Hepatitis C Virus (HCV)
Enveloped positive-sense ssRNA virus with a ~9.6 kb genome encoding a single large polyprotein processed by host signal peptidases and the viral NS3/4A serine protease. Entry into hepatocytes requires sequential co-receptor engagement: E2 glycoprotein binds SR-B1 and CD81, then migrates to tight junctions for CLDN1 and OCLN engagement, followed by clathrin-mediated endocytosis and low-pH E1-mediated fusion. NS3/4A is the master immune evasion factor: it cleaves MAVS (blocking RIG-I→IRF3→IFN-β signalling) and TRIF (blocking TLR3 signalling), producing a cytokine-poor hepatic environment that drives the 75% chronic infection rate. Chronic infection triggers hepatic stellate cell activation via TGF-β, fibrosis, cirrhosis, and HCC. Pangenotypic DAAs (sofosbuvir/velpatasvir or glecaprevir/pibrentasvir) cure >95% of patients in 8–12 weeks.
Classification & Structure
| Genome | ~9.6 kb positive-sense single-stranded RNA; single ORF flanked by conserved 5′ and 3′ UTRs with internal ribosomal entry site (IRES) driving cap-independent translation; seven major genotypes (GT1–7) with 60+ subtypes; GT1 most prevalent globally |
| Family / Genus | Flaviviridae / Hepacivirus; no approved vaccine; eradication feasible via DAAs + diagnosis scale-up |
| Envelope | Enveloped; E1/E2 glycoprotein heterodimer on virion surface; E2 HVR1 hypervariable region enables antibody escape; circulates in blood as lipoviroparticles (LVP) associated with VLDL/LDL — structural immune evasion masking E2 neutralising epitopes |
| Size | ~50–60 nm diameter; low buoyant density (~1.03–1.25 g/mL) due to lipoprotein association |
| Key proteins | Core (nucleocapsid + lipid droplet assembly); E1/E2 (entry); p7 (viroporin); NS2 (NS2-NS3 junction cleavage); NS3/4A (serine protease + helicase; MAVS/TRIF cleavage; primary immune evasion); NS4B (membranous web induction); NS5A (replication scaffold; assembly factor); NS5B (RNA-dependent RNA polymerase; sofosbuvir target) |
Infection Mechanism
1 · Multi-step receptor-coordinated hepatocyte entry
E2 engages SR-B1 and CD81 on hepatocytes for initial attachment. The virus-receptor complex migrates to tight junctions where CLDN1 and OCLN are recruited to complete the entry complex. Clathrin-mediated endocytosis internalises the intact four-receptor complex; endosomal acidification (~pH 5) triggers E1-mediated membrane fusion and nucleocapsid release into the cytoplasm. This multistep, hepatocyte-specific entry mechanism restricts HCV tropism almost entirely to the liver.
2 · Replication in the membranous web
The (+)ssRNA genome is directly translated at the IRES into a ~3,000 aa polyprotein, processed into 10 proteins. NS4B induces ER membrane rearrangements to form the membranous web — a protected replication organelle where NS5B RdRp synthesises a (−)ssRNA template then amplifies (+)ssRNA progeny. NS5B lacks proofreading; error rate ~10−&sup4; substitutions/site/cycle generates a quasispecies swarm (~10¹² virions/day) driving antibody escape and drug resistance.
3 · NS3/4A — dual innate immune sabotage
NS3/4A serine protease cleaves MAVS (mitochondrial antiviral signalling protein, the RIG-I/MDA5 adaptor) at Cys-508, releasing it from the mitochondrial outer membrane and abolishing downstream IRF3 phosphorylation and IFN-β production. NS3/4A simultaneously cleaves TRIF (the TLR3 adaptor), blocking dsRNA-triggered IFN induction. Infected hepatocytes produce minimal type I/III interferons, enabling viral persistence in an immune-silent liver. NS3/4A protease inhibitors (glecaprevir, grazoprevir) target this protein therapeutically.
4 · T cell exhaustion and chronic persistence
Persistent HCV antigenemia drives progressive upregulation of PD-1, TIM-3, and CTLA-4 on HCV-specific CD8+ T cells, impairing effector function (T cell exhaustion). CD4+ Th1 help is weakened, removing co-stimulation needed for CTL maintenance. Regulatory T cell expansion and IL-10 further dampen liver-resident immune surveillance. Spontaneous clearance (~25% of acutely infected) requires broad, polyfunctional CD4+/CD8+ T cell responses with early Th1 help — a correlate of protection not achieved in the majority.
