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Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes.

ABSTRACT: We have previously shown that alpha/beta interferon (IFN-alpha/beta) and IFN-gamma inhibit hepatitis B virus (HBV) replication noncytopathically in the livers of HBV transgenic mice and in hepatocyte cell lines derived from these mice. The present study was designed to identify transcriptionally controlled hepatocellular genes that are tightly associated with the inhibition of HBV replication and that might, therefore, mediate the antiviral effect of these cytokines. Twenty-nine genes were identified, many of which have known or potential antiviral activity. Notably, multiple components of the immunoproteasome and ubiquitin-like proteins were strongly induced by both IFN-alpha/beta and IFN-gamma, as were a number of GTP-binding proteins, including GTPases with known antiviral activity, chemokines, signaling molecules, and miscellaneous genes associated with antigen processing, DNA-binding, or cochaperone activity and several expressed sequence tags. The results suggest that one or more members of this relatively small subset of genes may mediate the antiviral effect of IFN-alpha/beta and IFN-gamma against HBV. We have already exploited this information by demonstrating that the antiviral activity of IFN-alpha/beta and IFN-gamma is proteasome dependent.

SUBMITTER: Wieland SF

PROVIDER: S-EPMC140855 | biostudies-literature | 2003 Jan

REPOSITORIES: biostudies-literature

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Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes.

Wieland Stefan F SF Vega Raquel G RG Müller Rolf R Evans Claire F CF Hilbush Brian B Guidotti Luca G LG Sutcliffe J Gregor JG Schultz Peter G PG Chisari Francis V FV

Journal of virology 20030101 2

We have previously shown that alpha/beta interferon (IFN-alpha/beta) and IFN-gamma inhibit hepatitis B virus (HBV) replication noncytopathically in the livers of HBV transgenic mice and in hepatocyte cell lines derived from these mice. The present study was designed to identify transcriptionally controlled hepatocellular genes that are tightly associated with the inhibition of HBV replication and that might, therefore, mediate the antiviral effect of these cytokines. Twenty-nine genes were ident ...[more]

PMID: 12502840

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Project description:Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon-? (IFN?) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFN? (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFN?. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach.We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFN? and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further.The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, ?-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, ? 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, ? isoform; peroxisomal proliferator-activated receptor-?-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFN?-mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFN? to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFN?; these genes represent a heretofore unknown class of non-IFN-stimulated gene IEGs.We performed a whole-genome loss-of-function screen to identify genes that mediate the effects of IFN? against human pathogenic viruses. We found that IFN? restricts HCV via actions of general and specific IEGs.

Dataset Information

Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes.

Publications

Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes.

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