title: Long-term HIV-1 infection induces an antiviral state in primary macrophages.
abstract: HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10. Infected macrophages showed increased expression of p21 and subsequent inactivation of cyclin-CDK2 activity leading to a hypo-phosphorylated active retinoblastoma protein (pRb) and deactivation of E2F1-dependent transcription and CDK1 downregulation. Additionally, HIV-1 infection limited deoxynucleotide pool by downregulation of the ribonucleotide reductase subunit R2 (RNR2) and reactivation of the HIV-1 restriction factor SAMHD1 together with increased cell death. In conclusion, HIV-1 induced an innate antiviral mechanism associated to IFN-I production, interferon stimulated gene activation, and p21-mediated G2/M arrest leading to elevated levels of cell death in monocyte derived macrophages. Upregulation of MDA5 and Rig-I may serve as targets for the development of antiviral strategies leading to the elimination of HIV-1 infected cells.
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Maria
authors: M
authors: Pujantell
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Roger
authors: R
authors: Badia
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Cristina
authors: C
authors: Ramirez
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Teresa
authors: T
authors: Puig
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Bonaventura
authors: B
authors: Clotet
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Ester
authors: E
authors: Ballana
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. Electronic address: jaeste@irsicaixa.es.
authors: José A
authors: JA
authors: Esté
authors: AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors: Eva
authors: E
authors: Riveira-Muñoz
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008262:Macrophage Activation / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D016173:Macrophage Colony-Stimulating Factor; D018844:Cyclin-Dependent Kinases
keywords: Cell cycle; Cell death; ISG; Interferon; Macrophage; p21