Many Ways to Communicate-Crosstalk between the HBV-Infected Cell and Its Environment

Abstract

Chronic infection with the hepatitis B virus (HBV) affects an estimated 257 million people worldwide and can lead to liver diseases such as cirrhosis and liver cancer. Viral replication is generally considered not to be cytopathic, and although some HBV proteins may have direct carcinogenic effects, the majority of HBV infection-related disease is related to chronic inflammation resulting from disrupted antiviral responses and aberrant innate immune reactions. Like all cells, healthy and HBV-infected cells communicate with each other, as well as with other cell types, such as innate and adaptive immune cells. They do so by both interacting directly and by secreting factors into their environment. Such factors may be small molecules, such as metabolites, single viral proteins or host proteins, but can also be more complex, such as virions, protein complexes, and extracellular vesicles. The latter are small, membrane-enclosed vesicles that are exchanged between cells, and have recently gained a lot of attention for their potential to mediate complex communication and their potential for therapeutic repurposing. Here, we review how HBV infection affects the communication between HBV-infected cells and cells in their environment. We discuss the impact of these interactions on viral persistence in chronic infection, as well as their relation to HBV infection-related pathology.

Keywords: cell-cell interactions; extracellular vesicles; hepatitis B virus; hepatocellular carcinoma; innate and adaptive immune response; viral spread.

Figure 1

Overview on HBV-influenced factors. In hepatitis B virus (HBV) infections (A), various mediators (B) are associated with HBV-induced immune dysfunction and liver damage (C). EVs: extracellular vesicles (EVs); HBsAg: hepatitis B surface antigen; HBeAg: hepatitis B early antigen; ApoA1: apolipoprotein A1; ROS: reactive oxygen species; NTCP: sodium taurocholate cotransporting polypeptide; TLRs: toll-like receptors; RIG-I: retinoic acid inducible gene I; MDA5: melanoma differentiation-associated protein 5; TC: T cells; BC: B cells; AB: antibodies; HCC: hepatocellular carcinoma.

Figure 2

Pattern recognition of HBV infection. Intracellular pathogenic nucleic acids are recognized by endosomal Toll-like receptors (TLR) and cytosolic retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (MDA-5) or cyclic GMP-AMP synthase (cGas), leading to cytokine production and transcription of interferon-stimulated genes (ISGs). Hepatitis B virus (HBV) is capable of both evading and suppressing pattern recognition of innate immunity. dsRNA: double-stranded RNA; IFN-α: interferon α; IL-6: interleukin 6; miRNA: microRNA; ssRNA: single-stranded RNA; tumour necrosis factor.

Figure 3

Roles of extracellular vesicles in hepatitis B virus infection. Extracellular vesicles (EVs) are released from the plasma membrane or multivesicular bodies and contain specific cargo such as proteins, nucleic acids, and microRNAs (miRNAs), which they transport to recipient cells and protect from enzymatic degradation. In hepatitis B virus (HBV) infection, HBV proteins, genomes, and virions are also incorporated into EVs and thus are shielded from neutralizing antibodies. HBV-induced EVs inhibit the immune response by shuttling interferon-induced transmembrane protein 2 (IFITM2) to plasmacytoid dendritic cells (pDC) blocking interferon-α (IFN-α) release and by inducing miR21 and miR29a, which downregulate interleukine (IL)-12 production (indicated with red arrow). Upregulation of programmed cell death ligand 1 (PD-L1) or interleukin 6 (IL-6) is indicated with green arrow.