title: Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.
abstract: 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 binding. 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 development, 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 patients 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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Mouquet
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Zoller
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.forename: Rene G
authors.initials: RG
authors.lastname: Ott
authors.forename: Shetha
authors.initials: S
authors.lastname: Shukair
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.forename: John
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Herman N
authors.initials: HN
authors.lastname: Eisen
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hope
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology*; D000937:Antigen-Antibody Reactions / Q000235:genetics / Q000276:immunology*; D002308:Cardiolipins / Q000276:immunology; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D009154:Mutation; D020349:Surface Plasmon Resonance; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D002308:Cardiolipins; D000939:Epitopes; D015483:HIV Antibodies; D015488:HIV Antigens; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1