title: Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells.
abstract: We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Hansen
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Ransom
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Hesselberth
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Nina N
authors.initials: NN
authors.lastname: Hosmane
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.|Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, United States.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Capoferri
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bruner
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Pollack
authors.affiliation: W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Michael Bradley
authors.initials: MB
authors.lastname: Drummond
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Siliciano
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, United States.|Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Siliciano
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: James T
authors.identifier: 0000-0003-2572-7807
authors.initials: JT
authors.lastname: Stivers
mesh_terms: D002478:Cells, Cultured; D004260:DNA Repair; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D009154:Mutation; D048348:Reverse Transcription; D014498:Uracil / Q000378:metabolism*; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; D014498:Uracil
keywords: U/A DNA base pairs in HIV; human; immunology; infectious disease; latency in macrophages; microbiology; uracil base excision repair; viral restriction