Molecular mechanism of innate immunity control of HBV replication

Drexel University, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): In this proposal we will study the antiviral mechanism of host cellular innate immunity against hepatitis B virus (HBV). Generally, host cells are able to sense viral components through multiple pattern recognition receptors (PRRs) that lead to activation of innate cellular defense responses to combat virus infection. In marked contrast, considerable evidence suggests that, for the most part, HBV does not apparently activate such cellular innate response and this is probably central to viral pathogenesis. Such phenomena indicate HBV infection either is stealth from the detection of the innate PRRs, or HBV has ability to block the innate signal cascades. However, our preliminary evidence shows that HBV replication in human hepatocyte-derived cell lines, such as HepG2 and Huh7, is dramatically inhibited by the innate immune response elicited by expression of PRR adaptors for either Toll-like receptors (TLR), TRIF and MyD88, or adaptor for intracellular RIG-I-like helicases (RLH), IPS-1. Perhaps most surprising is that the inhibition of HBV replication appears to be mediated by intracellular antiviral pathway(s), rather than the secretion of antiviral cytokines such as IFN-1/2. Furthermore, the data suggest that activation of these pathways result in the post-transcriptional degradation of HBV mRNAs. Moreover, we found that activation of NF-:B pathway is essential for all three adaptors to inhibit HBV replication and activation of additional pathway(s) is required for TRIF to induce the maximum antiviral effect. The proposed studies will focus on the molecular mechanism by which the innate immune response inhibits HBV replication. Specifically, the HBV RNA sequence elements responsible for the posttranscriptional RNA decay will be mapped, IPS-1-induced cellular effector molecules that lead to the decay of HBV RNAs will be identified. Understanding of the robust and intricate innate antiviral pathway could potentially lead to the development of novel therapeutics to control HBV infections.