Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability

Abstract

The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients' responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.

Keywords: HBV interference; HBV sensing; HBV variability; acute hepatitis B; acute liver failure; chronic hepatitis B; immune pathogenesis.

Figure 1

HBV (a) particle structures and (b) genome and ORFs. In red and green, the negative and positive strands (respectively) of HBV genome; colored boxes indicate the approximate location of the ORFs; green rectangles indicate enhancer regions and purple rectangles direct repeat regions. Abbreviations: HBV, hepatitis B virus; DR, direct repeat; Enh, enhancer; P, polymerase; S, surface; C, core; X, X protein gene.

Figure 2

A representation of the HBV mRNAs and the translation of viral proteins. 5′-cap is shown as a green dot and polyA tail in red; the rectangles in colors represent the ORFs while the dotted lines represent the translated segments to produce the viral proteins. Abbreviations: kb, kilobase; pgRNA, pregenomic RNA; HBcAg, HBV core antigen; HBVPol, HBV polymerase; C, core; TP, terminal protein; Pol(RT), polymerase reverse transcriptase; HBeAg, HBV e antigen; S-, M-, and L-HBsAg; HBV small, middle, and large size surface antigens; HBX, HBV X protein.

Figure 3

HBV replicative cycle. HBV undergoes endocytosis through the NTCP. Inside the cell, the rcDNA enters the nucleus, where it is repaired to form the cccDNA. The latter forms a viral minichromosome for the transcription of viral RNAs. The pgRNA binds to HBVPol in the cytosol to induce the packaging process that is followed by the synthesis of the HBV-DNA. The new viral particle is assembled in the ER and translocated to be secreted outside the hepatocytes as virions. Abbreviations: HBV, hepatitis B virus; NTCP, sodium taurocholate cotransporting polypeptide; rcDNA, relaxed circular DNA; cccDNA, covalently closed circular DNA; pgRNA, pregenomic RNA; ER, endoplasmic reticulum; HBVPol, HBV polymerase; dslDNA, double-stranded linear DNA.

Figure 4

The potential dynamic of the immune response during AHB. Before the peak of HBV-DNA, the antiviral process is primarily mediated by non-cytolytic mechanisms, mainly by NK cells with IFN-γ and TNF-α production. During this stage, the functions of T cells may be slowed down by regulatory cytokines. Infected hepatocytes collaborate by producing IFN-α and IFN-β to fight the infection. KC cells could be participating by stimulating NK cells and by acting as antigen-presenting cells. After the peak of viral DNA in serum, the antiviral activity is performed mostly by T cells producing cytokines and antibodies (anti-HBc followed by anti-HBe). The cytolytic mechanism induced by HBV-specific CTLs leads to serum ALT increase. Serum HBV-DNA and ALT graphic was modified [95]. Cells and their secreted cytokines are in the same color. Trunked red lines indicate inhibitory effects. Abbreviations: HBV, hepatitis B virus; HBV-DNA, HBV DNA in serum; ALT, alanine aminotransferase; NK, natural killer; KC, Kupffer cell; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; CTL, cytotoxic T lymphocyte.

Figure 5

The induction of tolerant state during chronic hepatitis B. T cells are induced to an exhausted state; the secretion of IL-10 and TGF-β by Treg cells inhibits the activity of immune cells such as DCs and NK cells. CTLs express higher levels of TRAILR2, which makes them susceptible to die by interacting with cells such as NK cells, which express higher levels of TRAIL in CHB patients. There is also metabolic regulation conducted by gMDSCs by consuming the L-arginine available in the medium. Cells and their secreted cytokines are colored the same. Trunked red lines indicate inhibitory effects, and red arrows indicate a reduction of secretion. Abbreviations: IFN, interferon; IL, interleukin; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; TRAILR2; or TNF-related apoptosis-inducing ligand (TRAIL) receptor 2; CTLA4, cytotoxic T-lymphocyte antigen 4; TIM3, T cell immunoglobulin domain and mucin domain-3; PD1, programmed cell death protein 1.

Figure 6

Probable signaling in the mechanism induced by TLRs, IFNRs, RIG-I, and STING in the control of the viral infection and how the virus interferes with them (marked with a red X). The stimulus of TLRs can induce a response to eliminate HBV. HBV presence leads to downregulation of the expression of TLRs (observed in PBMCs; indicated with red arrows) and/or interfere with its signaling (blocking the MyD88-IRAK4 axis, suppressing IRF3 activation, inhibiting the expression and nuclear translocation of IFR7). The virus can also inhibit RIG-I/MDA5-mediated response and STING-stimulated IRF3 activation; blocks: the activation of interferon IRF3 and IRF7, TBK1/IKKε activation, STING-stimulated IRF3 activation and, down-regulate the expression of MAVS. The presence of the virus can also interfere with IFN receptors signaling by avoiding nuclear translocations of STAT1/2 and IFN-α-induced STAT activation. Abbreviations: HBV, hepatitis B virus; NTCP, Na+-Taurocholate co-transporting polypeptide; TLR4, Toll-like receptor 4; TLR7/9, Toll-like receptor 7 and 9; MyD88, Myeloid differentiation primary response 88; TIRAP, TIR domain-containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRAF, TNF Receptor Associated Factor; NAP1, NF-kB–activating kinase-associated protein 1; IRF, interferon regulatory factor; TBK1, TANK binding kinase 1; IKKε, IκB kinase-ε; STING, stimulator of interferon genes; STAT, signal transducers and activators of transcription; IRF9, IFN regulatory factor 9; ISG, interferon stimulated genes; ISGF3, ISG factor 3; SOC; IFN-induced suppressor of cytokine signaling; GAS gamma IFN activated sequence (GAS) gamma IFN activated sequence GAS; MAVS, mitochondrial antiviral signaling; cGAMP, cyclic-GMP-AMP; cGAS, cyclic-GMP-AMP synthase; GAF, IFN-γ activated factor.