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Fc receptor but not complement binding is important in antibody protection against HIV

Abstract

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.

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Figure 1: Effector function variants of b12: location of substitutions, antigen binding and neutralization properties.
Figure 2: Interaction of b12 and variants with effector molecules.
Figure 3: Temporal analysis of plasma viral loads.
Figure 4: Antibody-dependent cell-mediated viral inhibition (ADCVI) by b12 and variants.

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Acknowledgements

We thank K. Saye-Francisco, P. and C. Carney, R. Aguilar-Sino and D. Tehrani for antibody production assistance at TSRI. We also thank T. Vink for expressing FcγR and the technical assistance of A. van den Broek and A. Ortiz Buijsse at Genmab. We are grateful for the assistance provided by C. Corbaci during the preparation of the manuscript. We also thank M. Zwick and R. Pantophlet for discussions. Support for this work was provided by an NIH grant (D.R.B.), by the Neutralizing Antibody Consortium of the International AIDS Vaccine Initiative, and by a Swiss National Foundation Fellowship (L.H.) and an NIH grant (D.N.F.).

Author Contributions Project planning was performed by A.J.H., L.H., P.W.H.I.P., P.A.M., D.R.B.; experimental work by A.J.H., L.H., M.H., C.E.G.H., F.J.B., G.L., D.N.F.; data analysis by A.J.H., L.H., J.M.B., C.M.S.L., G.L., D.N.F., P.W.H.I.P., P.A.M., D.R.B.; and manuscript composition by A.J.H., L.H., P.W.H.I.P. and D.R.B.

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Correspondence to Dennis R. Burton.

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D.R.B. is listed as an inventor on a patent describing the human neutralizing antibody b12.

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This file contains Supplementary Tables 1-4 and Supplementary Figure 1 with Legends. (PDF 1090 kb)

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Hessell, A., Hangartner, L., Hunter, M. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007). https://doi.org/10.1038/nature06106

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