title: Link between primate lentiviral coreceptor usage and Nef function.
abstract: Simian immunodeficiency virus (SIVsmm) infection of sooty mangabeys (Cercocebus atys) is characterized by stable CD4(+) T cell counts despite high plasma levels of CCR5-tropic viruses. However, in rare instances, SIVsmm acquires CXCR4 coreceptor tropism and causes severe CD4(+) T cell depletion, albeit without clinical signs of immunodeficiency. Here, we show that CXCR4-tropic SIVsmm strains lost their ability to downmodulate TCR-CD3 by evolving unusual Nef mutations that initially reduced (I132V) and subsequently disrupted (I123L and L146F) interaction with the CD3 ζ chain. This coevolution of Env and Nef function suggests that CD3 downmodulation is advantageous for viral replication in activated CCR5(+) memory T cells, but not in resting naive CXCR4(+) T cells that have not yet undergone TCR-CD3-mediated stimulation. This may explain why HIV-1, which generally lacks the CD3 downmodulation function, commonly switches to CXCR4 usage, whereas this is extremely rare for SIV strains that have retained this Nef activity.
authors.affiliation: Institute of Molecular Virology, University of Ulm, 89069 Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmökel
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Molecular Virology, University of Ulm, 89069 Ulm, Germany.
authors.forename: Asma
authors.initials: A
authors.lastname: Shabir
authors.affiliation: Institute of Molecular Virology, University of Ulm, 89069 Ulm, Germany.
authors.forename: Hangxing
authors.initials: H
authors.lastname: Yu
authors.affiliation: Center of Advanced European Studies and Research (CAESAR), Physical Biochemistry Group, 53175 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Sodora
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Institute of Molecular Virology, University of Ulm, 89069 Ulm, Germany. Electronic address: frank.kirchhoff@uni-ulm.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017252:CD3 Complex / Q000096:biosynthesis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016664:Cercocebus / Q000821:virology; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015498:HIV-2 / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D015686:Gene Products, env; D015693:Gene Products, nef; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019713:Receptors, CCR5; D019718:Receptors, CXCR4