Hepatitis C virus

Hepatitis C virus

The History of Virus Discovery

Long time accumulated clinical, epidemiological and laboratory data strongly indicated that it should be a widespread hepatitis agent not related to HAV or HBV. Intensive attempts to identify the enigmatic pathogen were protractedly unsuccessful until M. Houghton with colleagues, D. Bradley and H. Alter in 1985-1989 by the methods of molecular cloning isolated and then sequenced nucleic acid of a novel causative agent of viral hepatitis, later designated as hepatitis C virus or HCV.


Hepatitis C virus (HCV) belongs to Flaviviridae family. Currently this family contains 4 viral genera. The genus with the most numerous viral species here is Flavivirus. It harbors at least 53 zoonotic viral species that pertain to arboviruses, contracted by arthropod vectors to animal and human hosts.

Genus Hepacivirus contains single species of hepatitis C virus. HCV demonstrates extreme genetic variability being divided into 7 genotypes, each contains multiple genetic subtypes (totally more than 100). Subtype variations generate HCV quasispecies during the course of individual infection. HCV subtypes 1a and 1b have global distribution, they account for about 60% of total infection cases.

Structure of HCV

HCV is a positive single-stranded RNA virus of spherical shapes with lipid envelope, 60 nm in size. HCV virion has icosahedral symmetry. Viral particle has a core protein of nucleocapsid, two envelope glycoproteins E1 and E2. Proteins E1 and E2 promote HCV binding and fusion with membranes of hepatocytes facilitating viral entry. Viral genomic RNA encodes a number of non-structural proteins (NSP2NSP5A and NSP5B) with multiple functions. They possess enzymatic activity (helicase, protease), inhibit host interferon production, suppress lymphocyte activation, or induce apoptosis of infected cells. Non-structural protein NSP5B is viral RNA polymerase. Hepatitis C viruses can’t propagate in laboratory cell lines except hepatocyte cultures.

Virion Resistance

HCV as all flaviviruses is relatively unstable in the environment. Nevertheless, in plasma, if exposed to room temperature or dried, the virus maintains viability at least for 16 h. Viral survival expands at low temperatures. Heating at 60-70oC for 10 minutes irreversibly inactivates virus. HCV is sensitive to UV light and all conventional disinfectants (halides, aldehydes, phenol, H2O2, detergents, ether, ethanol, etc.)

Viral Replication Cycle

HCV infects hepatocytes, but it may replicate within lymphocytes and monocytes. Virus attachment is performed via binding of E1 and E2 viral proteins to a broad group of cell membrane receptors. Viruses enter hepatocytes by endocytosis. Viral uncoating is facilitated with endosome acidification resulting in fusion of lipid envelope with endosomal membrane. All cycle of virus propagation occurs in cytoplasm of infected cells.

Genomic (+) RNA translation results in primary polyprotein synthesis that further processed by viral and cellular proteases into mature viral proteins. Viral RNA polymerase NSP5B catalyzes genomic RNA replication through the stage of negative-sense RNA intermediate, which serves as template for genomic (+) RNA synthesis. Virion assembly and maturation is finalized by release of progeny viruses that leave hepatocytes by budding.

Pathogenesis, Clinical Findings and Immunity in Hepatitis C

Current infection by HCV demonstrates high prevalence throughout the world. According to WHO data, about 3% of human population are infected with HCV. Furthermore, some population subgroups (e.g., in Africa) have prevalence rates as high as 10%. Other high-prevalence areas are found in South America and Asia. It is estimated that totally there are more than 170 million HCV chronic carriers, who have elevated risk of progression of end-stage liver disease with cirrhosis, or hepatic carcinoma. Hepatitis C is solely anthroponotic disease. The source of infection is human (chronic patient or carrier).

Incubation period usually lasts from 1 to 3-4 months. The main route of transmission is parenteral. The major risk groups are intravenous drug abusers that apply non-sterile syringes for drug injections, and persons, undergoing frequent massive blood transfusions. Sexual or vertical transmission is much more seldom (less than 5%). Most new infections with HCV are subclinical. Hospitalization is rare, and jaundice occurs in less than 25% of patients. Self-recovery after primary HCV infection greatly varies in the range near 20-40%. The majority (more than 60%) of HCV patients develops primary chronic hepatitis, and many are at the risk of progressing towards chronic active hepatitis and cirrhosis (10-20%). About 40% of chronic liver disease is HCV-related.

Also HCV infection substantially elevates the risk hepatocellular carcinoma’ i.e., HCV is a potent biological carcinogen. HCV is regarded to exert low or moderate cytopathic effect (e.g., liver steatosis) but hepatocytes are damaged by cellular autoimmune reactions. Many isolates of HCV are resistant to interferons, as viral proteins can block interferon-inducible antiviral cell proteins. In a number of chronic HCV infections extrahepatic manifestations arise resulting in skin rashes, arthritis, progression of diabetes mellitus, etc. During the long course of chronic infection HCV undergoes active mutational process. It is essential for RNA-containing viruses with error-prone replication of genomic RNA with high mutation rate.

This results in generation of a great number of mutant genetic variants (quasispecies or “mutant cloud”) arisen from primary HCV virus in the course of individual viral infection. The emergence of quasispecies is extremely significant in progression of viral disease. The ongoing pressure from the side of host immune system and the influence of antiviral drugs promote the selection of resistant viral mutants. This leads to creation of new genetic lines resistant to antiviral therapy and therefore, leads to the progression of viral disease. Overall, in many patients the immunity almost fails to prevent chronic infections by HCV. What is more, the virus actively develops genetic variations during chronic infections resulting in change of viral antigenic structure.

Hepatitis C virus
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Laboratory Diagnosis of Hepatitis C

Serological testing is commonly elaborated for diagnosis of HCV infection. ELISA determines antibodies to HCV but don’t distinguish between acute, chronic, or resolved infection.

Nucleic acid-based assays (mainly, reverse transcriptase PCR) detect the presence of circulating HCV RNA. Quantitative real-time PCR is essential monitoring patients on antiviral therapy. Nucleic acid hybridization is used to determine genotypes of HCV isolates as well as for detection of viral RNA in liver biopsy specimens.

Principles of Disease Treatment and Prophylaxis

Active specific prophylaxis of HCV infection by vaccination is not available now. Great difficulties in design of HCV vaccines are inevitable due to high genetic diversity of hepatitis C virus.

Prior to 2013, combination therapy of hepatitis C patients with recombinant interferon-alpha and antiviral drug ribavirin was regarded as the method of choice for treatment of HCV infection. But only about 40-80% of chronic HCV patients depending on HCV genotype responded to this therapy regimen that lasted up to 48 weeks. The treatment was also followed by serious side effects. The results were improved with administration of prolonged interferons conjugated with polyethyleneglycol (PEG-interferons). Fortunately, almost simultaneously in 2013/2014 novel highly efficient anti-HCV drugs were introduced into clinical practice that literally revolutionized the treatment of this life-threatening infection.

With highest specificity they arrest the activity of viral proteins essential for HCV replication. In particular, simeprevir blocks viral protease action, sofosbuvir inhibits viral RNA polymerase NS5B, and ledipasvir inactivates non-structural protein NS5A, responsible for viral replication, assembly and egress. Taken in various combinations, they increased treatment success rate above 95% even for the most resistant 1 genotype of hepatitis C virus. The only serious obstacle still impeding the broad use of these life-saving drugs is a very high cost of treatment course.


  1. Hepatitis A Virus
  2. Hepatitis B virus