Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458:636-640

Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
Nature (Impact Factor: 42.35). 05/2009; 458(7238):636-40. DOI: 10.1038/nature07930
Source: PubMed

ABSTRACT Antibodies to conserved epitopes on the human immunodeficiency virus (HIV) surface protein gp140 can protect against infection in non-human primates, and some infected individuals show high titres of broadly neutralizing immunoglobulin (Ig)G antibodies in their serum. However, little is known about the specificity and activity of these antibodies. To characterize the memory antibody responses to HIV, we cloned 502 antibodies from HIV envelope-binding memory B cells from six HIV-infected patients with broadly neutralizing antibodies and low to intermediate viral loads. We show that in these patients, the B-cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity neutralizing antibodies to the gp120 variable loops, the CD4-binding site, the co-receptor-binding site, and to a new neutralizing epitope that is in the same region of gp120 as the CD4-binding site. Thus, the IgG memory B-cell compartment in the selected group of patients with broad serum neutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120.

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Available from: Richard Wyatt, Feb 11, 2014
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    • "). To determine whether these antibodies with limited activity (tier-1 strains only; here termed tier-1 neutralizing antibodies) are active against viruses that carry bNAb escape mutations, we assayed a panel of 34 tier-1 neutralizing mAbs directed against the V2 or the V3 loop, the CD4bs, the CD4-induced site (CD4i), and gp41 (Scheid et al., 2009; Pietzsch et al., 2010; Mouquet et al., 2011). Each of these antibodies was tested against WT HIV-1 YU2 and bNAb-resistant variants of HIV-1 YU2 with mutations that naturally arose in in vivo experiments (single mutations: N160K, N332K, and N280Y; HIV-1 YU2 triple mutations: TM1-3; Fig. 4 B; Klein et al., 2012; Horwitz et al., 2013). "
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    Journal of Experimental Medicine 11/2014; 211(12). DOI:10.1084/jem.20141050 · 13.91 Impact Factor
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    • "We have previously isolated a number of potent broadly neutralizing monoclonal antibodies to the V2 and N332 regions from HIV - infected donors ( Walker et al. , 2009 , 2011 ). These antibodies were isolated by direct functional screening rather than by anti - gen selection ( Scheid et al. , 2009 ). In this method , IgG + memory B cells from the donor were plated at approximately a single B cell per well , and after activation for 7 – 8 days , supernates were screened for their ability to neutralize indicator viruses. "
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    Immunity 04/2014; 40(5). DOI:10.1016/j.immuni.2014.04.009 · 19.75 Impact Factor
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    • "8ANC195 is classified as a bNAb because it neutralized 66% of viruses in a diverse viral panel (Scheid et al., 2011). Like other anti-HIV-1 bNAbs (Klein et al., 2013a; Scheid et al., 2009a), 8ANC195 is highly somatically mutated, including insertions and deletions in the complementarity determining regions (CDRs) and framework regions (FWRs) of its heavy chain (HC) and light chain (LC). Although initial efforts to map the 8ANC195 epitope were unsuccessful (Scheid et al., 2011), computational analyses of neutralization data predicted that intact potential N-linked glycosylation sites (PNGSs) at positions 234 gp120 and 276 gp120 were essential for its activity (Chuang et al., 2013; West et al., 2013). "
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    ABSTRACT: Broadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4-binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield by using a single variable-region CDR loop, 8ANC195 inserted its entire heavy-chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with nonoverlapping epitopes.
    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.04.001 · 8.36 Impact Factor
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