Increased Proinflammatory Cytokine Production by Chronic Hepatitis B Patients with Mutant Hepatitis B Virus: Plausible Mechanisms Underlying Severe Liver Diseases in These Patients

Viral Immunol. 2020 Sep;33(7):530-534. doi: 10.1089/vim.2019.0198. Epub 2020 Jun 8.

Abstract

Hepatitis B virus (HBV) is a noncytopathic virus and billions of HBV-infected patients live uneventful lives and do not suffer from notable liver damage. However, HBV also causes progressive liver diseases characterized by hepatic inflammation, hepatic fibrosis, and liver cancer in millions of HBV-infected patients. The goal of this study was to evaluate the role of mutant HBV in HBV pathogenesis. In a cohort of 360 chronic HBV-infected patients, mutations at T1762/A1764 of HBV genome were detected in most of the patients with HBV-induced liver cirrhosis and hepatocellular carcinoma. To explore if mutations at T1762/A1764 of HBV genome has any role in progressive liver disease, peripheral blood mononuclear cells (PBMCs) and antigen-presenting dendritic cells (DCs) were isolated from five chronic hepatitis B (CHB) patients with mutations at T1762/A1764 and five comparable patients of CHB without mutations at T1762/A1764. DCs were pulsed with hepatitis B surface antigen (HBsAg). The levels of cytokines produced by PBMCs and DCs as well as nitrite production by DCs were evaluated. Significantly higher levels of interleukin-12, tumor necrosis factor-alpha, interferon-gamma, and transforming growth factor-beta were detected in cultures of PBMCs, DCs, and HBsAg-pulsed DCs from CHB patients with mutations at T1762/A1764 compared with those without mutations (p < 0.05). DCs of all CHB patients with mutations produced significantly higher levels of nitrite compared with those without mutation at T1762/A1764 (p < 0.001). This study discusses the inflammatory potential of mutant HBV that may be responsible for diverse levels of pathogenicity of HBV. Further studies involving larger cohorts would provide more insight into these unresolved issues about HBV pathogenesis and these insights may aid in developing immune therapy for CHB patients.

Keywords: chronic hepatitis B; host immunity; viral mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / virology
  • Cells, Cultured
  • Cohort Studies
  • Cytokines / immunology*
  • Dendritic Cells / immunology
  • Disease Progression
  • Female
  • Genome, Viral
  • Hepatitis B virus / genetics*
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / virology
  • Host Microbial Interactions
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Leukocytes, Mononuclear / immunology
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / virology
  • Liver Diseases / immunology
  • Liver Diseases / metabolism
  • Liver Diseases / virology
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / virology
  • Male
  • Mutation
  • Nitrites / metabolism
  • Transforming Growth Factors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Nitrites
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Transforming Growth Factors
  • Interferon-gamma