Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon

Abstract

Hepatitis B virus (HBV) is a small (3.2-kb) DNA virus that causes acute and chronic inflammation of the liver, and the latter is a risk factor for the development of hepatocellular carcinoma (HCC) (39). Worldwide, an estimated 350 million people have chronic HBV and are at risk for severe liver disease (39). New insight into the virus-host interactions underlying chronic virus replication was provided with the demonstration that HBV infection fails to activate the innate immune response in chimpanzees (52). This observation was recently confirmed in acutely infected humans (10) and primary human hepatocytes exposed to HBV (17). Several studies have clearly demonstrated that HBV replication is controlled by an activated adaptive immune response (4,14,36,53,54), suggesting that HBV has evolved a strategy to dampen activation of the innate immune response.The sole HBV regulatory protein, the 17-kDa HBx protein, plays an essential role in virus replication in HepG2 cells (3) and in hydrodynamically injected mice (22). Given the abundance of properties attributed to HBx (reviewed in reference 2), it is likely that HBx has more than one function during the virus life cycle. These functions may be mediated, in part, through HBx interactions with cellular proteins. Indeed, screening protocols such as the yeast two-hybrid assay have been used to identify over 30 HBx-interacting proteins (reviewed in reference 13). The biologic importance of these virus-host protein interactions is difficult to assess due to a paucity of virus replication assays. In the related woodchuck virus replication model, it was demonstrated that the HBx interaction with cellular DDB1 is critical for virus replication (42), and this was confirmed in plasmid-transfected HepG2 cells (27). However, the role of other HBx binding partners in virus replication remains unknown. Cells respond to virus infection through the recognition of viral pathogen-associated molecular patterns (PAMPs). Several cytoplasmic host pattern recognition receptors (PRRs) are responsible for this, including the Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) and other RIG-Ilike receptors (RLRs), such as MDA-5 and LGP2 (43; also reviewed in reference 55). Following recognition of the viral DNA or RNA, the PRRs undergo conformational changes that activate downstream pathways, ultimately leading to the induction of type I interferon (IFN) and proinflammatory cytokines. A key adaptor protein in this process is the beta interferon promoter stimulator 1 (IPS-1) protein (21), also known as mitochondrial antiviral signaling protein (MAVS) (40), VISA (58), and Cardiff (35; also reviewed in reference 20). Upon its activation, IPS-1 recruits kinases that phosphorylate latent transcription factors required for the production of 21,25). Interestingly, IPS-1 is targeted for interaction by several viral proteins, effectively inactivating the innate antiviral immune response (43).The goal of the present study was to identify HBx-interacting proteins in the liver of the H...

Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I-dependent manner

“…[7][8][9] These findings strongly support the notion that HBV can escape from host innate and adaptive immunity. Thus, determining how to reverse HBV-induced immune tolerance has become an important approach in the treatment of CHB.…”

“…In keeping with this hypotheses, recent findings revealed that HBV polymerase and HBx can disturb the RIG-I pathway by interfering with IRF3 or down-regulating IPS-1. [6][7][8][9] However, the exact mechanism needs to be further clarified. RIG-I recognizes RNA viruses, 5 0 -triphosphate RNA, or short, blunt, double-stranded RNA in the cytosol of cells.…”

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

“…Because RLRs are cytosolic viral sensors and HBV nucleic acids may be present in the cytosol in addition to the nucleus as described in the aforementioned paragraph, HBV is more likely to be recognized by RLRs. Consistent with this notion, recent studies have demonstrated that overexpression of IPS-1 in a hepatoma cell line transfected with the HBV replicative plasmid significantly suppresses HBV replication (15), and that HBV X protein interacts with IPS-1 and disrupts the downstream signaling of RLRs to prevent the production of type I IFNs induced by Sendai virus, vesicular stomatitis virus (VSV), or poly (dA:dT) (16)(17)(18)(19). Furthermore, two studies have shown that HBV pol impairs the activation of TBK1/IKKε, the downstream signaling molecule of IPS-1 in the RLR signaling pathway (20,21).…”

“…Altogether, these studies suggest that IPS-1 is likely involved in the innate response against HBV infection. Given that RIG-I and MDA5 are upstream molecules of IPS-1 (22) and that IPS-1 is involved in the innate response against HBV (15)(16)(17)(18)(19)(20)(21), RIG-I and MDA5 may play a role in the regulation of HBV infection.…”

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

“…36 HBx protein was reported to inhibit RIG-I-mediated IFN-b induction by promoting ubiquitin-dependent degradation of IPS-1 in hepatoma cells. [37][38][39] HBV polymerase was shown to suppress RIG-I-induced IFN-b induction by interference with IRF3 phosphorylation and nuclear translocation and inhibiting the interaction between TBK1/IKKe and DDX3 in human hepatocytes. 34,40 The mechanisms employed by HBV to counteract innate immune system are summarized in Table 1.…”