A Cryptic Polyreactive Antibody Recognizes Distinct Clades of HIV-1 Glycoprotein 120 by an Identical Binding Mechanism

Abstract

Background: Polyreactive antibodies can efficiently neutralize HIV. Results: Heme induces polyreactivity of a human antibody, which recognizes distinct gp120 clades by an identical binding mechanism. Conclusion: Antigen-binding promiscuity of a polyreactive antibody allows recognition of antigen with high molecular heterogeneity. Significance: Characterization of the interaction of polyreactive antibodies with envelope proteins of HIV reveals novel strategies for control of the virus.

Prevalence and Gene Characteristics of Antibodies with Cofactor-induced HIV-1 Specificity

“…Conversely, a broadly neutralizing Ab isolated from an HIV-1-infected patient displayed more discriminative interactions and was not able to recognize all the variants of gp120 included in the study. The results obtained in the latter study also suggest that cofactor-bound Abs use the unique chemistry of the heme molecule to recognize gp120, wherein IgG-bound heme serves as an interfacial bridge to connect Ab and gp120 (31). Importantly, heme and its analogues have been demonstrated to bind to gp120 in the V3 region (46 -49).…”

“…Previous studies have demonstrated that exposure of some monoclonal Abs to the redox cofactor heme results in acquisition of reactivity to different structurally unrelated antigens (20,31). Spectroscopic analyses revealed that this phenomenon is mediated by binding of the macrocyclic cofactor molecule to the variable region of immunoglobulins (7,31).…”

“…Spectroscopic analyses revealed that this phenomenon is mediated by binding of the macrocyclic cofactor molecule to the variable region of immunoglobulins (7,31). The heme molecule may provide versatile types of non-covalent interactions: The table summarizes the reactivity of heme-treated Abs to different clades of gp120 and to unrelated proteins: transferrin, factor IX, tubulin, and hemoglobin, as well as to bacterial polysaccharide (pnC).…”

“…Our data suggest that the fraction of cofactor-binding Abs might also contribute to the documented inhibitory effect of heme on HIV-1. Importantly, heme-bound Abs display antigen binding polyreactivity (7,31). Our analyses revealed that a substantial fraction (16/23 or ϳ70%) of heme-induced gp120 binding Abs is polyreactive and could interact with unrelated protein antigens.…”

“…In addition, the unique chemistry of heme could extend the binding potential intrinsic to the polypeptide chain of Abs; thus, transient heme binding could serve as a cofactor of Abs for interaction with antigens (21). Recently, we performed a study with a prototypic heme-binding antibody that acquires reactivity to gp120 upon heme exposure, selected from the presented repertoire (31). Our data demonstrate that following interaction with heme, this Ab acquires antigen binding promiscuity and recognizes divergent variants of gp120 with quantitatively similar kinetic and thermodynamic parameters.…”