Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 08/2010; 329(5993):811-7. DOI: 10.1126/science.1192819
Source: PubMed


During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.

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Available from: Tongqing Zhou, Oct 05, 2015
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    • "Conversely, the development of broadly neutralizing antibodies (bnAbs) in natural HIV-1 infection often requires more extensive affinity maturation. As an example, bnAb VRC01, which neutralizes ~90% of circulating HIV-1 isolates, has 66 residue alterations encoded in its variable light and heavy genes (Zhou et al., 2010). The CH58 affinity maturation pathway deepens our understanding of the level of somatic hypermutation achievable by current vaccination technology and serves as a benchmark to evaluate whether re-elicitation of extensively mutated bnAbs like VRC01 might ever be feasible by vaccination. "
    07/2015; 2(7):632-3. DOI:10.1016/j.ebiom.2015.07.019
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    • "Recent work on antibodies against IFNβ (a potential side effect of treatment with IFNβ for multiple sclerosis ) showed that sera containing sustained neutralizing antibodies (NAbs) demonstrated significantly higher binding responses and slower dissociation rates than sera containing transient NAbs and that the anti- IFNβ antibody maturation response acted over time to decrease dissociation rates thus increasing relative antibody binding affinity (Gibbs et al., 2014; Gibbs and Oger, 2008). Importantly, kinetic analysis of IgG framework region reversion mutations in HIV-1 bNAbs VRC01, NIH45- 46, 12A21, and 3BNC117 (Scheid et al., 2011; Wu et al., 2011; Zhou et al., 2010, 2013) showed that the loss of affinity appeared to be primarily due to an increased dissociation rate (Klein et al., 2013). Lastly, the same effect was shown for the unmutated ancestor of the anti- gp41 MPER antibody 2F5 (Alam et al., 2011). "
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    ABSTRACT: Structural analyses show the second light chain complementarity determining region Glu-Asp motif of the CH58 antibody isolated from an RV144 vaccinee is optimally pre-conformed from germline to interact with the gp120 V2 loop. The increased binding affinity and neutralization capacity of the mature antibody compared to its germline precursor were achieved with only 2-3% mutation from germline, and the fact that these gains appeared to be a result of the tuning of local interactions rather than gross sequential or conformational changes provides hope that a rational immunogen design for HIV-1 treatment may become a reality.
    06/2015; 66(7). DOI:10.1016/j.ebiom.2015.06.016
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    • "Equation 1 is, however, just a starting point for the affinity between a particular BCR and Ag, as BCRs do not interact with peptide chains in a linear fashion, and interactions between residues are not independent, as Equation 1 may imply. Epitopeparatope interactions are distinctly 3-dimensional, and structural aspects of CD4bs bnAbs also point to the importance of how interactions with some residues on the viral spike might influence interactions with other epitope residues (Zhou et al., 2010). For instance, most CD4bs bnAbs avoid contact with almost the entire V1/V2 loop except for a few conserved residues near the stem, and the very potent VRC01 Ab avoids the V5 loop. "
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    ABSTRACT: Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(4). DOI:10.1016/j.cell.2015.01.027 · 32.24 Impact Factor
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