title: A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo.
abstract: The CD4 binding site (CD4bs) on the envelope glycoprotein is a major site of vulnerability that is conserved among different HIV-1 isolates. Many broadly neutralizing antibodies (bNAbs) to the CD4bs belong to the VRC01 class, sharing highly restricted origins, recognition mechanisms and viral escape pathways. We sought to isolate new anti-CD4bs bNAbs with different origins and mechanisms of action. Using a gp120 2CC core as bait, we isolated antibodies encoded by IGVH3-21 and IGVL3-1 genes with long CDRH3s that depend on the presence of the N-linked glycan at position-276 for activity. This binding mode is similar to the previously identified antibody HJ16, however the new antibodies identified herein are more potent and broad. The most potent variant, 179NC75, had a geometric mean IC80 value of 0.42 μg/ml against 120 Tier-2 HIV-1 pseudoviruses in the TZM.bl assay. Although this group of CD4bs glycan-dependent antibodies can be broadly and potently neutralizing in vitro, their in vivo activity has not been tested to date. Here, we report that 179NC75 is highly active when administered to HIV-1-infected humanized mice, where it selects for escape variants that lack a glycan site at position-276. The same glycan was absent from the virus isolated from the 179NC75 donor, implying that the antibody also exerts selection pressure in humans.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Natalia T
authors.initials: NT
authors.lastname: Freund
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Horwitz
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Lilian
authors.initials: L
authors.lastname: Nogueira
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Sievers
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Louise
authors.initials: L
authors.lastname: Scharf
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Scheid
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Cassie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Klara
authors.initials: K
authors.lastname: Velinzon
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Ariel
authors.initials: A
authors.lastname: Goldenthal
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, New York, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D011134:Polysaccharides / Q000737:chemistry*
chemical_list: D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D011134:Polysaccharides