Studies On The Suppressive Effect Of The Hepatitis B Virus Pol Protein On The NF-κB Pathway

Nuclear-factor kB (NF-kB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and survival. To establish persistent infection, many viruses have evolved strategies to evade the host’s antiviral immune defenses. For the hepatitis B virus (HBV), which could cause chronic infection in the liver, the immune evasion strategy was not fully understood. It was recently reported that HBV polymerase (Pol protein) inhibited interferon-B (IFN-B) activity by disrupting the interaction between IKKe and DDX3Dead Box RNA helicase. In this study, we found that HBV Pol protein could suppress NF-kB signaling activity which could also contribute to IFN-B production. We proved that HBV Pol protein did not alter the level of NF-kB expression but prevented the NF-kB subunits from entering the nucleus in both canonical and non-canonical NF-kB pathways. Further experiments showed that HBV Pol protein could preferentially suppress the activity of IkB Kinase Complex (IKK) by disrupting the association of IKK/NEMO with Cdc37/Hsp90which is critical for the assembly of IKK complex and also for the recruitment of IKK to the Tumor necrosis factor receptor type1(TNF-R1). Consequently, we found that HBV Pol protein inhibited the transcription of NF-KB-mediated downstream genes (interleukin6[IL-6], IL-8) through down-regulation of NF-kB. Taken all together, these observations indicate that HBV Pol protein is the viral molecule that effectively counteracts host innate immune response by interfering two distinct signaling pathways in the early phase of the infection and shed light on the further therapeutic resolution of the HBV persistent infection.