5 · Assembly via the VLDL secretory pathway
Core protein accumulates on cytosolic lipid droplets and recruits NS5A and the replication complex. Nascent virions bud into the ER lumen and traffic through the VLDL secretory pathway, acquiring their lipoprotein coat. Released LVPs mask neutralising epitopes on E2 through lipoprotein association — a structural immune evasion mechanism complementing NS3/4A innate blockade.
Host Immune Response
Disease Spectrum
| Stage | Presentation | Severity | Approximate frequency |
|---|---|---|---|
| Acute HCV (0–6 months) | Usually subclinical; 20–30% have fatigue, jaundice, RUQ discomfort; ALT/AST elevated; HCV RNA detectable 1–2 weeks after exposure | Mild–moderate; acute liver failure rare (<1%) | 100% of newly infected |
| Spontaneous clearance | HCV RNA becomes undetectable; ALT normalises; associated with IL28B CC genotype, female sex, symptomatic acute illness | Favourable; immune-mediated resolution | ~25% of acutely infected |
| Chronic infection | Persistent HCV RNA >6 months; most asymptomatic; ongoing hepatocyte inflammation and silent fibrosis accumulate over decades | Moderate; slowly progressive | ~75% of acutely infected |
| Compensated cirrhosis (F4) | Asymptomatic or mild portal hypertension; varices forming; HCC risk rising | Serious; HCC risk 2–5%/year | ~20–30% of chronically infected within 20 years |
| Decompensated cirrhosis | Ascites, variceal haemorrhage, hepatic encephalopathy, spontaneous bacterial peritonitis | Severe; liver transplant is definitive therapy | ~5–7%/year from compensated cirrhosis |
| Hepatocellular carcinoma (HCC) | Usually on background of cirrhosis; often asymptomatic until advanced; elevated AFP; confirmed by CT/MRI; 5-year survival <15% without resection or transplant | Life-threatening | ~2–5%/year in cirrhotic patients |
Treatment & Prevention
| NS5B inhibitor (nucleotide) | Sofosbuvir — nucleotide analogue chain terminator at NS5B RdRp active site; backbone of all current pangenotypic regimens; very high barrier to resistance; once-daily oral |
| NS5A inhibitors | Ledipasvir, velpatasvir, pibrentasvir — block NS5A phosphoprotein (replication scaffold + assembly); resistance-associated substitutions (RASs) possible at Y93H/L31M; pibrentasvir has highest barrier to resistance across genotypes |
| NS3/4A protease inhibitors | Glecaprevir, grazoprevir — block polyprotein processing; lower barrier to resistance than NS5B NUCs; hepatotoxic at high doses; avoid in decompensated cirrhosis |
| Pangenotypic regimens | Sofosbuvir/velpatasvir (Epclusa) 12 weeks; glecaprevir/pibrentasvir (Maviret) 8 weeks (treatment-naive, non-cirrhotic); both achieve >95% SVR12 across all genotypes; once-daily oral; minimal drug interactions |
| Vaccine | No approved vaccine. Challenges include 7 genotypes with 60+ subtypes, LVP lipoprotein masking of E2 neutralising epitopes, and NS3/4A innate evasion impairing adaptive priming. Broadly cross-neutralising anti-E2 antibodies and T cell vaccine strategies are in clinical trials |
| Post-SVR management | Liver fibrosis can partially regress after SVR; HCC surveillance (ultrasound ± AFP every 6 months) continues indefinitely in cirrhotic patients even after cure; HCC risk falls substantially but does not reach uninfected-individual levels |
Cross-Atlas Connections
References
- Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-62. doi:10.1126/science.2523562 · PubMed 2523562
- Lindenbach BD, Rice CM. The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol. 2013;11(10):688-700. doi:10.1038/nrmicro3098 · PubMed 24018384
- Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signalling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA. 2005;102(49):17717-22. doi:10.1073/pnas.0508531102 · PubMed 16301520
- Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs. Gastroenterology. 2016;151(1):70-86. doi:10.1053/j.gastro.2016.04.003 · PubMed 27147299
- World Health Organization. Hepatitis C. WHO Fact Sheet. 2023. who.int/news-room/fact-sheets/detail/hepatitis-c
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660 · PubMed 33538338
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This entry covers HCV biology, NS3/4A immune evasion, chronic liver disease, and DAA cure. Extrahepatic manifestations (cryoglobulinaemia, MPGN, lymphoma), fibrosis regression post-SVR, and HCV vaccine immunology are planned expansions. Every entry follows the same schema: structured frontmatter, peer-reviewed citations, and cross-atlas links.