Hepatitis C

Research

By:
Ahmed Faiz
Sameer
 Hepatitis C
Introduction
“Hepatitis C is a disease that causes an
inflammation of the liver”(1), “sometimes leading to
serious liver damage”(2) which is a severe problem
as the liver is considered a vital organ which
contributes to and regulates significant aspects of
the human body. Hepatitis C is caused by HCV
(Hepatitis C Virus). So HC can be defined as an
Acute(Can develop and become chronic), Viral,
Infectious, Respiratory Disease that affects humans
and chimpanzees only.

Hepatitis C Virus General Structure(3)

Hepatitis C Virus is the name of the pathogen which causes Hepatitis. It is an
enveloped, positive-strand RNA virus classified in the Hepacivirus genus within
the Flaviviridae family. spherical and heterogenous in size, ranging from 40 to 80
nm in diameter or size. HCV is an RNA virus which makes it unique given the fact
RNA viruses are not known for their ability to cause a chronic infection for almost
all exposed adults. The Virus consists of a long-RNA-stranded viral genome
(approximately 9600 nucleotides long).

The genome is covered up by the HCV capsid, also known as the HCV core, which
is the protein shell that encapsidates and protects the HCV RNA, is made up
entirely of protein. The capsid consists of an outer and inner surface. The inner
surface binds with some of the HCV viral segments, while the outer layer
interacts with the virus’ membrane. The HCV capsid is spherical and
heterogenous in size, with an approximate diameter of 30 to 35 nm.

On top of that polypeptide layer (capsid) is the livid envelope. This lipid
membrane is composed primarily of cholesterol, cholesteryl esters,
phosphatidylcholine, and sphingomyelin. The virus itself contains a very large
amount of incorporated cholesterol which gives it a feature resembling (VLDL)
which is a very low-density lipoprotein that the liver forms and releases into the
bloodstream. This specific ratio found on the HCV membrane distinguishes it
totally from various viruses and host cells. Scientists nowadays state that “It
appears that cholesterol and sphingolipid both play a role in the entry of HCV
into host cells”.

