title: Disruption of Type I Interferon Induction by HIV Infection of T Cells.
abstract: Our main objective of this study was to determine how Human Immunodeficiency Virus (HIV) avoids induction of the antiviral Type I Interferon (IFN) system. To limit viral infection, the innate immune system produces important antiviral cytokines such as the IFN. IFN set up a critical roadblock to virus infection by limiting further replication of a virus. Usually, IFN production is induced by the recognition of viral nucleic acids by innate immune receptors and subsequent downstream signaling. However, the importance of IFN in the defense against viruses has lead most pathogenic viruses to evolve strategies to inhibit host IFN induction or responses allowing for increased pathogenicity and persistence of the virus. While the adaptive immune responses to HIV infection have been extensively studied, less is known about the balance between induction and inhibition of innate immune defenses, including the antiviral IFN response, by HIV infection. Here we show that HIV infection of T cells does not induce significant IFN production even IFN I Interferon production. To explain this paradox, we screened HIV proteins and found that two HIV encoded proteins, Vpu and Nef, strongly antagonize IFN induction, with expression of these proteins leading to loss of expression of the innate immune viral RNA sensing adaptor protein, IPS-1 (IFN-β promoter stimulator-1). We hypothesize that with lower levels of IPS-1 present, infected cells are defective in mounting antiviral responses allowing HIV to replicate without the normal antiviral actions of the host IFN response. Using cell lines as well as primary human derived cells, we show that HIV targeting of IPS-1 is key to limiting IFN induction. These findings describe how HIV infection modulates IFN induction providing insight into the mechanisms by which HIV establishes infection and persistence in a host.
authors.affiliation: Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: David Jesse
authors.initials: DJ
authors.lastname: Sanchez
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Miranda
authors.affiliation: UCLA AIDS Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Marsden
authors.affiliation: Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Thomas Michael A
authors.initials: TM
authors.lastname: Dizon
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Johnny R
authors.initials: JR
authors.lastname: Bontemps
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Sergio J
authors.initials: SJ
authors.lastname: Davila
authors.affiliation: Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Del Mundo
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Thai
authors.initials: T
authors.lastname: Ha
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ashkon
authors.initials: A
authors.lastname: Senaati
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America; UCLA AIDS Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D015398:Signal Transduction; D014779:Virus Replication / Q000276:immunology*
chemical_list: D016207:Cytokines; D054298:Human Immunodeficiency Virus Proteins; D007370:Interferon Type I