Hepatitis B Virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells

J Immunol. 2018 Oct 15;201(8):2331-2344. doi: 10.4049/jimmunol.1701726. Epub 2018 Sep 5.


Effective B cell responses such as cytokine secretion, proliferation, and Ab-specific responses are essential to clear hepatitis B virus (HBV) infection. However, HBV alters numerous immune pathways to persist in the host. B cell activity depends on activation of the innate sensor TLR9 by viral or bacterial DNA motifs. How HBV can deregulate B cell functions remains unknown. In this study, we show that HBV can enter and decrease TLR9 expression in human primary B cells. Using PBMCs from human blood donors, we show that TLR9 expression was reduced in all peripheral B cells subsets exposed to HBV. B cell function mediated by TLR9, but not TLR7, such as proliferation and proinflammatory cytokines secretion, were abrogated in the presence of HBV; however, global Ig secretion was not downregulated. Mechanistically, we show, using human myeloma B cell line RPMI 8226, that the surface Ag hepatitis B surface Ag was responsible for TLR9 dysfunction. hepatitis B surface Ag suppressed the phosphorylation and thus the activation of the transcription factor CREB, preventing TLR9 promoter activity. Finally, we corroborated our in vitro findings in a cohort of chronic HBV carriers and found that TLR9 expression and function were significantly suppressed. The effect of HBV on TLR9 activity in B cells gives insights into oncoviral immune escape strategies, providing knowledge to develop novel immunotherapeutic approaches in chronic HBV-carrier patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / virology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cohort Studies
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cytokines / metabolism
  • Down-Regulation
  • Female
  • Hepatitis B Surface Antigens / immunology
  • Hepatitis B Surface Antigens / metabolism*
  • Hepatitis B virus / physiology*
  • Hepatitis B, Chronic / immunology*
  • Humans
  • Immune Evasion
  • Immune Tolerance
  • Integrases / genetics
  • Integrases / metabolism
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Toll-Like Receptor 9 / metabolism*
  • Young Adult


  • Cyclic AMP Response Element-Binding Protein
  • Cytokines
  • Hepatitis B Surface Antigens
  • Toll-Like Receptor 9
  • Cre recombinase
  • Integrases