CD4 mimetics sensitize HIV-1-infected cells to ADCC.
HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.
Centre de Recherche du Centre hospitalier de l'Université de Montréal and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada H2X 0A9;
Jonathan
J
Richard
Centre de Recherche du Centre hospitalier de l'Université de Montréal and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada H2X 0A9;
Maxime
M
Veillette
Centre de Recherche du Centre hospitalier de l'Université de Montréal and.
Nathalie
N
Brassard
Department of Medicine and Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076;
Shilpa S
SS
Iyer
Centre de Recherche du Centre hospitalier de l'Université de Montréal and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada H2X 0A9;
Michel
M
Roger
Commissariat à l'énergie atomique, Institut de biologie et de technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif sur Yvette, France;
Loïc
L
Martin
Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201;
Marzena
M
Pazgier
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218-2685;
Arne
A
Schön
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218-2685;
Ernesto
E
Freire
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada H3A 2B4;
Jean-Pierre
JP
Routy
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323;
Amos B
AB
Smith
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323;
Jongwoo
J
Park
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323;
David M
DM
Jones
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323;
Joel R
JR
Courter
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323;
Bruno N
BN
Melillo
Centre de Recherche du Centre hospitalier de l'Université de Montréal and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139-3583; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada H2X 0A9; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037;
Daniel E
DE
Kaufmann
Department of Medicine and Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076; andres.finzi@umontreal.ca bhahn@upenn.edu.
Beatrice H
BH
Hahn
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710;
Sallie R
SR
Permar
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710;
Barton F
BF
Haynes
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, MA 02115; and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115.
Navid
N
Madani
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, MA 02115; and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115.
Joseph G
JG
Sodroski
Centre de Recherche du Centre hospitalier de l'Université de Montréal and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada H2X 0A9; Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada H3A 2B4; andres.finzi@umontreal.ca bhahn@upenn.edu.
Andrés
A
Finzi
D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D057809:HEK293 Cells; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D015704:CD4 Antigens; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus
ADCC; CD4 mimetics; HIV-1; envelope glycoproteins; gp120