title: Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.
abstract: Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.
authors.affiliation: 1] Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas 77555, USA.
authors.forename: Netanya G
authors.initials: NG
authors.lastname: Sandler
authors.affiliation: 1] Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA [2] Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Richard T R
authors.initials: RT
authors.lastname: Zhu
authors.affiliation: 1] Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA [2] Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Tharp
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Boritz
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Levin
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sathi
authors.initials: S
authors.lastname: Wijeyesinghe
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Krystelle Nganou
authors.initials: KN
authors.lastname: Makamdop
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.
authors.forename: Gregory Q
authors.initials: GQ
authors.lastname: del Prete
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J Katherina
authors.initials: JK
authors.lastname: Timmer
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Reiss
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ganit
authors.initials: G
authors.lastname: Yarden
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Darko
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Contijoch
authors.affiliation: Laboratory of Animal Medicine, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Todd
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Nason
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Norgren
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Laboratory of Animal Medicine, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Pharmacology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Langer
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
authors.affiliation: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008253:Macaca mulatta / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha