ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication. (April 2018)

• Record Type: Journal Article
• Authors: Radetskyy, Roman; Daher, Aïcha; Gatignol, Anne
• Is Part Of: Cytokine & growth factor reviews. Volume 40(2018)
• Page Start: 48
• Page End: 58
• Publication Date: 2018-04
• Subjects: ADAR1 adenosine deaminase acting on RNA 1 -- AGS Aicardi-Goutières syndrome -- APOBEC3 apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 -- ds double-stranded -- dsRBD dsRNA binding domains -- eIF2α translation initiation factor2 -- HIV-1 human immunodeficiency virus-1 -- HLA human leukocyte antigens -- IFITM interferon-induced transmembrane -- IFITs IFN-induced proteins with tetratricopeptide repeats -- IFN-I type I IFNs -- IFNAR1 IFN-α receptor 1 -- IFNs Interferons -- IP-10 IFNγ inducible protein 10 -- IRF IFN regulatory factor -- ISGs interferon stimulated genes -- IV influenza virus -- JAK/STAT Janus kinases/signal transducers and activators of transcription -- LCMV lymphocytic choriomeningitis -- MAVS mitochondrial antiviral-signaling protein -- MDA-5 melanoma-differentiation-associated 5 -- MHCs major histocompatibility complexes -- MV measles virus -- Mx myxovirus resistance -- NK natural killer -- NF-κB nuclear factor kappa B -- OAS oligoadenylate synthetase -- PACT PKR activator -- PAMPs pathogen-associated molecular patterns -- PBMCs peripheral blood mononuclear cells -- PKR RNA activated protein kinase R -- RLI RNAse L inhibitor -- RVFV Rift valley fever virus -- SAMHD1 sterile alpha motif and HD-domain containing protein 1 -- SIV simian immunodeficiency virus -- SLFN Schlafen -- ss single-stranded -- TAR trans-activation response -- TLRs toll-like receptors -- TRAIL tumor necrosis factor-related apoptosis-inducing ligand -- TRIM tripartite motif -- TRBP TAR RNA binding protein -- Tsg101 tumor susceptibility gene 101 -- Vif virion infectivity factor -- Vpu viral protein U -- Vpx viral protein X -- VSV vesicular stomatitis virus -- VV vaccinia virus -- WNV West Nile virus; Interferon -- PKR -- ADAR1 -- HIV -- Interferon stimulated genes; Cytokines -- Periodicals; 571.84
• DOI: 10.1016/j.cytogfr.2018.03.007
• Languages: English
• ISSNs: 1359-6101

Abstract

Graphical abstract: Regulation of antiviral PKR and proviral functions of ADAR1 during HIV-1 infection. Upon HIV-1 entry in the cell, viral RNA is released and edited by ADAR1, marking it as self and thus preventing its detection by the RIG-I pathway (1). This event prevents the induction of IFNs and subsequent stimulation of neighboring cells to produce ISGs. In virus producing cells, ADAR1 edits viral RNA leading to a generation of virions with increased infectivity and replication rates (2). ADAR1 also contributes to viral pathogenesis by inhibiting PKR (3). In addition to ADAR1, cellular factors TRBP and PACT prevent PKR activation during HIV-1 replication (4). Viral factor Tat also prevents detection of viral RNA by PKR and inhibits its activation (5). Highlights: Interferon response induced during HIV-1 infection exhibits antiviral and deleterious effects. Interferon stimulated genes are produced during HIV-1 infection and have both antiviral and proviral effects. PKR has antiviral effects, is activated during acute HIV-1 infection and is deactivated during chronic infection. ADAR1 enhances HIV-1 replication by inhibiting RNA sensing, by RNA editing and by preventing PKR activation. Abstract: The induction of hundreds of Interferon Stimulated Genes (ISGs) subsequent to virus infection generates an antiviral state that functions to restrict virus growth at multiple steps of their replication cycles. In the context of Human Immunodeficiency Virus-1 (HIV-1), ISGs also possess antiviral functions, but some ISGs show proapoptotic or proviral activity. One of the most studied ISGs, the RNA activated Protein Kinase (PKR), shuts down the viral protein synthesis upon activation. HIV-1 has evolved to evade its inhibition by PKR through viral and cellular mechanisms. One of the cellular mechanisms is the induction of another ISG, the Adenosine Deaminase acting on RNA 1 (ADAR1). ADAR1 promotes viral replication by acting as an RNA sensing inhibitor, by editing viral RNA and by inhibiting PKR. This review challenges the orthodox dogma of ISGs as antiviral proteins, by demonstrating that two ISGs have opposing and clashing effects on viral replication.