Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in Chimeric Mice.

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Gastroenterology. 2011 Mar 1. [Epub ahead of print]

Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in

Chimeric Mice.

Lütgehetmann M, Bornscheuer T, Volz T, Allweiss L, Bockmann JH, Pollok JM,

Lohse AW, sen J, Dandri M.

Dept. Internal Medicine, University Medical Hospital Hamburg-Eppendorf; D-20246

Hamburg, Germany; Department of Medical Microbiology, Virology and Hygiene,

University Medical Hospital Hamburg-Eppendorf; D-20246 Hamburg, Germany.

Abstract

BACKGROUND & AIMS: Interferon (IFN)-α therapy is not effective for most

patients with chronic hepatitis B virus (HBV) infection, for unclear reasons. We

investigated whether HBV infection reduced IFN-α-mediated induction of

antiviral defence mechanisms in human hepatocytes.

METHODS: Human hepatocytes were injected into severe combined immune deficient

mice (SCID/beige) that expressed transgenic urokinase plasminogen activator

under control of the albumin promoter. Some mice were infected with HBV;

infected and uninfected mice were given injections of human IFN-α. Changes in

viral DNA and expression of human interferon-stimulated genes (ISGs) were

measured by real-time PCR, using human-specific primers, and by

immunohistochemistry.

RESULTS: Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased

3-fold by 8 or 12 h after each injection of IFN-α, but then increased within 24

h. IFN-α activated expression of human ISGs and nuclear translocation of STAT-1

in human hepatocytes that repopulated the livers of uninfected mice. Although

baseline levels of human ISGs were slightly increased in HBV-infected mice,

compared with uninfected mice, IFN-α failed to increase expression of the ISGs

OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in

HBV-infected mice. Remarkably, IFN-α did not induce nuclear translocation of

STAT-1 in HBV-infected human hepatocytes. Administration of the nucleoside

analogue entecavir (for 20 days) suppressed HBV replication but did not restore

responsiveness to IFN-α.

CONCLUSIONS: HBV prevents induction of IFN-α signaling by inhibiting nuclear

translocation of STAT-1; this can interfere with transcription of ISGs in human

hepatocytes. These effects of HBV might contribute to the limited effectiveness

of endogenous and therapeutic IFN-α in patients and promote viral

persistence.Copyright © 2011 AGA Institute. Published by Elsevier Inc. All

rights reserved.

PMID: 21376046 [PubMed - as supplied by publisher]