Dataset Information

Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes.

ABSTRACT: Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.

SUBMITTER: Lee S

PROVIDER: S-EPMC7797372 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes.

Lee Sooyoung S Goyal Ashish A Perelson Alan S AS Ishida Yuji Y Saito Takeshi T Gale Michael M

iScience 20210104 1

Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small mole ...[more]

PMID: 33458618

Similar Datasets

Project description:UnlabelledDengue virus (DENV) replication is inhibited by the prior addition of type I interferon or by RIG-I agonists that elicit RIG-I/MAVS/TBK1/IRF3-dependent protective responses. DENV infection of primary human endothelial cells (ECs) results in a rapid increase in viral titer, which suggests that DENV inhibits replication-restrictive RIG-I/interferon beta (IFN-β) induction pathways within ECs. Our findings demonstrate that DENV serotype 4 (DENV4) nonstructural (NS) proteins NS2A and NS4B inhibited RIG-I-, MDA5-, MAVS-, and TBK1/IKKε-directed IFN-β transcription (>80%) but failed to inhibit IFN-β induction directed by STING or constitutively active IRF3-5D. Expression of NS2A and NS4B dose dependently inhibited the phosphorylation of TBK1 and IRF3, which suggests that they function at the level of TBK1 complex activation. NS2A and NS4B from DENV1/2/4, as well as the West Nile virus NS4B protein, commonly inhibited TBK1 phosphorylation and IFN-β induction. A comparative analysis of NS4A proteins across DENVs demonstrated that DENV1, but not DENV2 or DENV4, NS4A proteins uniquely inhibited TBK1. These findings indicate that DENVs contain conserved (NS2A/NS4B) and DENV1-specific (NS4A) mechanisms for inhibiting RIG-I/TBK1-directed IFN responses. Collectively, our results define DENV NS proteins that restrict IRF3 and IFN responses and thereby facilitate DENV replication and virulence. Unique DENV1-specific NS4A regulation of IFN induction has the potential to be a virulence determinant that contributes to the increased severity of DENV1 infections and the immunodominance of DENV1 responses during tetravalent DENV1-4 vaccination.ImportanceOur findings demonstrate that NS2A and NS4B proteins from dengue virus serotypes 1, 2, and 4 are inhibitors of RIG-I/MDA5-directed interferon beta (IFN-β) induction and that they accomplish this by blocking TBK1 activation. We determined that IFN inhibition is functionally conserved across NS4B proteins from West Nile virus and DENV1, -2, and -4 viruses. In contrast, DENV1 uniquely encodes an extra IFN regulating protein, NS4A, that inhibits TBK1-directed IFN induction. DENV1 is associated with an increase in severe patient disease, and added IFN regulation by the DENV1 NS4A protein may contribute to increased DENV1 replication, immunodominance, and virulence. The regulation of IFN induction by nonstructural (NS) proteins suggests their potential roles in enhancing viral replication and spread and as potential protein targets for viral attenuation. DENV1-specific IFN regulation needs to be considered in vaccine strategies where enhanced DENV1 replication may interfere with DENV2-4 seroconversion within coadministered tetravalent DENV1-4 vaccines.

Dataset Information

Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes.

Publications

Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets