title: Adenosine deaminase acting on RNA-1 (ADAR1) inhibits HIV-1 replication in human alveolar macrophages.
abstract: While exploring the effects of aerosol IFN-γ treatment in HIV-1/tuberculosis co-infected patients, we observed A to G mutations in HIV-1 envelope sequences derived from bronchoalveolar lavage (BAL) of aerosol IFN-γ-treated patients and induction of adenosine deaminase acting on RNA 1 (ADAR1) in the BAL cells. IFN-γ induced ADAR1 expression in monocyte-derived macrophages (MDM) but not T cells. ADAR1 siRNA knockdown induced HIV-1 expression in BAL cells of four HIV-1 infected patients on antiretroviral therapy. Similar results were obtained in MDM that were HIV-1 infected in vitro. Over-expression of ADAR1 in transformed macrophages inhibited HIV-1 viral replication but not viral transcription measured by nuclear run-on, suggesting that ADAR1 acts post-transcriptionally. The A to G hyper-mutation pattern observed in ADAR1 over-expressing cells in vitro was similar to that found in the lungs of HIV-1 infected patients treated with aerosol IFN-γ suggesting the model accurately represented alveolar macrophages. Together, these results indicate that ADAR1 restricts HIV-1 replication post-transcriptionally in macrophages harboring HIV-1 provirus. ADAR1 may therefore contribute to viral latency in macrophages.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Departments of Medicine and Environmental Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiden
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Departments of Medicine and Environmental Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Satomi
authors.initials: S
authors.lastname: Hoshino
authors.affiliation: Department of Basic Sciences and Craniofacial Biology, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Levy
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America; VA New York Harbor Healthcare System-Manhattan Campus, New York, New York, United States of America.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Basic Sciences and Craniofacial Biology, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Burke
authors.affiliation: Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America; VA New York Harbor Healthcare System-Manhattan Campus, New York, New York, United States of America.
authors.forename: Catarina E
authors.initials: CE
authors.lastname: Hioe
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Borkowsky
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Departments of Medicine and Environmental Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Departments of Medicine and Environmental Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshino
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D001992:Bronchoalveolar Lavage Fluid; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000145:classification / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000627:therapeutic use; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000821:virology*; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism; D056189:Viral Tropism; D014779:Virus Replication
chemical_list: D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D007371:Interferon-gamma; C000595356:ADAR protein, human; D000243:Adenosine Deaminase