title: Short Communication: Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates.
abstract: Recent studies have linked antibody Fc-mediated effector functions with control of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus infections. Interestingly, the presence of antibodies with potent antibody-dependent cellular cytotoxicity (ADCC) activity in RV144 vaccine trial participants correlated inversely with HIV-1 acquisition risk. These antibodies were recently found to recognize epitopes on the HIV-1 envelope (Env) glycoprotein exposed upon Env-CD4 binding. Accordingly, small-molecule CD4 mimetics (CD4mc) that induce Env to sample the CD4-bound conformation were shown to sensitize HIV-1-infected cells to ADCC mediated by sera from HIV-1-infected individuals. However, it remains unknown whether antibodies elicited through immunization can also mediate CD4mc-induced ADCC. In this study, we tested the capacity of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from Env-vaccinated nonhuman primates using a FACS-based ADCC assay. In parallel, we evaluated the ability of CD4mc to sensitize HIV-1 viral particles to neutralization by sera from these immunized animals. We found that the vaccine-induced antibodies were able to mediate ADCC and viral neutralization in the presence, but not the absence, of CD4mc. Thus, CD4mc are capable of sensitizing HIV-1-infected cells to ADCC and infectious viral particles to neutralization by easy-to-elicit antibodies that are otherwise unable to mediate these activities.
authors.affiliation: 1 Centre de Recherche du CHUM , Montreal, Canada .|2 Department of Microbiology, Infectiology and Immunology, Université de Montréal , Montreal, Canada .
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: 1 Centre de Recherche du CHUM , Montreal, Canada .|3 McGill University , Montreal, Canada .
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Verly
authors.affiliation: 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, Massachusetts.|5 Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts.
authors.forename: Amy
authors.initials: A
authors.lastname: Princiotto
authors.affiliation: 6 Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Bruno
authors.initials: B
authors.lastname: Melillo
authors.affiliation: 7 Duke Human Vaccine Institute, Duke University Medical Center , Durham, North Carolina.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Moody
authors.affiliation: 7 Duke Human Vaccine Institute, Duke University Medical Center , Durham, North Carolina.
authors.forename: Todd
authors.initials: T
authors.lastname: Bradley
authors.affiliation: 7 Duke Human Vaccine Institute, Duke University Medical Center , Durham, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Easterhoff
authors.affiliation: 1 Centre de Recherche du CHUM , Montreal, Canada .|2 Department of Microbiology, Infectiology and Immunology, Université de Montréal , Montreal, Canada .
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
authors.affiliation: 8 Department of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, Massachusetts.|5 Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.affiliation: 6 Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: 7 Duke Human Vaccine Institute, Duke University Medical Center , Durham, North Carolina.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, Massachusetts.|5 Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts.|9 Department of Immunology and Infectious Diseases, Harvard School of Public Health , Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.affiliation: 1 Centre de Recherche du CHUM , Montreal, Canada .|2 Department of Microbiology, Infectiology and Immunology, Université de Montréal , Montreal, Canada .|3 McGill University , Montreal, Canada .
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D032701:Biomimetics; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D005434:Flow Cytometry; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D008253:Macaca mulatta
chemical_list: D015704:CD4 Antigens; D015483:HIV Antibodies
keywords: ADCC; CD4 mimetics; Env; HIV-1; neutralization; nonneutralizing antibodies