On the outermost layer, the envelope is found. This envelope is formed out of two
layers of glycoproteins (proteins containing glycans attached to amino acid side
chains, it is found on the outside of the plasma membrane of human blood). E1
which is a “well-conserved protein, about
100kD in size”(5), “is a type I transmembrane
protein that forms a complex with the E2
glycoprotein to facilitate viral entry into host
cells”(6). “It comprises mainly of about 192
amino acids and it contains two of the
N-linked glycosylation sites that facilitate the
fusion that occurs during the invasion of the
host cell and the viral”(7). And E2 which is the
“main target for neutralising antibody (NAb)
responses, Is another important structural
polypeptide that is found on the outermost membrane. It is also involved in the
viral entry into the host cell”(8). “The antibodies attacking those proteins have
been shown to prevent HCV infection in vitro and animal models and Some
studies have suggested that the E2 protein may be a better target for vaccine
development than the E1 protein due to its higher immunogenicity”(9).
Hepatitis C Invasion(3)
The Hepatitis C virus invades the human body cells and follows certain steps. The
HCV life cycle begins with the HCV binding to two host receptors on the surface
of a hepatocyte: low-density lipoprotein receptor (LDLr) and heparin sulphate
proteoglycans (HSPGs). This initial interaction triggers the HCV outer E1/E2
heterodimer membrane protein to bind to the scavenger receptor B1 (SRB1) and
the tetraspanin protein CD81. The interactions between these proteins create a
wave in the lipid membrane, propelling the HCV particle to a tight junction
between hepatocytes. Then the Virus starts propelling itself until it reaches the
tight junction, CD81 interacts with claudin-1 (CLDN1), starting a folding viral
particle and hepatocyte cell membrane into a pit-like region covered by a protein
called clathrin. This results in an internal endosome composed of a viral particle
coated by the host cell membrane. When the virus reaches into the cell, the
clathrin cover that surrounds the endosome starts dispersing, leaving the
endosomal vesicle free. The endosome contains an acidic pH that triggers fusion
between the viral and host membranes, in a process referred to as endosomal
fusion. This process enables the uncoating of the capsid shell, releasing the HCV
RNA into the cytosol for translation and replication. Then this RNA goes through
translation generating a single polyprotein that is approximately 3,000 amino
acids long. Viral proteolytic processing occurs within the rough endoplasmic
reticulum which results in 10 mature HCV proteins, including structural and
nonstructural proteins. Then those proteins go through replication which results
in newly synthesised HCV RNAs. Those new synthesised RNAs are either
incorporated into nucleocapsid particles or used for RNA translation and
replication. The RNA replication process is supported by multiple HCV
nonstructural proteins (replication complex). Then the maturation stage occurs
resulting in a mature HCV lipoviral particle. Then They fuse with the hepatocyte
cell membrane. The generation of the HCV lipoviral particle is coupled to the
cellular VLDL pathway and during this process, both HCV lipoviral particles and
VLDL particles are released into the extracellular compartments.
Historical discovery of Hepatitis C(10)
Hepatitis has been a part of past human history, but it is unfortunately confused
with various diseases because of its common. It was during the twentieth century
that scientists discovered that most cases of hepatitis were caused by viruses that
infect cells in the liver. Researchers divided viral hepatitis cases into two separate
diseases based on their traits, both diseases were potentially serious, but they
differed in how they spread and made people sick. “Hepatitis A” spreads
person-to-person contact or through contaminated food or water, is
characterised by a short incubation period, and results in an acute (temporary yet
serious) illness. “Hepatitis B” spreads through blood and other bodily fluids, has
a longer incubation period, and could lead to a chronic (long-lasting) infection.
However, there were still cases of hepatitis that could not be attributed to either
virus, leading to the recognition of a third type, called non-A, non-B hepatitis. In
1984, scientists in the NIDDK Intramural Research Program led a study of 10
patients at the NIH Clinical Center in Bethesda, Maryland. The patients were
given daily doses for about 15-16 weeks, and the health of their liver was
monitored by testing their blood for a marker of liver damage. The results of the
test or study were immediate and surprising, most of the patients showed signs of
a healthier liver after one month of treatment. The patients relapsed when the
treatment was stopped for 4 months; however, once the treatment was restarted,
their liver health showed an improvement and stayed normal even after the doses
were lowered gradually until stopped after a full year. Some of the patients had
only the tiniest responses to interferon, while others responded despite then
relapsing, but, in the end, half the patients in the test showed no signs of liver
infection in follow-ups that were eventually extended for a range of 10-25 years.
These were the first patients to be cured of the disease that would eventually be
known as hepatitis C. The results of these studies and more made it clear that
more research was required. While interferon-based therapy was typically
successful for almost half of the total patients, it was usually accompanied by
some side effects that included fever, fatigue, muscle aches, and depression that
often caused limitations when it came to the dosage and duration of the
treatments. Nevertheless, those beginning with tests furnished important insights
into how the virus responds to (or resists) therapy and provided important pieces
of evidence about the virus’ biology and strength. This information would be
useful while designing therapies based on more effective treatments, showing a
huge development that would bring those treatments within reach. In 1989, a
team of excellent researchers led by Dr Michael Houghton at the Chiron
Corporation in California used a unique technique referred to as polymerase
chain reaction (PCR) in which a small piece of genetic material was identified.
That small piece was present in the blood of patients with non-A, non-B hepatitis.
This piece of genetic material was later identified as the HCV genome. In 1990, a
Japanese team at a pharmaceutical company was able to identify and reach the
same piece of genetic material using a different method of approach, this
discovery resulted in the development of a blood test for HCV. And finally, the
discovery of HCV was announced by the World Health Organization in 1992 and
the blood test was made available around the globe. After the discovery of HCV,
researches were still conducted for the sake of developing new treatments.

