title: Nef Proteins from HIV-1 Elite Controllers Are Inefficient at Preventing Antibody-Dependent Cellular Cytotoxicity.
abstract: Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). Elimination of HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) requires the presence of envelope glycoproteins (Env) in the CD4-bound conformation, raising the possibility that accumulating CD4 at the surface of virus-infected cells in EC could interact with Env and thereby sensitize these cells to ADCC. We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC. Altogether, our results suggest that enhanced susceptibility of HIV-1-infected cells to ADCC may contribute to the EC phenotype.
  
  
  OBJECTIVE
  Nef clones derived from elite controllers (EC) have been shown to be attenuated for CD4 downregulation; how this contributes to the nonprogressor phenotype of these infected individuals remains uncertain. Increasing evidence supports a role for HIV-specific antibody-dependent cellular cytotoxicity (ADCC) in controlling viral infection and replication. Here, we show that residual CD4 left at the surface of cells expressing Nef proteins isolated from ECs are sufficient to allow Env-CD4 interaction, leading to increased exposure of Env CD4-induced epitopes and increased susceptibility of infected cells to ADCC. Our results suggest that ADCC might be an active immune mechanism in EC that helps to maintain durable suppression of viral replication and low plasma viremia level in this rare subset of infected individuals. Therefore, targeting Nef's ability to downregulate CD4 could render HIV-1-infected cells susceptible to ADCC and thus have therapeutic utility.
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Nirmin
authors.initials: N
authors.lastname: Alsahafi
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Tristan
authors.initials: T
authors.lastname: Markle
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brassard
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.affiliation: Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA Department of Medicine, Université de Montréal, Montreal, Quebec, Canada Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, California, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada andres.finzi@umontreal.ca.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000821:virology; D015483:HIV Antibodies / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D054299:env Gene Products, Human Immunodeficiency Virus / Q000032:analysis*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1