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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 binding1-3. 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 respondingnaiveandmemoryBcells producepolyreactive 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.
Although most B cells in the nascent repertoire are poly- or selfreactive, only 5% of the B cells in the mature naive B cell compartment retain this unusual form of reactivity4,6.
Surprisingly, however, B cells can re-acquire poly- and self-reactivity during the germinal centre reaction7, and self-reactivity is also associated with serum antibody responses in several persistent infections, including vaccinia virus inmice8 and HIV, Epstein-Barr virus and hepatitisCvirus in humans. This strange though relatively common feature of antibodies was first documented in studies of anti-hapten-specific myeloma proteins over three decades ago9; however, its role (if any) in the antibody response to a specific antigen has yet to be explored.
One possible functionfor polyreactivitywould be to increase antibody affinity for a pathogen where simple homotypic bivalent ligation is not feasible. To test this idea we studied antibody response to HIV because its gp140 surface spike is present at a very lowdensity of only 10-15 viral spikes per virion1,2,10,11. Homotypic bivalent binding is therefore unlikely3, but an anti-HIV antibody might increase its overall apparent affinity to the virus by heterogenous ligand binding or heteroligation. In this model, one combining site would bind...