The hepatitis C virus

The hepatitis C virus (HCV) is very small even in terms of viruses. So small that until recently it is has been very hard to study.

It is highly infectious through blood to blood contact and it is extremely resilient. The virus can survive outside the body in a droplet of blood for up to three months. This is why it is so important to sterilise equipment and medical tools that regularly come into contact with blood such as dental and tattooing equipment. It is unstable and so prone to frequent mutation.

HCV is often described as an indolent virus. This means that it is usually slow to establish itself and it can take time to cause chronic infection. This may be for a variety of reasons: As it is so unstable it may make many copies of itself which do not survive. It may also be that many virus particles are neutralised by the immune system but crucially this will still be at a lower rate than that of viral replication and so the virus still gains the upper hand but only slowly.

HCV bears little structural resemblance to the hepatitis A virus or the hepatitis B virus, even though all three viruses target the liver. The hepatitis C virus belongs to the Flaviviridae family of viruses, which includes viruses such as dengue fever and yellow fever, as well as the japanese and tick-borne encephalitis viruses.

HCV like all Flaviviridae viruses is an RNA virus. The difference between RNA and DNA viruses is how they package their genetic information. RNA viruses are much less stable than that of DNA viruses and so are more prone to mutation. Some scientists now think that some of the differences in the copies RNA viruses makes are actually intentionally initiated to increase their genetic variation and so their ability to survive. The viruses use what is called genomic intelligence to solve the problems they face.

This ability to mutate makes it much harder to make a vaccine and design drugs for RNA viruses. These viruses begin creating solutions to drugs the minute they encounter one. There is now evidence that mutation rates of HCV accelerate in response to interferon and ribavirin therapy.

The ability ability of the virus to mutate has resulted in seven recognised different genetic variations of HCV. These variations are known as genotypes and are numbered 1 to 7. These are linked largely but not exclusively to various part of the world. Genotypes 1, 2 and 3 have a worldwide distribution. Types 1a and 1b are the most common, accounting for about 60% of global infections. They predominate in Northern Europe and North America, and in Southern and Eastern Europe and Japan, respectively. Type 2 is less frequently represented than type 1. Type 3 is endemic in south-east Asia and is variably distributed in different countries.Genotype 4 is principally found in the Middle East, Egypt, and central Africa. Type 5 is almost exclusively found in Africa and the Middle East. Type 6 in Southeast Asia and the latest genotype - 7 is found in Central Africa.

It is still unclear whether the type of virus influences the progression of the disease within an individual. If it does, it is not thought to be dramatic. However, HCV genotype does strongly influence the response to treatment. So it is very important to know which genotype (and ideally the subtype) you are infected with if you are considering treatment.

Within each genotype there are also less pronounced variations known as subtypes. These are numbered a,b,c,d etc in order of their discovery.
A person chronically infected with hepatitis C will have a viral population that consists of a mass of minor genetic variations. These are called quasi species. These quasi species present an even more complex problem for the immune system.

HCV is also described as having positive-sense, single-stranded RNA genomes. This means that each viral particle contains a single RNA strand and that within HCV the RNA has two functions. It holds not just the information about HCV genetics but also the information about how to make the proteins the virus needs both from its own components and from that of the host liver cell.

Once it is has gained access to the human body the virus enters the blood stream and seeks out cells which will let it in. Until it does this is cannot reproduce itself. It was originally thought that HCV only infected liver cells but this is now known not to be case. HCV is also found in parts of the immune system, in bone marrow cells and in cerebrospinal fluid.

Once the virus reaches the liver on its journey in the bloodstream it attaches itself to receptors on the outside of liver cells. The proteins encasing the virus confuse the receptors so that it does not recognise it as a danger. The receptors consequently allow the virus into the cell. Once inside, the virus sheds its protein shells. The virus then unravels itself releasing the instructions to build up new protein structures using its own components and those of the host cell. The RNA genome reproduces itself and then reassemblies itself around the newly made protein shells into a new protected virus particle. It is now ready to break out of the cell to infect new cells. Normally when cells are infected by viruses they immediately begin to self destruct and release a type of interferon that instructs all nearby cells to die to prevent the virus spreading. HCV like many viruses has developed ways of interfering with this cell destruction to increase its chances of surviving and thriving.

The exact nature of these complex processes is still far from being fully understood and until they are more successful treatment or the creation of a vaccine will be more difficult to produce. Scientific research has been hampered by two key obstacles. Up until very recently it had not been possible to develop an efficient cell culture system of HCV in the laboratory. The last part of the virus lifes cycle: viral replication, assembly and release from the host cell can now be closely studied but another model system is still needed to show the beginning stages of the virus life cycle: how it enters host cells, and how it behaves in the cell before it replicates. The other obstacle is the lack of an animal model. The chimpanzee is virtually the only species besides humans susceptible to HCV infection. As a primate it would provide particularly useful information because of its genetic closeness to humans. However, as chimpanzees are an endangered species they are very expensive to use and the ethics of using them is a major issue.