The Hepatitis C Virus (HCV) was discovered in the 80s thanks to the work of Harvey J. Alter, Michael Houghton, and Charles M. Rice, who jointly received the Nobel Prize in Physiology or Medicine in 2020.
Before that, two other viruses called Hepatitis A virus and Hepatitis B virus (HAV, HBV) were known to infect the human liver, but many cases of liver disease with similar characteristics were not due by either of them, did not have a known cause, and were therefore defined as “non-A non-B”.
According to the World Health Organization, 71 million people in the world have an HCV chronic infection, with a higher prevalence in Europe and the Middle East. In 2015 alone, there were 1.75 million new infections, and in 2016, 399.000 death caused by the consequences of this infection were registered. Since HCV, HBV, and HIV share the same mode of transmission, co-infection by combinations of these three viruses is common.
HCV is an RNA virus belonging to the Flaviviridae family, with 8 genotypes differing by 30% of their sequence, which can influence both the severity of the pathology and the reaction to treatment. The viral genome encodes 10 proteins, several of which are involved in the virus immune evasion. Hepatitis C Virus exclusively infects humans and chimpanzees and replicates very quickly: within days since the beginning of the infection, 1 million viral particles can be detected per ml of blood (taking into account that an adult has about 6 liters of blood, it can host 6 billion viral particles in total).
This virus can be transmitted through contact with contaminated blood (including very small amounts) and infects the liver causing either an acute or chronic infection. Chronicity is achieved by the viral ability to go unnoticed for a long time without any symptoms and to evade the immune defenses of the host by accumulating mutations, and inhibiting the activity of specific cell types of the immune system.
One of the viral mechanisms to evade the immune response consists in mutate very often the proteins of its surface (E1 and E2), making them hardly recognizable by the antibodies. Moreover, the virus produces huge amounts of subviral particles,that are made of the external viral envelope but don’t carry any genome and are incapable of replication, outnumber the proper viral particles, and act as decoys for neutralizing antibodies. This is one of the reasons why, despite HCV has been known for more than 30 years, an effective preventive vaccine is not yet available.
Only 30% of the acute HCV infections are symptomatic (malaise, abdominal pain, dark urine, edema of lower extremities, jaundice – yellow skin, mucosae, and eyes). During the first weeks of the infection, T cells are recruited to the liver where they kill the infected cells and produce Interferon gamma, a molecule that inhibits viral replication, ending the infection in 30% of cases. In this early phase, 90% of patients with an HCV diagnosis can be cured with an Interferon alpha-based treatment.
The dangerousness of this virus lies in its ability to not causing any symptom in 70% of cases: the infection cannot be diagnosed and it progresses to chronicity. Usually, if the infection becomes chronic, the organism is no longer able to spontaneously get rid of the virus, despite a continuous production of Interferon gamma; in this phase, even the Interferon alpha treatment becomes ineffective. The virus keeps replicating and eludes the immune system. Both the viral replication and the immune system activation contribute to the inflammation of the liver and to the associated pathology. As for HBV, a chronic HCV infection severely damages the liver and leads to cirrhosis and hepatocarcinoma (liver cancer).
In addition to viral characteristics, there are specific variations in human genes involved in the immune response, that can determine whether an individual is more or less susceptible to develop a chronic infection, and to respond to treatment.
Recently, a new antiviral therapy has been developed, based on the so-called DAA, direct-acting antivirals; it is efficient in 95% of cases and with all genotypes. However, access to treatment is not broadly available, in part because of its cost, and in part because in many cases the infection is not diagnosed.
Unfortunately, there is no vaccine available to prevent HCV infection; this is due to the great genetic variability of the virus, but also to the lack of animal models for the experimental study of this virus and its vaccines and treatments.
The only measures we have to limit HCV spread are the screening of all blood donors, the correct handling and disposal of tools for injections, tattooing, piercing, and acupuncture, and the avoidance of any contact with even small amounts of blood.
Image: “Hepatitis C.jpg” by http://www.scientificanimations.com is licensed with CC BY-SA 4.0.
Bibliography
Nobel Prize in Physiology or Medicine 2020 https://www.nobelprize.org/prizes/medicine/2020/press-release/
World Health Organisation https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
European Centre for Disease Prevention and Control https://www.ecdc.europa.eu/en/hepatitis-c/facts
The hunt for a vaccine for hepatitis C virus continues, Editorial of The Lancet Hepatology and Gastroenterology 2021, https://doi.org/10.1016/S2468-1253(21)00073-X
Innate immunity and HCV, M.H. Heim, Journal of Hepatology 2013, https://doi.org/10.1016/j.jhep.2012.10.005
Hepatitis C Virus Infection: Host–Virus Interaction and Mechanisms of Viral Persistence, D.I. Chigbu et al, Cells 2019, https://doi.org/10.3390/cells8040376
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