An effective vaccine against HIV/AIDS will likely need to induce broadly (b) neutralizing (Nt) antibodies (Abs). Such Abs are produced rarely during natural infection, take years to develop, and have unusual genetic and reactivity features. The research presented here is part of continuing investigations into the origins of Abs bearing these features within HIV-infected hosts. First, the reactivity profiles of monoclonal bNt Abs were analyzed and compared with those of pathogenic autoAbs. Unlike pathogenic autoAbs, HIV bNt Abs were minimally self-reactive and modestly polyreactive only at high concentrations, supporting a fundamental distinction between their binding behaviour. Moreover, the polyreactivity of HIV bNt Abs, but not of pathogenic autoAbs, was abrogated in assays using complex blocking proteins, which more closely reflect in vivo conditions. Second, HIV serum cohorts were assayed for reactivity to envelope glycoproteins and self-antigens, and for idiotypic composition. No HIV sera were significantly self-reactive, but most displayed a novel form of ‘conditional’ non-specific polyreactivity, and all contained high titers of IGHV1-69-encoded IgGs. Multiple lines of evidence supported a division between the serum Abs of cross-Nt and slow progressor sera, which were focused against particular sites on Env and displayed the lowest degree of self-reactivity and polyreactivity, and those from recent seroconverters and rapid progressors, which were cross-reactive against diverse Env epitopes, mildly self-reactive and highly polyreactive. Finally, novel methods were developed to interrogate expressed VH gene repertoires of rare B-cell subsets in HIV+ and healthy individuals. Immunogenetic analyses revealed that Ab repertoires of HIV+ individuals accrue somatic mutations indiscriminately, primarily in resting memory B-cells but also in other compartments. Other genetic features of bNt Abs, including long CDR-H3s and biased VH gene usage, were not observed in the overall repertoire, and so presumably emerge via antigen selection by HIV Env. Taken together, our data indicate that HIV infection induces fundamental changes in the reactivity and immunogenetic features of Abs. In addition to providing a plausible genetic and immunological mechanism for the development of highly mutated, polyreactive Abs, HIV-associated immunomodulation could significantly enhance secondary Ab repertoire diversification, potentially contributing to the development of bNt specificities.
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