Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike.
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.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Louise
L
Scharf
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Johannes F
JF
Scheid
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Jeong Hyun
JH
Lee
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Anthony P
AP
West
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Courtney
C
Chen
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Han
H
Gao
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Priyanthi N P
PN
Gnanapragasam
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
René
R
Mares
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Michael S
MS
Seaman
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Andrew B
AB
Ward
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
Michel C
MC
Nussenzweig
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: bjorkman@caltech.edu.
Pamela J
PJ
Bjorkman
D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D057134:Antibodies, Neutralizing; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; D054299:env Gene Products, Human Immunodeficiency Virus