دورية أكاديمية
HIV-1 Accessory Protein Vpr Interacts with REAF/RPRD2 To Mitigate Its Antiviral Activity.
العنوان: | HIV-1 Accessory Protein Vpr Interacts with REAF/RPRD2 To Mitigate Its Antiviral Activity. |
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المؤلفون: | Gibbons JM; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Marno KM; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Pike R; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Lee WJ; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Jones CE; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Ogunkolade BW; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Pardieu C; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Bryan A; Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom., Fu RM; Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom., Warnes G; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom., Rowley PA; Department of Biological Sciences, University of Idaho, Moscow, Idaho, USA., Sloan RD; Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.; ZJU-UoE Institute, Zhejiang University, Jiaxing, Zhejiang, People's Republic of China., McKnight Á; The Blizard Institute, Queen Mary University of London School of Medicine and Dentistry, London, United Kingdom a.mcknight@qmul.ac.uk. |
المصدر: | Journal of virology [J Virol] 2020 Jan 31; Vol. 94 (4). Date of Electronic Publication: 2020 Jan 31 (Print Publication: 2020). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Washington Dc : American Society For Microbiology Original Publication: Baltimore, American Society for Microbiology. |
مواضيع طبية MeSH: | Antiviral Agents/*metabolism , HIV-1/*metabolism , Virus Replication/*physiology , vpr Gene Products, Human Immunodeficiency Virus/*physiology, Carrier Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Gene Products, vpr/metabolism ; Gene Products, vpr/physiology ; HEK293 Cells ; HIV Infections/virology ; HIV-1/physiology ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Macrophages/metabolism ; Primary Cell Culture ; Ubiquitin-Protein Ligases/metabolism ; Virion/metabolism ; vpr Gene Products, Human Immunodeficiency Virus/metabolism |
مستخلص: | The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and, to a lesser extent, cycling T cells. Virion-packaged Vpr is released in target cells shortly after entry, suggesting it is required in the early phase of infection. Previously, we described REAF (RNA-associated early-stage antiviral factor; RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without an intact vpr gene is more highly restricted by REAF and, using delivery by virus-like particles (VLPs), that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells, and we detected, by coimmunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts quickly during the early phase of replication and induces the degradation of REAF within 30 min of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localization and interaction with cullin 4A-DBB1 (DCAF1) E3 ubiquitin ligase are required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, that impedes HIV infection in macrophages. IMPORTANCE For at least 30 years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1 in vivo A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages or to explain why Vpr is carried in the virus particle. Here, we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one that inhibits virus replication during reverse transcription. REAF is degraded by Vpr within 30 min of virus entry in a manner dependent on the nuclear localization of Vpr and its interaction with the cell's protein degradation machinery. (Copyright © 2020 American Society for Microbiology.) |
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معلومات مُعتمدة: | United Kingdom Wellcome Trust; G117/547 United Kingdom MRC_ Medical Research Council; 101604/Z/13/Z United Kingdom WT_ Wellcome Trust |
فهرسة مساهمة: | Keywords: HIV; REAF; RPRD2; Vpr; innate immunity; restriction factors |
المشرفين على المادة: | 0 (Antiviral Agents) 0 (Carrier Proteins) 0 (DNA-Binding Proteins) 0 (Gene Products, vpr) 0 (vpr Gene Products, Human Immunodeficiency Virus) 0 (vpr protein, Human immunodeficiency virus 1) EC 2.3.2.27 (Ubiquitin-Protein Ligases) |
تواريخ الأحداث: | Date Created: 20191129 Date Completed: 20200821 Latest Revision: 20220129 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC6997760 |
DOI: | 10.1128/JVI.01591-19 |
PMID: | 31776272 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1098-5514 |
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DOI: | 10.1128/JVI.01591-19 |