title: Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface.
abstract: 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 (IC50) <50 μg ml(-1). The median IC50 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.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jinghe
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Byong H
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.affiliation: 1] The Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California 92121, USA.
authors.forename: Tommy
authors.initials: T
authors.lastname: Tong
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Imamichi
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Druz
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Laub
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands.
authors.forename: Kwinten
authors.initials: K
authors.lastname: Sliepen
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands.
authors.forename: Marit J
authors.initials: MJ
authors.lastname: van Gils
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands.
authors.forename: Alba Torrents
authors.initials: AT
authors.lastname: de la Peña
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Derking
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Klasse
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Munir
authors.initials: M
authors.lastname: Alam
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pugach
authors.affiliation: Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: 1] The Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.affiliation: 1] Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands [2] Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: San Diego Biomedical Research Institute, San Diego, California 92121, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
authors.affiliation: 1] The Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000915:Antibody Affinity; D000918:Antibody Specificity; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000821:virology; D017124:Conserved Sequence; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000648:ultrastructure; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007140:Immunoglobulin Fab Fragments; D019713:Receptors, CCR5