Hepatitis B: Model Systems and Therapeutic Approaches

Abstract

Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current antiviral medications, including nucleot(s)ide analogs and interferons, could inhibit the replication of HBV and alleviate the disease, HBV cannot be fully eradicated. The development of cellular and animal models for HBV infection plays an important role in exploring effective anti-HBV medicine. During the past decades, advancements in several cell culture systems, such as HepG2.2.15, HepAD38, HepaRG, hepatocyte-like cells, and primary human hepatocytes, have propelled the research in inhibiting HBV replication and expression and thus enriched our comprehension of the viral life cycle and enhancing antiviral drug evaluation efficacy. Mouse models, in particular, have emerged as the most extensively studied HBV animal models. Additionally, the present landscape of HBV therapeutics research now encompasses a comprehensive assessment of the virus's life cycle, targeting numerous facets and employing a variety of immunomodulatory approaches, including entry inhibitors, strategies aimed at cccDNA, RNA interference technologies, toll-like receptor agonists, and, notably, traditional Chinese medicine (TCM). This review describes the attributes and limitations of existing HBV model systems and surveys novel advancements in HBV treatment modalities, which will offer deeper insights toward discovering potentially efficacious pharmaceutical interventions.

Figure 1

Structure of the HBV genome. A double-stranded circular DNA genome linked to a polymerase enzyme, surrounded by a nucleocapsid and three envelope proteins. It contains four open reading frames, i.e., the S, C, P, and X frames. The S frame, which contains the pre-S1, pre-S2, and S frames, can be transcribed into HBsAg. The C frame, which contains the pre-C and C frames, can be transcribed into HBcAg and HBeAg. The X frame can be transcribed into HBxAg. The P frame can be transcribed into DNA polymerase.

Figure 2

The life cycle of the hepatitis B virus and antiviral compounds. (a) The complete hepatitis B virus first binds to the sodium taurocholate cotransporting polypeptide (NTCP) receptor on the host cell via the pre-S1 domain of the hepatitis B surface antigen. Myrcludex, bacitracin, NTI-007, SCY446, SCY450, N, and PD8716 could inhibit the entry of the virus. (b) rcDNA is delivered into the nucleus. (c) The rcDNA is converted into a molecular DNA template (covalently closed circular DNA, cccDNA), and cccDNA is integrated into host cells. Ezetimibe, TALENs, ZFNs, and CRISPR/Cas9 nucleases inhibit the formation of cccDNA. (d) DNA is transcribed into viral RNAs, such as pgRNA, precure mRNA, pre-S/S mRNAs, and HBx mRNA. (e) pgRNA is reverse-transcribed into viral DNA. JNJ-3989 and ARC520 promote RNA degradation; GSK3228836 and GSK3380404 result in ribonuclease cleavage. (f) Mature nucleocapsids are bounded by large HBsAg molecules. The virus then acquires an envelope via the endosomal sorting complex, which is required for protein transportation. JNJ56136379, ABI-H0731, RO7049389, AB-506, and ABI-H2158 block the assembly nucleocapsid. REP2139 inhibited the release of HBsAg. Source: created with BioRender.com. CRISPR: cluster regularly interspaced short palindromic repeats; TALENs: transcription activator-like effector nucleases; ZFNs: zinc-finger nuclease.

Figure 3

Immunotherapeutic targets. Immunotherapies aim to restore endogenous, depleted HBV-specific CD4⁺and CD8⁺T cells, and memory B cells and restore their function. (a) Therapeutic vaccines could increase the number and function of HBV-specific CD8⁺T, CD4⁺T, and B cells. (b) TLR7/8 agonists can stimulate monocytes to secrete a variety of factors, such as antiviral cytokines to activate HBV-specific CD8⁺T cells, and immunomodulatory cytokines to regulate the function of NK, DC, and Treg cells. (c) Checkpoint inhibitors may partially restore the dysregulated activity of HBV-specific T cells by preventing interactions between PD-1 and PD-L1.