Hepatitis B Virus Does Not Interfere With Innate Immune Responses in the Human Liver

Background & Aims Most viruses are detected at early stages of cell infection and induce an innateimmune response mediated by production interferons (IFNs). IFNs induce expression of hundreds of IFN-stimulated genes (ISGs). Infection of chimpanzees with hepatitis C virus, but not hepatitis B virus (HBV), induces ISG expression in the liver. HBV might not induce an innateimmune response because it is not detected by pattern recognition receptors(the stealth properties of HBV) or because HBV suppresses IFN production or signaling despite detection by pattern recognition receptors. We studied innateimmune signaling in liver biopsies from patients with different stages of chronic HBV infection and uninfected individuals (controls). Methods We obtained liver within 10 minutes after collection from 30 patients with chronic HBV infection (hepatitis B e antigen-positive or -negative, with or without hepatitis) and 42 controls (most with fatty liver disease). The liver tissues were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, HBV RNA quantification, and HBV genotyping; some specimens were incubated with toll-like receptor (TLR) ligands (polyinosinic-polycytidylic acid) or infected with Sendai virusand then analyzed. Results Liver specimens from patients with HBV infection were not expressing more IFN or ISGs than those from control patients, indicating that chronic HBV infection did not activate an innateimmune response. However, liver specimens from patients with HBV infection did produce IFN and induce expression of ISGs following activation of TLR3with poly(I:C) or Sendai virusinfections, so the innateimmune response is not suppressed in these tissues. Conclusion Liver tissues from patients with chronic HBV infection do not have induction of an innateimmune response, but this response can be activated by other factors ( TLR3binding, Sendai virusinfection) in HBV-infected liver tissue. These findings support the hypothesis that HBV is invisible to pattern recognition receptors.