Journal Article

Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface

Migueles, Stephen A., Connors, Mark, Kwong, Peter D., Pancera, Marie, Huang, Jinghe, Kang, Byong H., Feng, Yu, Lee, Jeong Hyun, Sliepen, Kwinten, Imamichi, Hiromi, Druz, Aliaksandr, van Gils, Marit J., Georgiev, Ivelin S., Sanders, Rogier W., Binley, James M., Mascola, John R., Wyatt, Richard T., Chuang, Gwo-Yu, Doria-Rose, Nicole A., Tong, Tommy, Laub, Leo, Klasse, Per-Johan, Alam, Munir, de la Peña, Alba Torrents, Derking, Ronald, Bailer, Robert T., Pugach, Pavel, Ward, Andrew B., Haynes, Barton F.

2014

Overview

Molecular and structural characterization is reported for a new broad and potent monoclonal antibody against HIV that binds to an epitope bridging the gp41 and gp120 subunits — the antibody affects a step in virus entry after binding to CD4 and before engagement of CCR5. Novel vaccine target on HIV-1 This paper describes a broadly neutralizing HIV-specific monoclonal antibody that binds with high potency to a novel HIV-1 envelope glycoprotein epitope. Molecular and structural characterization of the new antibody, named 35O22, show that it is specific for a new site of vulnerability made up of amino acids and glycans bridging the gp41 and gp120 subunits. The antibody affects a step in virus entry after binding to CD4 and before engagement of CCR5. Serologic analysis indicates that antibodies to this newly recognized site of vulnerability are commonly elicited by natural infection, raising the prospect that in may be a promising potential vaccine target. The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1 ). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC 50 ) <50 μg ml −1 . The median IC 50 of neutralized viruses was 0.033 μg ml −1 , among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 101/28 / 13/1 / 13/109 / 13/31 / 13/44 / 14/1 / 14/34 / 14/63 / 42/109 / 42/70 / 631/250/2152/2153/1291 / 631/250/255/1901 / 631/535/1258 / 631/535/1266 / 82/47 / AIDS Vaccines - chemistry / AIDS Vaccines - immunology / Amino acids / Antibodies / Antibodies, Monoclonal - chemistry / Antibodies, Monoclonal - genetics / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - genetics / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - pharmacology / Antibody Affinity / Antibody Specificity / Antigenic determinants / Binding sites / Care and treatment / CD4 Antigens - metabolism / Cell Line / Cell Membrane - virology / Conserved Sequence / Epitope Mapping / Epitopes - chemistry / Epitopes - immunology / Genetic aspects / HIV / HIV Antibodies - chemistry / HIV Antibodies - genetics / HIV Antibodies - immunology / HIV Antibodies - pharmacology / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - immunology / HIV Envelope Protein gp41 - chemistry / HIV Envelope Protein gp41 - immunology / HIV infection / HIV-1 - drug effects / HIV-1 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunoglobulin Fab Fragments - chemistry / Immunoglobulin Fab Fragments - genetics / Immunoglobulin Fab Fragments - immunology / Immunoglobulin Fab Fragments - ultrastructure / Inhibitory Concentration 50 / letter / Leukocytes, Mononuclear / Models, Molecular / Molecular Sequence Data / multidisciplinary / Mutation / Neutralization / Physiological aspects / Prophylaxis / Receptors, CCR5 - metabolism / Science / Vaccines / Viral antibodies / Virus Internalization - drug effects