Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Philipp Schommers; Henning Gruell; Morgan E Abernathy; My-Kim Tran; Adam S Dingens; Harry B Gristick; Christopher O Barnes; Till Schoofs; Maike Schlotz; Kanika Vanshylla; Christoph Kreer; Daniela Weiland; Udo Holtick; Christof Scheid; Markus M Valter; Marit J van Gils; Rogier W Sanders; Jörg J Vehreschild; Oliver A Cornely; Clara Lehmann; Gerd Fätkenheuer; Michael S Seaman; Jesse D Bloom; Pamela J Bjorkman; Florian Klein

doi:10.1016/j.cell.2020.01.010

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Cell. 2020 Feb 6;180(3):471-489.e22. doi: 10.1016/j.cell.2020.01.010. Epub 2020 Jan 30.

Authors

Philipp Schommers¹, Henning Gruell², Morgan E Abernathy³, My-Kim Tran⁴, Adam S Dingens⁵, Harry B Gristick³, Christopher O Barnes³, Till Schoofs⁴, Maike Schlotz⁴, Kanika Vanshylla⁴, Christoph Kreer⁴, Daniela Weiland⁴, Udo Holtick⁶, Christof Scheid⁶, Markus M Valter⁷, Marit J van Gils⁸, Rogier W Sanders⁹, Jörg J Vehreschild¹⁰, Oliver A Cornely¹¹, Clara Lehmann¹², Gerd Fätkenheuer¹³, Michael S Seaman¹⁴, Jesse D Bloom¹⁵, Pamela J Bjorkman³, Florian Klein¹⁶

Affiliations

¹ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
² Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁴ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁵ Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
⁷ Department of Gynecology and Obstetrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁸ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
⁹ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
¹⁰ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Medical Department 2, University Hospital of Frankfurt, 60590 Frankfurt, Germany.
¹¹ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Clinical Trials Centre Cologne (ZKS Köln), University of Cologne, 50935 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
¹² Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
¹³ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
¹⁴ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁵ Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seattle, WA 98109, USA.
¹⁶ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. Electronic address: florian.klein@uk-koeln.de.

Abstract

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V_H1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC₅₀ = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505_SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

Keywords: CD4 binding site; HIV-1; HIV-1 escape restriction; broadly neutralizing antibodies; cryogenic electron microscopy; deep mutational scanning; escape mutations; humanized mice; immunotherapy; mutational antigenic profiling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Binding Sites
Broadly Neutralizing Antibodies / immunology*
CD4 Antigens / metabolism
CHO Cells
Cohort Studies
Cricetulus
Epitopes / immunology
Female
HEK293 Cells
HIV Antibodies / immunology*
HIV Infections / immunology*
HIV Infections / prevention & control
HIV Infections / virology
HIV-1 / immunology*
Heterografts
Humans
Male
Mice
Mice, Inbred NOD
Middle Aged
Mutation
Protein Binding / immunology
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

Antibodies, Monoclonal
Broadly Neutralizing Antibodies
CD4 Antigens
Epitopes
HIV Antibodies
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding