Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts

Abstract

The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity.

Pathogenesis of Hepatitis B Virus Associated Chronic Liver Disease

“…The second ORF, or core gene, encodes the hepatitis B core antigen (HBcAg) or nucleocapsid protein that polymerizes as an icosahedron around the virus replication complex, the latter of which consists of the virus nucleic acid and HBV encoded polymerase [20]. The fact that the pregenomic RNA and the reverse transcribed viral DNA product are sequestered within a nucleocapsid means that they are not readily detected by pattern recognition receptors, (e.g., toll-like receptors, retinoic acid inducible gene 1 [RIG-1], and mitochondrial anti-viral signaling [MAVS]) that trigger innate immunity [21]. Moreover, innate immune responses do not develop in the liver of acutely infected chimpanzees [22], suggesting that HBV replication and spread may be conducted in "stealth" mode with virus nucleocapsids upon infection and again during virus replication.…”

“…In addition, mitochondrial associated HBx induces oxidative stress, which activates selected transcription factors, such as NF-ĸB, STAT3 and activating protein 1 [86]. However, HBx is also known to block mitochondrial triggered cell death, not only by activation of survival [21,92] and hepato-protective pathways such as NF-ĸB that over-ride apoptosis signaling, but also by blocking key caspases and promoting autophagy [93] and mitophagy [94]. The maintenance of mitochondrial and cellular homeostasis by mitophagy acts to attenuate virus induced apoptosis, so that on the one hand, autophagy and mitophagy promote cell survival and virus persistence, while simultaneous mitochondrial damage may contribute to CLD [94].…”

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial

“…by data suggesting that liver macrophages and hepatocytes may be involved in early recognition of HBV while the IFN mediated response is inhibited by some ill-defined viral components. [13][14][15] Three T-cell based immunotherapeutic approaches for treatment of CHB are currently pursued: 3 one aiming at inducing novel functional HBV-specific immune responses similar to those described in natural resolution of infection (e.g. de novo priming of functional T-cells); one aiming at rescuing dysfunctional HBV-specific T-cell responses (e.g.…”

INASL Guidelines on Management of Hepatitis B Virus Infection in Patients receiving Chemotherapy, Biologicals, Immunosupressants, or Corticosteroids

“…HBV viral proteins down regulate pattern recognition by cells, bring about changes in Natural Killer cell receptors and lead to CD4 and CD8 T cell exhaustion. 15 Only hepatocyte death can lead to cccDNA clearance.…”