Hepatitis B Virus Polymerase Blocks Pattern Recognition Receptor Signaling via Interaction with DDX3: Implications for Immune Evasion

Abstract

Viral infection leads to induction of pattern-recognition receptor signaling, which leads to interferon regulatory factor (IRF) activation and ultimately interferon (IFN) production. To establish infection, many viruses have strategies to evade the innate immunity. For the hepatitis B virus (HBV), which causes chronic infection in the liver, the evasion strategy remains uncertain. We now show that HBV polymerase (Pol) blocks IRF signaling, indicating that HBV Pol is the viral molecule that effectively counteracts host innate immune response. In particular, HBV Pol inhibits TANK-binding kinase 1 (TBK1)/IκB kinase-ε (IKKε), the effector kinases of IRF signaling. Intriguingly, HBV Pol inhibits TBK1/IKKε activity by disrupting the interaction between IKKε and DDX3 DEAD box RNA helicase, which was recently shown to augment TBK1/IKKε activity. This unexpected role of HBV Pol may explain how HBV evades innate immune response in the early phase of the infection. A therapeutic implication of this work is that a strategy to interfere with the HBV Pol-DDX3 interaction might lead to the resolution of life-long persistent infection. Viral infection is sensed by the host innate immune system, which acts to limit viral infection by inducing antiviral cytokines such as the interferons. To establish infection, many viruses have strategies to evade the innate immunity. For the hepatitis B virus (HBV), which causes chronic infection in the liver, the evasion strategy remains mysterious. An earlier study using the chimpanzee as a model suggested that the host innate immune system failed to detect HBV. As a result, it was dubbed “stealth virus”. In contrast, subsequent studies performed in vitro have suggested that HBV is, in fact, detected by the innate immune system but can effectively counteract this response. Whether HBV is detected by the innate immune system remains controversial; however, it is widely accepted that, regardless of detection, HBV effectively inhibits the host innate immune response early in infection through an unknown mechanism. The data presented here indicate that HBV Pol (polymerase or reverse transcriptase) blocks the innate immune response. This unexpected role of HBV Pol may explain why HBV appears to act as a “stealth virus” in the early phase of the infection.