Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins
Jonathan Richard,
Beatriz Pacheco,
Neelakshi Gohain,
Maxime Veillette,
Shilei Ding,
Nirmin Alsahafi,
William D. Tolbert,
Jérémie Prévost,
Jean-Philippe Chapleau,
Mathieu Coutu,
Manxue Jia,
Nathalie Brassard,
Jongwoo Park,
Joel R. Courter,
Bruno Melillo,
Loïc Martin,
Cécile Tremblay,
Beatrice H. Hahn,
Daniel E. Kaufmann,
Xueling Wu,
Amos B. Smith III,
Joseph Sodroski,
Marzena Pazgier,
Andrés Finzi
Affiliations
Jonathan Richard
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Beatriz Pacheco
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Neelakshi Gohain
Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
Maxime Veillette
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Shilei Ding
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Nirmin Alsahafi
Centre de Recherche du CHUM, QC H2X 0A9, Canada
William D. Tolbert
Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
Jérémie Prévost
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Jean-Philippe Chapleau
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Mathieu Coutu
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Manxue Jia
Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY, USA
Nathalie Brassard
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Jongwoo Park
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Joel R. Courter
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Bruno Melillo
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Loïc Martin
CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif sur Yvette, France
Cécile Tremblay
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Beatrice H. Hahn
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA
Daniel E. Kaufmann
Centre de Recherche du CHUM, QC H2X 0A9, Canada
Xueling Wu
Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY, USA
Amos B. Smith III
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Joseph Sodroski
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA
Marzena Pazgier
Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to “push” Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. Here we test whether CD4mc also expose epitopes recognized by anti-cluster A monoclonal antibodies such as A32, thought to be responsible for the majority of ADCC activity present in HIV+ sera and linked to decreased HIV-1 transmission in the RV144 trial. We made the surprising observation that CD4mc are unable to enhance recognition of HIV-1-infected cells by this family of antibodies in the absence of antibodies such as 17b, which binds a highly conserved CD4-induced epitope overlapping the co-receptor binding site (CoRBS). Our results indicate that CD4mc initially open the trimeric Env enough to allow the binding of CoRBS antibodies but not anti-cluster A antibodies. CoRBS antibody binding further opens the trimeric Env, allowing anti-cluster A antibody interaction and sensitization of infected cells to ADCC. Therefore, ADCC responses mediated by cluster A antibodies in HIV-positive sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells. The understanding of the conformational changes required to expose these vulnerable Env epitopes might be important in the design of new strategies aimed at fighting HIV-1.
