Rapid reversal of innate immune dysregulation in blood of patients and livers of humanized mice with HCV following DAA therapy

• Published in: PloS one 2017-10, Vol.12 (10), p.e0186213
• Main Authors: Burchill, Matthew A, Roby, Justin A, Crochet, Nanette, Wind-Rotolo, Megan, Stone, Amy E, Edwards, Michael G, Dran, Rachael J, Kriss, Michael S, Gale, Jr, Michael, Rosen, Hugo R
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antiviral agents; Antiviral Agents - administration & dosage; Benzazepines - administration & dosage; Biology and Life Sciences; Blood; Carbamates; Chemokines; Chronic infection; CXCL10 protein; CXCL11 protein; Cytokines; Disease Models, Animal; Double-stranded RNA; Female; Fibrosis; Gastroenterology; Gene expression; Gene Expression Regulation - drug effects; Genes; Health aspects; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - virology; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - virology; Hepatology; Humans; Imidazoles - administration & dosage; Immune clearance; Immune response; Immune system; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunology; Indoles - administration & dosage; Infections; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - virology; Innate immunity; Interferon; Interleukin 1; Isoquinolines - administration & dosage; Liver; Liver - drug effects; Liver - virology; Liver diseases; Male; Medicine; Medicine and Health Sciences; Mice; Middle Aged; Patients; Peripheral blood; Pyrrolidines; RAG2 protein; Research and Analysis Methods; Ribonucleic acid; RNA; Rodents; Sulfonamides - administration & dosage; Therapy; Transcription activation; Transcription factors; USP18 protein; Valine - analogs & derivatives; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186213

First, in patients receiving two different combinations of DAAs, we found that DAAs induced not only rapid viral clearance, but also a re-setting of antiviral immune responses in the peripheral blood. Specifically, we see a rapid decline in the expression of genes associated with chronic IFN stimulation (IFIT3, USP18, IFIT1) as well as a rapid decline in genes associated with inflammation (IL1β, CXCL10, CXCL11) in the peripheral blood that precedes the complete removal of virus from the blood. Interestingly, this rapid reversal of innate immune activation was not seen in patients who successfully clear chronic HCV infection using IFN-based therapy. Next, using a novel humanized mouse model (Fah-/-RAG2-/-IL2rgnull-FRG), we assessed the changes that occur in the hepatic tissue following DAA treatment. DAA-mediated rapid HCV clearance resulted in blunting of the expression of proinflammatory responses while functionally restoring the RIG-I/MAVS axis in the liver of humanized mice. Collectively, our data demonstrate that the rapid viral clearance following treatment with DAAs results in the rebalancing of innate antiviral response in both the peripheral blood and the liver as well as enhanced antiviral signaling within previously infected hepatocytes.