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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.

SUBMITTER: Mouquet H

PROVIDER: S-EPMC3699875 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.

Mouquet Hugo H Scheid Johannes F JF Zoller Markus J MJ Krogsgaard Michelle M Ott Rene G RG Shukair Shetha S Artyomov Maxim N MN Pietzsch John J Connors Mark M Pereyra Florencia F Walker Bruce D BD Ho David D DD Wilson Patrick C PC Seaman Michael S MS Eisen Herman N HN Chakraborty Arup K AK Hope Thomas J TJ Ravetch Jeffrey V JV Wardemann Hedda H Nussenzweig Michel C MC

Nature 20100901 7315

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 ...[more]

PMID: 20882016

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Project description:UnlabelledIt is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 clades are often polyreactive or autoreactive. Whereas polyreactivity or autoreactivity has been proposed to be crucial for neutralization breadth, no systematic, quantitative study of self-reactivity among nonneutralizing HIV-1 Abs (nNAbs) has been performed to determine whether poly- or autoreactivity in bNAbs is a consequence of chronic antigen (Ag) exposure and/or inflammation or a fundamental property of neutralization. Here, we use protein microarrays to assess binding to >9,400 human proteins and find that as a class, bNAbs are significantly more poly- and autoreactive than nNAbs. The poly- and autoreactive property is therefore not due to the infection milieu but rather is associated with neutralization. Our observations are consistent with a role of heteroligation for HIV-1 neutralization and/or structural mimicry of host Ags by conserved HIV-1 neutralization sites. Although bNAbs are more mutated than nNAbs as a group, V(D)J mutation per se does not correlate with poly- and autoreactivity. Infrequent poly- or autoreactivity among nNAbs implies that their dominance in humoral responses is due to the absence of negative control by immune regulation. Interestingly, four of nine bNAbs specific for the HIV-1 CD4 binding site (CD4bs) (VRC01, VRC02, CH106, and CH103) bind human ubiquitin ligase E3A (UBE3A), and UBE3A protein competitively inhibits gp120 binding to the VRC01 bNAb. Among these four bNAbs, avidity for UBE3A was correlated with neutralization breadth. Identification of UBE3A as a self-antigen recognized by CD4bs bNAbs offers a mechanism for the rarity of this bNAb class.ImportanceEliciting bNAbs is key for HIV-1 vaccines; most Abs elicited by HIV-1 infection or immunization, however, are strain specific or nonneutralizing, and unsuited for protection. Here, we compare the specificities of bNAbs and nNAbs to demonstrate that bNAbs are significantly more poly- and autoreactive than nNAbs. The strong association of poly- and autoreactivity with bNAbs, but not nNAbs from infected patients, indicates that the infection milieu, chronic inflammation and Ag exposure, CD4 T-cell depletion, etc., alone does not cause poly- and autoreactivity. Instead, these properties are fundamentally linked to neutralization breadth, either by the requirement for heteroligation or the consequence of host mimicry by HIV-1. Indeed, we show that human UBE3A shares an epitope(s) with HIV-1 envelope recognized by four CD4bs bNAbs. The poly- and autoreactivity of bNAbs surely contribute to the rarity of membrane-proximal external region (MPER) and CD4bs bNAbs and identify a roadblock that must be overcome to induce protective vaccines.

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Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.

Publications

Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.

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