title: Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease.
abstract: BACKGROUND
  Tetrapyrrole substrates and products of heme oxygenase are potent inhibitors of hepatitis C virus (HCV) replication. It is not clear whether this occurs through primary induction of type I interferon (IFN), inhibition of viral NS3/4A protease, or a combination of these mechanisms. We studied the antiviral actions of tetrapyrroles and their potential influence on type I IFN induction.
  
  
  METHODS
  The effects of tetrapyrrole on NS3/4A protease activity and type I IFN induction were assessed in HCV-permissive cells, replicons, or human embryonic kidney (HEK) 293 cells transfected with NS3/4A protease. Activation of innate immune signaling was determined after transfection of double-strand surrogate nucleic acid antigens or infection with defined sequence HCV cell culture (HCVcc) RNA.
  
  
  RESULTS
  Tetrapyrroles failed to directly induce IFN expression at concentrations that inhibited HCV replication and NS3/4A protease activity. However, they potently restored IFN induction after attenuation with NS3/4A protease, a process accompanied by preservation of the adapter protein, mitochondrial antiviral signaling protein, nuclear localization of IFN regulatory factor 3, and augmentation of IFN-stimulated gene products.
  
  
  CONCLUSIONS
  Tetrapyrroles do not directly induce IFN, but they dramatically restore type I IFN signaling pathway after attenuation with NS3/4A protease. They show immunomodulatory as well as antiprotease activity and may be useful for treatment of HCV infection.
authors.affiliation: Department of Internal Medicine and Research Service, Veterans Affairs Medical Center.
authors.forename: Zhaowen
authors.initials: Z
authors.lastname: Zhu
authors.forename: M Meleah
authors.initials: MM
authors.lastname: Mathahs
authors.forename: Warren N
authors.initials: WN
authors.lastname: Schmidt
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006418:Heme / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D045725:Tetrapyrroles / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D006418:Heme; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D045725:Tetrapyrroles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus
keywords: HCV protease inhibitors; heme metalloporphyrins; hepatitis C virus; type I interferon
references.citation: Gastroenterology. 2008 Nov;135(5):1710-1718.e2
references.pmid: 18725224
references.citation: J Virol. 1994 Aug;68(8):5045-55
references.pmid: 8035505
references.citation: Science. 1999 Jul 2;285(5424):110-3
references.pmid: 10390360
references.citation: World J Gastroenterol. 2010 Jul 7;16(25):3112-9
references.pmid: 20593496
references.citation: Front Pharmacol. 2012 Oct 04;3:129
references.pmid: 23060790
references.citation: J Virol. 2002 Dec;76(24):13001-14
references.pmid: 12438626
references.citation: J Virol. 1995 Jul;69(7):4373-80
references.pmid: 7769699
references.citation: Cell. 2006 Feb 24;124(4):783-801
references.pmid: 16497588
references.citation: Trends Pharmacol Sci. 2007 May;28(5):200-5
references.pmid: 17416426
references.citation: J Biol Chem. 2005 Mar 11;280(10):9049-57
references.pmid: 15637067
references.citation: J Immunol. 2006 Apr 1;176(7):4252-7
references.pmid: 16547262
references.citation: Gastroenterology. 2007 Oct;133(4):1166-74
references.pmid: 17919492
references.citation: J Biol Chem. 2009 Dec 25;284(52):36302-36311
references.pmid: 19850937
references.citation: Arch Biochem Biophys. 2007 Jun 15;462(2):254-65
references.pmid: 17467654
references.citation: Hepatology. 2010 Feb;51(2):398-404
references.pmid: 20044809
references.citation: Proc Natl Acad Sci U S A. 2007 May 22;104(21):9035-40
references.pmid: 17517627
references.citation: J Biol Chem. 1999 Jan 15;274(3):1549-56
references.pmid: 9880532
references.citation: Clin Infect Dis. 2009 Feb 1;48(3):313-20
references.pmid: 19123867
references.citation: Cell. 2005 Sep 9;122(5):669-82
references.pmid: 16125763
references.citation: Hepatology. 2008 Nov;48(5):1430-9
references.pmid: 18972446
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7
references.pmid: 15710891
references.citation: Hepatology. 2010 Dec;52(6):1897-905
references.pmid: 21105106
references.citation: Gut. 2006 Sep;55(9):1350-9
references.pmid: 16905701
references.citation: J Hepatol. 2007 Jul;47(1):12-22
references.pmid: 17399844
references.citation: Arch Med Res. 2007 Aug;38(6):678-90
references.pmid: 17613359
references.citation: Int J Cancer. 2007 Dec 1;121(11):2567-74
references.pmid: 17683071
references.citation: Trends Pharmacol Sci. 2009 Mar;30(3):129-37
references.pmid: 19217170
references.citation: Nature. 2005 Aug 18;436(7053):939-45
references.pmid: 16107833
references.citation: Biochem J. 1996 Dec 1;320 ( Pt 2):681-6
references.pmid: 8973584
references.citation: Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1756-9
references.pmid: 2000384
references.citation: J Exp Med. 2006 Jul 10;203(7):1795-803
references.pmid: 16785313
references.citation: J Biol Chem. 2010 Jul 23;285(30):22741-7
references.pmid: 20457596
references.citation: Physiol Rev. 2006 Apr;86(2):583-650
references.pmid: 16601269
references.citation: Nat Immunol. 2009 Oct;10(10):1065-72
references.pmid: 19609254
references.citation: J Virol. 2005 Mar;79(5):2689-99
references.pmid: 15708988
references.citation: J Biol Chem. 2005 Apr 29;280(17):16739-47
references.pmid: 15737993
references.citation: J Virol. 1994 Jun;68(6):3753-60
references.pmid: 8189513
references.citation: J Exp Med. 2009 May 11;206(5):1167-79
references.pmid: 19398754
references.citation: N Engl J Med. 2011 Jun 23;364(25):2429-38
references.pmid: 21696309
references.citation: Cell. 2009 Aug 7;138(3):576-91
references.pmid: 19631370
references.citation: Nature. 2005 Oct 20;437(7062):1167-72
references.pmid: 16177806
references.citation: Arthritis Res Ther. 2010;12 Suppl 1:S1
references.pmid: 20392288
references.citation: J Med Chem. 1992 Sep 4;35(18):3426-8
references.pmid: 1527792