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Review
. 2018 Jul 18:9:1611.
doi: 10.3389/fmicb.2018.01611. eCollection 2018.

When Hepatitis B Virus Meets Interferons

Guangyun Tan  1 , Hongxiao Song  1 , Fengchao Xu  1 , Genhong Cheng  1   2   3   4
Affiliations
Review

When Hepatitis B Virus Meets Interferons

Guangyun Tan et al. Front Microbiol. .

Abstract

Chronic hepatitis B virus (HBV) infection imposes a severe burden on global public health. Currently, there are no curative therapies for millions of chronic HBV-infected patients (Lok et al., 2017). Interferon (IFN; including pegylated IFN) is an approved anti-HBV drug that not only exerts direct antiviral activity, but also augments immunity against HBV infection. Through a systematic review of the literature, here we summarize and present recent progress in research regarding the interactions between IFN and HBV as well as dissect the antiviral mechanisms of IFN. We focus on inhibition of HBV replication by IFN-stimulated genes (ISGs) as well as inhibition of IFN signaling by HBV and viral proteins. Finally, we briefly discuss current IFN-based HBV treatment strategies. This review may help to better understand the mechanisms involved in the therapeutic action of IFN as well as the crosstalk between IFN and HBV, and facilitate the development of both direct-acting and immunology-based new HBV drugs.

Keywords: HBV; HBV drug; ISGs; TRIMs; cccDNA; interferon.

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Figures

FIGURE 1
FIGURE 1
Illustration of the hepatitis B virus (HBV) genome and its overlapping open reading frames and transcripts. HBV is a partially double-stranded DNA virus that transcribes four major transcripts: pgRNA (3.5 kb), preS1 (2.4 kb), preS2/S (2.1 kb), and X (0.7 kb) and synthesizes seven proteins: P, polymerase; LS, large S; MS, middle S; SS, small S; preC, pre-Core; C, core; X, HBx.
FIGURE 2
FIGURE 2
Hepatitis B virus life cycle. Please see the text for details. P, polymerase; LS, large S; MS, middle S; SS, small S; preC, pre-Core; C, core; X, HBx; RC DNA, relaxed circular DNA; NTCP, sodium taurocholate co-transporting polypeptide; cccDNA, covalently closed circular DNA.
FIGURE 3
FIGURE 3
Classical interferon (IFN) and IFN-stimulated gene (ISG) induction in response to viral infection. In the cytoplasm, viral DNA is recognized by cGAS, DDX41, or IFI16, leading to the activation of STING, which further recruits TBK1 for IRF activation and translocates to the nucleus to initiate IFN production. Viral RNA is detected by RIG-I and MDA5, and recruits another adaptor protein: MAVS (IPS-1), resulting in TBK1 activation, IRF phosphorylation, and IFN induction. Then, IFNs are secreted from the cells and bind to IFNAR1/2, leading to JAK/STAT activation. The activated ISGF3 trimer or STAT1 dimer bind to the ISRE or GAS sequence and promote the expression of ISGs. ISGs inhibit HBV as shown in the black box. cGAS, cyclic GMP-AMP synthase; DDX41, DEAD-box protein 41; IFI16, γ-IFN-inducible protein 16; STING, stimulator of IFN genes; TBK1, TANK-binding kinase 1; IFNAR1, type I IFN receptor 1; JAK, Janus tyrosine kinase; STAT, signal transducer and activator of transcription.
FIGURE 4
FIGURE 4
Hepatitis B virus interrupts interferon (IFN) signaling. As indicated, HBV induces several host factors, including rubicon, parkin, MMP9, and CTHRC1. These proteins inhibit IFN production in a different mechanism, and HBV proteins including HBx, Pol (polymerase), HBsAg, and HBeAg can also block IFN induction or directly inhibit ISG induction. Please see the text for details. MVP, major vault protein; MMP9, matrix metalloproteinase 9; NEMO, nuclear factor-κB essential modulator; LUBAC, linear ubiquitin assembly complex; RIG-I, retinoic acid inducible gene I; MAVS, mitochondrial antiviral-signaling protein.
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