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: 31.48). 08/2010; 329(5993):811-7. DOI: 10.1126/science.1192819
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Tongqing Zhou, Aug 22, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 33.12 Impact Factor
  • Source
    • "Importantly, passive transfer of these antibodies can protect against intravenous (Mascola et al., 1999) and mucosal (Burton et al., 2011; Hessell et al., 2009a, 2009b, 2010; Mascola et al., 2000; Parren et al., 2001) challenge in macaque models of simian/HIV (SHIV) infection. In recent years, several extraordinarily potent neutralizing antibodies with activity against a wide range of HIV clades have been discovered, including the somatically related antibodies PG9 and PG16 (Davenport et al., 2011; Pancera et al., 2010; Walker et al., 2009); VRC01 and VRC07 (Wu et al., 2010; Zhou et al., 2010); CH01-CH04 (Bonsignori et al., 2011); and 3BNC117, NIH45-46, PGV04, and PGT121 and PGT128 (Diskin et al., 2013, 2011; Falkowska et al., 2012; Scheid et al., 2011; Walker et al., 2011; Wu et al., 2011). Sterilizing protection against vaginal mucosal SHIV challenge has been achieved in macaques with PGT121 (IC 50 of 0.005 mg/ml against SHIV SF162P3 ) by passive intravenous transfer of as little as 0.2 mg/kg, corresponding to a " single-digit " serum concentration of 1.8 mg/ml at the time of virus challenge (Moldt et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Highly potent broadly neutralizing human monoclonal antibodies hold promise for HIV prophylaxis and treatment. We used the SCID-hu Thy/Liv and BLT humanized mouse models to study the efficacy of these antibodies, primarily PG16, against HIV-1 clades A, B, and C. PG16 targets a conserved epitope in the V1/V2 region of gp120 common to 70–80% of HIV-1 isolates from multiple clades and has extremely potent in vitro activity against HIVJR-CSF. PG16 was highly efficacious in SCID-hu mice as a single intraperitoneal administration the day before inoculation of R5-tropic HIV directly into their Thy/Liv implants and demonstrated even greater efficacy if PG16 administration was continued after Thy/Liv implant HIV inoculation. However, PG16 as monotherapy had no activity in humanized mice with established R5-tropic HIV infection. These results provide evidence of tissue penetration of the antibodies, which could aid in their ability to prevent infection if virus crosses the mucosal barrier.
    Virology 08/2014; s 462–463:115–125. DOI:10.1016/j.virol.2014.05.036 · 3.28 Impact Factor
  • Source
    • "The trimer surface is also shielded by an extensive array of glycans. Nonetheless, sites of vulnerability on the virus do exist and four bnAb epitope clusters have been characterized: a linear region of gp41 close to the viral membrane (the membrane-proximal external region or MPER) (Huang et al., 2012; Muster et al., 1993; Zwick et al., 2001), the CD4 binding site (CD4bs) on gp120 (Burton et al., 1994; Scheid et al., 2011; Wu et al., 2011; Zhang et al., 2012; Zhou et al., 2010), an N332- dependent epitope cluster on the glycosylated face of gp120 (Kong et al., 2013; Walker et al., 2011), and a site including the N160 glycan on V2 at the trimer apex (Julien et al., 2013b; McLellan et al., 2011; Walker et al., 2009, 2011). Another suspected bnAb site on gp120 has also been partially characterized (Klein et al., 2012a; Thali et al., 1993; Xiang et al., 2002; Zhang et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151-PGT158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. Because PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer.
    Immunity 04/2014; 40(5). DOI:10.1016/j.immuni.2014.04.008 · 19.75 Impact Factor
Show more