Ways of Spread
Hepatitis C infection, which is caused by the hepatitis C virus (HCV), can be
spread from one host, infecting others. For the virus to be transmitted, blood
contact should be done, this contact can be through sharing drug needles or other
drug materials with someone who has HCV which is the most common way that
people get hepatitis C in the United States. Getting an accidental stick with a
needle that was used on someone who has HCV. This can happen in healthcare
settings. Tattooed or pierced with tools or inks that were not sterilised after being
used on someone who has HCV. Having contact with the blood or open sores of
someone who has HCV. Sharing personal care items that may have come in
contact with another person's blood, such as razors or toothbrushes. Being born
to a mother with HCV. Having unprotected sex with someone who has HCV.

Symptoms
When it comes to symptoms the majority of people
infected with hepatitis C experience no symptoms.
The disease has an incubation period that ranges
from 2 to 6 weeks. Some people who acquired an
acute hepatitis C infection may have symptoms for 1
to 3 months after exposure to the virus. These
symptoms may include
● pain in your abdomen
● vomiting
● yellowish eyes and skin dark yellow urine
● feeling tired
● Fever
 ● grey- or clay-coloured stools,
● joint pain
● loss of appetite, nausea

Testing, Cure and Vaccination

As we discovered earlier, Hepatitis C is a serious disease that should not be given
less care than others. Various tests were made for diagnosing purposes in order
to detect the presence of HCV inside your body. The Antibody test is a test that
determines whether you were infected with or exposed to HCV before by
diagnosing and looking for the presence of the Virus’ antibodies. The test will not
result in a positive indicator for some months after infection because the
formation of antibodies takes time. If the test is negative, but symptoms are or it’s
suspected that you may have been exposed to hepatitis C before, you may be
advised to retake the test. A positive test indicates that you have been infected at
some stage of your life. It doesn't necessarily mean you are currently infected, as
you may have since cleared the virus from your body.

The only way to tell if you are currently infected is to have a second blood test,
called a PCR test which is a blood test that checks if the virus is still present by
detecting whether it is reproducing inside your body. A positive result test means
your body has not fought off the virus and you are currently infected. Magnetic
resonance elastography (MRE), Transient elastography and Liver biopsy are also
effective tests that detect damage in the liver which is referred to as chronic
Hepatitis C, after detecting the Hepatitis C virus, genotype tests are done in order
to identify which of the six kinds (genotypes) of hepatitis C you have.

If the infection is diagnosed in the early stages, known as acute hepatitis,

treatment may not need to begin straight away, instead, tests are taken a few
months after to check if your body is fighting off the virus. If the infection
continues for several months, known as chronic hepatitis, treatment will usually
be recommended. There are 6 main strains of the virus. In the UK, the most
common strains are genotype 1 and genotype 3. You can be infected with more
than 1 strain. You are given a cure according to the genotype you have, but in
general, the cure is a combination of direct-acting antiviral (DAA) drugs. These
drugs work by targeting different stages of the HCV lifecycle, blocking the virus
from replicating and reducing the amount of virus in the blood. The treatment
generally lasts for 8-12 weeks, although the duration may vary according to the
specific medications used and the severity of the infection. Treatment success
rates are very high, with cure rates of over 95% in most cases.

After the cure, HCV inside your body is monitored to make sure that it is 100%
eliminated from your body. Although the cure rates are high, there is currently no
official, certified, effective vaccination against this disease, but research is still
being conducted.
1. Centers of Disease Control and Prevention
2. Mayo Clinic
3. Hepatitis C online
4. Medical Microbiology, A book written by Samuel Baron
5. Krieger, N., & Lohmann, V. (2019). Hepatitis C virus: From molecular
virology to antiviral therapy. Journal of hepatology
6. Drummer, H. E. (2015). Challenges to the development of vaccines to
hepatitis C virus that elicit neutralizing antibodies
7. Zeisel, M. B., Felmlee, D. J., & Baumert, T. F. (2013). Hepatitis C virus
entry. Current topics in microbiology and immunology
8. Hepatitis C virus envelope glycoproteins: Antigenic diversity, humoral
response and vaccine development
9. Neutralizing Antibodies to Hepatitis C Virus E2 Protein Block Virus
Infection
10. NIDDK (National Institute of Diabetes and Digestive and Kidney
Diseases)
11. WHO
12.Healthline