Hepatitis B Virus (HBV)
The 42 nm Dane particle carries a 3.2 kb relaxed-circular partially double-stranded DNA genome — the smallest DNA virus infecting humans — wrapped in a lipid envelope studded with three surface antigens (HBsAg large, medium, small). Four overlapping open reading frames maximise encoding density. Entry is strictly hepatotropic: the preS1 domain of large-HBsAg binds NTCP on hepatocyte basolateral membranes, triggering endocytosis. rcDNA is then transported to the nucleus and converted to cccDNA, which forms a stable minichromosome associated with histones — the viral reservoir that persists even after functional immune control. Chronic infection (persisting >6 months) affects 254 million people globally and carries a 15–40% lifetime risk of cirrhosis or hepatocellular carcinoma — the third leading cause of cancer death worldwide.
Genome — 4 Overlapping ORFs
| S / HBsAg | Encodes three surface antigens (preS1+preS2+S = Large HBsAg; preS2+S = Medium HBsAg; S alone = Small HBsAg). Secreted as 22 nm subviral particles in vast excess over Dane particles (~10,000:1). preS1 is the NTCP-binding domain essential for hepatocyte entry. |
| C / HBcAg | Core ORF encodes HBcAg (nucleocapsid) and, via alternate upstream ATG, HBeAg (secreted e-antigen). HBeAg is not structural but serves as immunotolerance-promoting protein; loss of HBeAg (seroconversion) is a major treatment milestone. Anti-HBc IgM signals acute/reactivation; IgG signals past or chronic exposure. |
| P / Polymerase | The largest ORF, overlapping all others. Encodes a 90 kDa multifunctional polymerase: N-terminal terminal protein (TP) primes reverse transcription; RT domain converts pregenomic RNA (pgRNA) to DNA; C-terminal RNase H degrades pgRNA template. HBV uses reverse transcription like retroviruses but packages DNA, not RNA. |
| X / HBx transactivator | Smallest ORF; encodes a 17 kDa protein that transactivates viral and cellular promoters, inhibits p53 and Smc5/6 (host restriction factor), promotes proteasomal degradation of SMC complexes, and is essential for productive infection in vivo. HBx is implicated in HCC oncogenesis via upregulation of cyclin D1, Wnt/β-catenin, and NF-κB pathways. |
Entry Mechanism and cccDNA Formation
1 · Attachment via preS1 → NTCP
The preS1 domain (aa 2–48) of large-HBsAg binds NTCP (SLC10A1) with high affinity. NTCP is expressed exclusively on hepatocyte basolateral (sinusoidal) membranes — this explains HBV's complete hepatic tropism. NTCP normally mediates bile acid re-uptake from portal blood. Bulevirtide (formerly MyrB) is a synthetic myristoylated preS1 peptide that competitively blocks this interaction — the first entry inhibitor approved for chronic HBV (EU/UK 2020).
2 · cccDNA — the nuclear reservoir
After endosomal release, nucleocapsid translocates to the nucleus. Host DNA repair enzymes (PCNA, tyrosyl-DNA phosphodiesterase 2, DNA ligase) convert the gapped rcDNA to covalently closed circular DNA (cccDNA). cccDNA is chromatinised with histones H3/H4, forming a persistent minichromosome. It is not replicated by the viral polymerase — only through cell division. In non-dividing hepatocytes, cccDNA half-life is measured in months to years; it serves as the transcriptional template for all viral RNAs, including the pregenomic RNA (pgRNA). Current NAs (tenofovir, entecavir) suppress rcDNA synthesis from pgRNA but do not touch existing cccDNA — explaining why <10% of patients achieve functional cure (HBsAg loss) after years of therapy.
3 · Immune evasion and tolerance
Perinatal/childhood infection establishes immune tolerance via neonatal thymic clonal deletion of HBV-specific T cells and the massive HBeAg secretion that acts as a peripheral tolerogen. Adult-acquired HBV typically produces vigorous multi-specific CD4+/CD8+ responses and spontaneous clearance in 95% of cases. Chronic infection reflects exhaustion of HBV-specific T cells via PD-1/PD-L1, CTLA-4, and Tim-3 upregulation. HBx additionally suppresses innate immunity by blocking STING-mediated cGAS-cGAMP signalling and degrading Smc5/6 — a host restriction complex that normally silences viral episomal DNA.
