title: Human pegivirus (GB virus C) NS3 protease activity inhibits induction of the type I interferon response and is not inhibited by HCV NS3 protease inhibitors.
abstract: We previously found that human pegivirus (HPgV; formerly GBV-C) NS3 protease activity inhibits Human Immunodeficiency Virus (HIV) replication in a CD4+ T cell line. Given the protease׳s similarity to the Hepatitis C virus (HCV) NS3 protease, we characterized HPgV protease activity and asked whether it affects the type I interferon response or is inhibited by HCV protease antagonists. We characterized the activity of proteases with mutations in the catalytic triad and demonstrated that the HCV protease inhibitors Telaprevir, Boceprevir, and Danoprevir do not affect HPgV protease activity. HPgV NS3 protease cleaved MAVS but not TRIF, and it inhibited interferon responses sufficiently to enhance growth of an interferon-sensitive virus. Therefore, HPgV׳s inhibition of the interferon response could help promote HPgV persistence, which is associated with clinical benefits in HIV-infected patients. Our results also imply that HCV protease inhibitors should not interfere with the beneficial effects of HPgV in HPgV/HCV/HIV infected patients.
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, St. Louis, MO, USA; Saint Louis University School of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, St. Louis, MO, USA. Electronic address: chowdhay@slu.edu.
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Chowdhury
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, St. Louis, MO, USA. Electronic address: tavisje@slu.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, St. Louis, MO, USA; Saint Louis University School of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, St. Louis, MO, USA; Saint Louis Veterans Administration Medical Center, St. Louis, MO, USA. Electronic address: georgesl@slu.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: George
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002460:Cell Line; D003521:Cyclopropanes; D004252:DNA Mutational Analysis; D029407:GB virus C / Q000201:enzymology* / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D054833:Isoindoles; D007769:Lactams / Q000378:metabolism; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism*; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003521:Cyclopropanes; D007370:Interferon Type I; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C505371:MAVS protein, human; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C470409:TICAM1 protein, human; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C553752:danoprevir
keywords: GB Virus-C; Hepatitis C virus; Human pegivirus; MAVS; Protease inhibitors; Serine protease; TRIF; Type I interferon