During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding1,2,3. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development4, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients5 with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.
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Zhu, P. et al. Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441, 847–852 (2006)
Liu, J., Bartesaghi, A., Borgnia, M. J., Sapiro, G. & Subramaniam, S. Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008)
Klein, J. S. et al. Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10. Proc. Natl Acad. Sci. USA 106, 7385–7390 (2009)
Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003)
Scheid, J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636–640 (2009)
Tsuiji, M. et al. A checkpoint for autoreactivity in human IgM+ memory B cell development. J. Exp. Med. 203, 393–400 (2006)
Tiller, T. et al. Autoreactivity in human IgG+ memory B cells. Immunity 26, 205–213 (2007)
Zinkernagel, R. M. et al. Virus-induced autoantibody response to a transgenic viral antigen. Nature 345, 68–71 (1990)
Michaelides, M. C. & Eisen, H. N. The strange cross-reaction of menadione (vitamin K3) and 2,4-dinitrophenyl ligands with a myeloma protein and some conventional antibodies. J. Exp. Med. 140, 687–702 (1974)
Chertova, E. et al. Envelope glycoprotein incorporation, not shedding of surface envelope glycoprotein (gp120/SU), is the primary determinant of SU content of purified human immunodeficiency virus type 1 and simian immunodeficiency virus. J. Virol. 76, 5315–5325 (2002)
Karlsson, G. B., Gao, F., Robinson, J., Hahn, B. & Sodroski, J. Increased envelope spike density and stability are not required for the neutralization resistance of primary human immunodeficiency viruses. J. Virol. 70, 6136–6142 (1996)
Aguilera, I., Melero, J., Nunez-Roldan, A. & Sanchez, B. Molecular structure of eight human autoreactive monoclonal antibodies. Immunology 102, 273–280 (2001)
Ichiyoshi, Y. & Casali, P. Analysis of the structural correlates for antibody polyreactivity by multiple reassortments of chimeric human immunoglobulin heavy and light chain V segments. J. Exp. Med. 180, 885–895 (1994)
Shibata, R. et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nature Med. 5, 204–210 (1999)
Zolla-Pazner, S. Identifying epitopes of HIV-1 that induce protective antibodies. Natl. Rev. 4, 199–210 (2004)
Karlsson Hedestam, G. B. et al. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nature Rev. Microbiol. 6, 143–155 (2008)
Mascola, J. R. HIV/AIDS: allied responses. Nature 449, 29–30 (2007)
Sather, D. N. et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J. Virol. 83, 757–769 (2009)
Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005)
Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005)
Yurasov, S. et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med. 201, 703–711 (2005)
Jay, J. I. et al. Modulation of viscoelasticity and HIV transport as a function of pH in a reversibly crosslinked hydrogel. Adv. Funct. Mater. 19, 2969–2977 (2009)
Buchacher, A. et al. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res. Hum. Retroviruses 10, 359–369 (1994)
Burton, D. R. et al. A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Natl Acad. Sci. USA 88, 10134–10137 (1991)
Muster, T. et al. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J. Virol. 67, 6642–6647 (1993)
Trkola, A. et al. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70, 1100–1108 (1996)
Meffre, E. et al. Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies. J. Exp. Med. 199, 145–150 (2004)
Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008)
Scheid, J. F. et al. A method for identification of HIV gp140 binding memory B cells in human blood. J. Immunol. Methods 343, 65–67 (2009)
Alam, S. M. et al. Role of HIV membrane in neutralization by two broadly neutralizing antibodies. Proc. Natl Acad. Sci. USA 107, 5972–5977 (2010)
Cheskis, B. & Freedman, L. P. Modulation of nuclear receptor interactions by ligands: kinetic analysis using surface plasmon resonance. Biochemistry 35, 3309–3318 (1996)
We thank J. R. Mascola and R. T. Wyatt for discussion and supplying gp140 and gp120 proteins. This research was supported by the Rockefeller University, the National Institutes of Health (NIH 1 PO1 AI081677), the International AIDS Vaccine Initiative and the Bill and Melinda Gates Foundation. T.J.H. was supported by the National Institutes of Health (R01 AI047770). M.J.Z. and H.W. were supported by the German Research Foundation (GRK1121). B.D.W. and M.C.N. are Howard Hughes Medical Institute investigators.
The authors declare no competing financial interests.
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Mouquet, H., Scheid, J., Zoller, M. et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467, 591–595 (2010). https://doi.org/10.1038/nature09385
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