Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection

Abstract

Hepatitis B virus (HBV) infection is a serious health threat around the world. Despite the availability of an effective hepatitis B vaccine, the number of HBV carriers is estimated to be as high as 240 million worldwide. Global mortality due to HBV-related liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) may be as high as 1 million deaths per year. HBV is transmitted via blood and body fluids, and is much more infectious than both human immunodeficiency virus (HIV) and hepatitis C virus. While HBV infection exhibits a variety of clinical presentations, even asymptomatic carriers can develop HCC without liver fibrosis. Current therapeutic options against HBV include pegylated interferon (Peg-IFN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs), with clinical studies showing a significant association between loss of HBV DNA and a decrease in cancer risk. However, the ultimate goal of HBV therapy is a complete cure of HBV-including the elimination of covalently closed circular DNA (cccDNA)-in order to further decrease the risk of developing HCC. The development of hepatitis B is associated with the host immune response to virus-infected hepatocytes, as HBV is understood to lack direct cytotoxicity. While HBV-specific CD8+ T cells are thus involved in hepatitis development, they also play an important role in eliminating HBV infection. Indeed, the innate immune response during the initial phase of HBV infection is essential to the induction of acquired immunity. However, the innate immune response to HBV infection, including the roles of specific immunocompetent cells and associated molecules, is not well understood. In this review, we focus on the current understanding of the mechanisms underlying hepatitis development by HBV infection. We also address the mechanisms by which HBV protects cccDNA.

Keywords: Hepatitis B virus (HBV); covalently closed circular DNA (cccDNA); immune response.

Figure 1

Schematic of HBV life cycle and mechanisms by which HBV counteracts the host immune response and protects cccDNA. HBV infection of hepatocyte induces interferons through RIG-I-mediated sensing of the 5’ ε region of HBV pregenomic RNA. However, HBV-encoded proteins can inhibit host viral-sensing pathways. The Smc 5/6 complex can bind to cccDNA, thereby inhibiting transcription of HBV mRNA. To trigger degradation of the Smc 5/6 complex by the host ubiquitin-proteasome system, HBx interacts with DDB1, a component of CUL4-E3 ubiquitin ligase complex. HBV, hepatitis B virus; cccDNA, covalently closed circular DNA; RIG-I, retinoic acid-inducible gene I; Smc, structural maintenance of chromosomes; HBx, HBV X protein; DDB1, damaged DNA binding protein 1; CUL4, cullin 4; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRF-3, interferon regulatory factor 3; MAVS, mitochondrial antiviral signaling protein; STING, stimulator of interferon genes; pgRNA, pregenomic RNA; ISG, interferon-stimulated gene.