Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity
Annemarie Laumaea,
Lorie Marchitto,
Shilei Ding,
Guillaume Beaudoin-Bussières,
Jérémie Prévost,
Romain Gasser,
Debashree Chatterjee,
Gabrielle Gendron-Lepage,
Halima Medjahed,
Hung-Ching Chen,
Amos B. Smith, III,
Haitao Ding,
John C. Kappes,
Beatrice H. Hahn,
Frank Kirchhoff,
Jonathan Richard,
Ralf Duerr,
Andrés Finzi
Affiliations
Annemarie Laumaea
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Corresponding author
Lorie Marchitto
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada
Shilei Ding
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada
Guillaume Beaudoin-Bussières
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada
Jérémie Prévost
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada
Romain Gasser
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada
Debashree Chatterjee
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada
Gabrielle Gendron-Lepage
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada
Halima Medjahed
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada
Hung-Ching Chen
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Amos B. Smith, III
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Haitao Ding
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
John C. Kappes
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, AL 35233, USA
Beatrice H. Hahn
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA
Frank Kirchhoff
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
Jonathan Richard
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada
Ralf Duerr
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
Andrés Finzi
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Corresponding author
Summary: HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more “open” conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4+ T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4+ T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC.