Serological Marker Interpretation
| Marker | What it is | Interpretation |
|---|---|---|
| HBsAg (+) | Surface antigen; present in serum from ~4–8 weeks post-infection | Active infection (acute or chronic). Chronic = HBsAg+ >6 months. |
| Anti-HBs (+) | Antibody to HBsAg | Immunity — either from vaccination (anti-HBs only, without anti-HBc) or from past resolved infection (anti-HBs + anti-HBc IgG) |
| HBeAg (+) | Secreted e-antigen; marker of active replication | High viral replication, high infectivity. Absent in precore/core-promoter mutants despite active replication. |
| Anti-HBe (+) | Antibody to HBeAg | HBeAg seroconversion — reduced replication, lower infectivity. Key treatment milestone. |
| Anti-HBc IgM (+) | IgM antibody to core antigen | Acute infection or reactivation. Appears early; fades within 6–12 months. |
| Anti-HBc IgG (+) | IgG antibody to core antigen | Past or chronic exposure. Persists for life; present in all exposed individuals. |
| HBsAg (−), anti-HBs (−), anti-HBc (+) | "Isolated core" pattern | Occult HBV infection or old resolved infection with waned anti-HBs. Check HBV DNA. |
| HBsAg (−), anti-HBs (+), anti-HBc (−) | Post-vaccination pattern | Vaccine-induced immunity only (never infected). |
Metavir Fibrosis Staging
| Stage | Histological description | Clinical significance |
|---|---|---|
| F0 | No fibrosis | Minimal liver damage; low HCC risk; treatment decision depends on viral load and ALT |
| F1 | Portal fibrosis without septa | Early fibrosis; monitor; NAs generally not started unless high viral load or elevated ALT |
| F2 | Portal fibrosis with rare septa | Significant fibrosis; most guidelines recommend starting antiviral therapy |
| F3 | Numerous septa without cirrhosis | Severe fibrosis (bridging); treat; HCC surveillance every 6 months |
| F4 | Cirrhosis | Established cirrhosis; high HCC risk (3–8%/year); portal hypertension complications; transplant evaluation |
Pathology — Natural History
| Phase | HBeAg status | Viral load | ALT | Histology / outcomes |
|---|---|---|---|---|
| Immune tolerant | + | Very high (>10↽ IU/mL) | Normal | Minimal inflammation; low fibrosis progression; perinatal infection typical; not usually treated |
| Immune active (HBeAg+) | + | High | Elevated | Active hepatitis, fibrosis progression; treatment indicated |
| Inactive carrier | − (seroconverted) | Low/undetectable (<2000 IU/mL) | Normal | Low risk of progression; monitor; rare spontaneous reactivation |
| HBeAg-negative chronic hepatitis | − (precore mutant) | Moderate–high | Elevated or fluctuating | Active hepatitis despite HBeAg negativity; treat; rapid fibrosers |
| Cirrhosis / HCC | Variable | Variable | May be normal | HCC in 20–30% of cirrhotics; risk even in non-cirrhotic HBeAg+ patients |
Taiwan Childhood Vaccination — HCC Prevention Landmark
Universal childhood HBV vaccination — the natural experiment
Taiwan introduced universal neonatal HBV vaccination in 1984 — the first country to do so. A landmark 1997 NEJM paper (Chang et al.) showed that HCC incidence in children aged 6–14 fell from 0.70/100,000 (1981–1986, pre-vaccination) to 0.36/100,000 (1990–1994, post-vaccination) — a reduction of nearly 50%. This was the first direct demonstration that a vaccine could prevent a human cancer. Subsequent 30-year follow-up data confirm sustained HCC reduction. The mechanism: eliminating perinatal HBV infection prevents immune-tolerant chronic carriage — which carries the highest lifetime HCC risk. The WHO now includes HBV vaccination in all childhood immunisation programmes globally.
Antiviral Therapy
Nucleoside / Nucleotide Analogues (NAs) — tenofovir, entecavir
Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are first-line; high barrier to resistance; suppress HBV DNA to undetectable in >90% of patients. Entecavir (ETV) equally effective; preferred in renal disease. NAs are not curative — they suppress but do not eliminate cccDNA. Long-term (often lifelong) therapy required for most patients.
Pegylated interferon-α (Peg-IFN)
48-week finite course; stimulates innate and adaptive immune responses; modest HBsAg decline; HBeAg seroconversion in ~30% of treated HBeAg+ patients. Preferred when functional cure (HBsAg loss) is the goal. Significant side-effect profile (flu-like symptoms, neutropenia, neuropsychiatric).
Bulevirtide — entry inhibitor
First-in-class entry inhibitor (approved EU/UK); myristoylated preS1 peptide blocks NTCP binding. Used in chronic HBV/HDV co-infection. Subcutaneous injection. Reduces HBsAg and HDV RNA; combination with Peg-IFN shows functional cure rates in HDV.
Immune Signature
Cross-Atlas Connections
References
- WHO. Hepatitis B fact sheet. 2024. who.int/news-room/fact-sheets/detail/hepatitis-b
- Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med. 1997;336(26):1855–9. doi:10.1056/NEJM199706263362602 · PubMed 9197213
- Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife. 2012;1:e00049. doi:10.7554/eLife.00049 · PubMed 23150796
- Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99. doi:10.1002/hep.29800 · PubMed 29405329
- Lucifora J, Xia Y, Reisinger F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343(6176):1221–8. doi:10.1126/science.1243462 · PubMed 24557838
- BEDORE Study Group / Lenz O, et al. Bulevirtide 2 mg and 10 mg combined with tenofovir disoproxil fumarate in patients with chronic HBV/HDV coinfection. Lancet Infect Dis. 2023. doi:10.1016/S1473-3099(23)00178-4
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This entry covers HBV biology, natural history, and current therapy. Planned expansions: HDV co-infection, cccDNA-targeting cure strategies, RNA interference therapies (siRNA, ASO), and HBV vaccine immunology. Every entry follows the same open schema.