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PLoS One. 2017 Oct 17;12(10):e0186213. doi: 10.1371/journal.pone.0186213. eCollection 2017.

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

Author information

1
Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, Colorado, United States of America.
2
Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, United States of America.
3
Department of Immunology, University of Washington, Seattle, Washington, United States of America.
4
Bristol-Myers Squibb, Exploratory Clinical and Translational Research, Lawrenceville, New Jersey, United States of America.
5
Bioinfo Solutions LLC, Parker, Colorado, United States of America.

Abstract

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
29040318
PMCID:
PMC5645093
DOI:
10.1371/journal.pone.0186213
[Indexed for MEDLINE]
Free PMC Article

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