nile virus by modulating the stoichiometric requirements for neutralization. The addition of C1q does not result in virolysis but instead reduces the number of antibodies that must bind the virion to neutralize infectivity. For IgG subclasses that bind C1q avidly, this reduced stoichiometric threshold falls below the minimal number of antibodies required for antibody-dependent enhancement (ADE) of infection of cells expressing Fc-γ receptors (CD32) and explains how C1q restricts the ADE of flavivirus infection.",
keywords = "MICROBIO, MOLIMMUNO",
author = "Erin Mehlhop and Steevenson Nelson and Jost, {Christiane A.} and Sergey Gorlatov and Syd Johnson and Fremont, {Daved H.} and Diamond, {Michael S.} and Pierson, {Theodore C.}",
note = "Funding Information: We thank J. Atkinson and members of our laboratories for helpful discussions; H. Hickman, H. Virgin, T. Kristie, and B. Moss for critical comments on the manuscript; and J. Bramson and M. Loeb for the convalescent human WNV sera. This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID) and grants from the Pediatric Dengue Vaccine Initiative (T.C.P. and M.S.D.), the National Institutes of Health (NIH) (grants U01 AI061373 and R01 AI073755 to M.S.D. and D.H.F.), and the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (U54 AI057160). S.J. generated hu-E16 IgG subclass-switch variants and characterized antibody affinity; E.M., C.A.J., and S.N. analyzed neutralization of mouse and human mAbs; S.N. performed the stoichiometry studies; S.J. and S.G. characterized antibody-affinity measurements by SPR; E.M. analyzed the in vivo protective capacity of E16 variants; E.M., S.N., D.H.F., M.S.D., and T.C.P. designed the studies, analyzed the data, and wrote the paper; all authors discussed the data and commented on the manuscript. S.G. and S.J. are employees of MacroGenics, a company that has licensed the E16 antibody from Washington University for commercial use. M.S.D. is a consultant for MacroGenics. ",
year = "2009",
month = nov,
day = "22",
doi = "10.1016/j.chom.2009.09.003",
language = "English",
volume = "6",
pages = "381--391",
journal = "Cell Host and Microbe",
issn = "1931-3128",
number = "4",
}