title: Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity.
abstract: Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins.
  
  
  OBJECTIVE
  HIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Veillette
authors.forename: Anik
authors.initials: A
authors.lastname: Désormeaux
authors.forename: Halima
authors.initials: H
authors.lastname: Medjahed
authors.forename: Nour-Elhouda
authors.initials: NE
authors.lastname: Gharsallah
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coutu
authors.forename: Joshua
authors.initials: J
authors.lastname: Baalwa
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Guan
authors.forename: George
authors.initials: G
authors.lastname: Lewis
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D015483:HIV Antibodies / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D015483:HIV Antibodies; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins