hepatitis c, hepatitis virus, hepatitis liver

Hepatitis means inflammation (itis) of the liver (hepar), a worsening or swelling of the liver cells. There are many reasons for hepatitis which include infections A, B and C that many of us have come across, but also the disease also includes auto-immune hepatitis, fatty liver hepatitis, alcoholic hepatitis and toxin induced hepatitis. Globally, it’s estimated that around 250 million people are impacted by hepatitis C. Moreover, around 400 million persons are chronic carriers of hepatitis B.

How big is the Hepatitis Problem?
Hepatitis is an enormous ailment; so extensive in fact that there’s a good chance you keep company with at least one or more people who have hepatitis. There’s an equally high chance that you know nothing about them because with hepatitis comes a stigma. Often people with hepatitis find it easier to get on with their life by not informing others. This is mainly due to the difficulties they can experience due to the ignorance of others. The issue may however be compounded by the fact that some forms of hepatitis are infectious. However, those who know they’ve infectious hepatitis only need take a few basic precautions to prevent passing the infection around.

The Liver
Hepatitis affects the liver. The liver is a wedge shaped organ located on the upper right side of the body, lying beneath the rib cage. The largest organ it accocunts for 2 to 3 percent of the body’s total weight. Unlike the heart or stomach, the liver has no one function. Doctors specialising in the liver, hepatologists, think that it has over 140 functions. Such as producing bile needed for digestion, storing minerals and vitamins, assisting in blood clotting (vitamin k supplement), neutralising poisons, producing amino acids to build healthy muscles, regulating energy, maintaining hormonal balance, processing drugs. When someone gets hepatitis the function of the liver is compromised and the functions of it can be affected to varying degrees.

The History of Hepatitis
Hepatitis was believed to exist in viral form from ancient times. It is well known that a disease existed that affected the liver and caused yellowing of the skin (jaundice). İnvolving the 1800s and early 1900s, 2 types were recognized as either serum type or viral type. In 1963 there was clearly an important breakthrough which identified the cause of serum hepatitis and named the hepatitis B virus (HBV). 10 years later the source of infectious hepatitis was found and named the Hepatitis A virus (HAV), and although scientists knew other viruses existed it was not until 1989 that the hepatitis C virus (HCV) was isolated.

Even though hepatitis delta virus (HDV) was known about since the mid 1970s, it was only in the late 1980s -1990s that it was understood to exist only in the presence of hepatitis B. In 1990, hepatitis E virus (HEV) and in 1995, Hepatitis G virus (HGV), were identified. Other viruses, hepatitis F virus (HFV) and transfusion transmission virus (TTV) are believed to exist, but are not as yet proven.

Viral Hepatitis
Each type of viral hepatitis is different. They’ve different characteristics and are known by alphabetical names – hepatitis A through to E. Four other types exist F, G, TTV (Transfusion Transmitted Virus) and S.E.N-V (these are the initials of the person in which this form of the virus was initially identified – V standing for virus). Behavioral precautions and treatment will depend on the sort of hepatitis.

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hepatitis, hepatitis viruses, hepatitis a, hepatitis b, hepatitis c, hepatitis d, hepatitis g

This picornavirus is the causative agent of contagious liver disease. Picornaviruses have a single strand, positive sense RNA genome surrounded by a undressed (unenveloped) icosahedral capsid that is around 28 nm in dimension. At the RNA strand is a viral healthy proteins called VPg. There is only one serotype of HAV.

Replication

The disease binds to a receptor that is observed on the surface of hepatocytes and a few other cells. HAV cellular receptor 1 (havcr-1) has an ectodomain that possesses an N-terminal cysteine-rich immunoglobulin-like region, superseded by a mucin-like community that expands the immunoglobulin-like location well above the cell covering. The immunoglobulin-like region is requested for binding of HAV. The virus requires its complete life in the cytoplasm where it replicates using a virus-encoded RNA-dependent RNA polymerase. For further information on picornavirus reproduction see Virology Component Chapter 4.

HEPATITIS B VIRUS

Real human hepatitis B virus is the prototype virus of the hepadnavirus family and causes serum liver disease. HBV has a diameter of about 40nm. It infects humans and chimpanzees but there are closely correlated users of this family that infect other mammals and birds. HBV is a DNA virus and is surrounded. The Genetics is only mainly double leg stranded and forms a eliptical of approximately 3,200 basics. Eventhough surrounded by a host cell-derived package, HBV is unexpectedly consistent to natural solvents. It is also heat- and pH-resistant. The genome is associated with the P (polymerase) health proteins and this complicated is, in turn, encompassed with the core antigens (HBcAg and HBeAg). These two healthy proteins have most of their collection in widespread and most of the HBeAg is produced since it is enhanced otherwise from the HBcAg and thus not gathered together into progeny virus. Embedded in the covering lipid bilayer is the surface antigen (HBsAg). The HBsAg (Australia antigen) is made up of 3 glycoproteins that are encoded by the same gene. The prote is are converted in the same studying frame but start at a numerous AUG start codon; thus, all have the same C-terminus. The largest protein is the L proteins (42kd) and secured within this is the M glycoprotein. The S glycoprotein (27kD) is enclosed within the M protein. The HBsAg healthy proteins is also produced into the patient?s serum where it can be seen as circular (generally self-associated S protein) or filamentous particles (also mostly S healthy proteins but with some L and M). The previous are tinier than the true virus but the filaments can be quite large (several hundred nanometers). This large variety of free HBsAg consideration for the inability to detect antibodies opposing the protein beginning throughout infection (the so-called “window” in between the presence HBsAg (indicative of the presence of virus) and the presence of anti-HBsAg).
The glycoproteins on the virus outside contain antigenic determinants that are group particular and type specific. Using these determinants, epidemiologists determine eight subtypes of HBV. HBV virions are also known as Dane allergens.

Replication

HBV has a very interested way of replicating itself seeing that , although it is a DNA virus, it uses a RNA proviral advanced that has to be copied back to DNA. The copying of RNA to DNA is not a normal perform of an uninfected cellular but is throughout retroviruses that also have an RNA genome and a DNA more advanced that gets incorporated into host cell chromosomes. For the purpose of copying RNA to DNA, retroviruses and HBV have a virally-encoded DNA polymerase (P) called reverse transcriptase.
After the HBV has attached to the cell covering receptor (which has yet to be identified but may be a person of the ovalbumin family of serine protease inhibitors), the viral membrane combines with the cell membrane launching the core into the cytoplasm. The core healthy proteins dissociate from the partially double stranded DNA. DNA polymerase now finishes the DNA so that it is thoroughly dual stranded. This is done by the virally-encoded polymerase in the cytoplasm that is one of the primary healthy proteins (whereas the cell’s DNA polymerase is in the nucleus). The double stranded DNA goes in the nucleus and the ends are ligated by host enzymes so that the virus is in the form of a spherical episome. The viral DNA representatives with host nuclear histones and is transcribed by cellular RNA polymerase II into mRNAs. In contrast to the situation with retroviruses, nonetheless, the DNA form of HBV is generally not incorporated into cellular DNA; instead it is uncovered as an independent episome. This is because, unlike retroviruses, hepadnaviruses have no integrase exercise. However, integrated parts of the HBV genome are found in the chromosomes of many hepatocellular carcinoma patients.
Four mRNAs are made from the HBV genome. The host cell RNA polymerase interacts with four promoters but transcription generally ceases at the same polyadenylation site so that the the overlap golf mRNAs have a common 3? terminus. One of these mRNAs is slightly longer than the DNA sequence because of the polyadenylation at one end and a repeated region. This is the full duration c-RNA that will be the template for the genome. The full length messenger RNA codes for the polymerase and core HBcAg and HBeAg proteins. The latter are very corresponding because they are converted in the same examining frame from two distinctive start codons. Two smaller mRNAs (2.4 and 2.1 bases) which overlap code for the surface glycoproteins. There is also a small mRNA of 700 bases that codes for a protein that is a protein kinase and is a transactivator of transcription.
In the cytoplasm, the full-length (3,500 base) positive strand c-RNA is encapsidated by core proteins. Inside the core, the RNA is transcribed to minus strand DNA by the same DNA polymerase (reverse transcriptase) that finished the dual stranded DNA and, at the same time, the RNA is degraded by a ribonuclease H that is also part of the change transcriptase. Unlike the opposite transcriptase of the retroviruses, the HBV reverse transcription reaction does not require a tRNA primer. Rather, the polymerase itself acts as a primer and remains covalently associated to the 5? end of the negative strand DNA. A variety cell chaperone protein, heat shock protein 90, is also necessary. The chaperone affiliates with the reverse transcriptase allowing it to fold into an active conformation.
The virus now buds through the endoplasmic reticulum and/or Golgi Body membranes (or conceivably a novel pre-Golgi compartment) of the host cell from which it receives HBsAg. At this period or later, the minus stand of DNA is partly transcribed into a plus follicle. When the viral DNA polymerase is used to transcribe RNA to DNA, it is acting as a reverse transcriptase similar to that found in retroviruses; in fact, HBV DNA polymerase and retroviral reverse transcriptase are very similar, and may have evolved from a common ancestor.
Virus particles that contain RNA or DNA at various stages of replication can be found in the blood stream recommending that nucleic acid reproduction is not tightly controlled with the penetration out of the cell. In addition, empty envelopes containing the envelope proteins inserted in a lipid bilayer are endlessly being shed.

RNA polymerase main problem

There is a different main problem caused from using host cell RNA polymerase II to transcribe a DNA viral genome to an RNA form (See section on retroviruses). The normal function of RNA polymerase II is to transcribe a gene into messenger RNA for subsequent translation into protein. In the mRNA, all that is required is the details to make the health proteins. In the DNA gene, even more details is current that is needed to make the RNA. This more information (that is not transcribed into RNA) contains the supporter (the site at which the RNA polymerase binds), the boosters that are up- and down- approach of the community transcribed to mRNA and the polyadenylation site. Thus, a messenger RNA is smaller than the DNA gene, even if there are no introns.
Retroviruses get over the loss of promoter/enhancer details as a result of using RNA polymerase II transcription by carrying interior replicates of the promoter and enhance locations (these are the U3 and U5 sequences respectively). They duplicate their internal U3 supporter sequence and transpose it to the opposite end when the DNA is transcribed from RNA. Similarly, the boosters and other 3? details are stored internally (as U5) and transposed to the other end. These events give rise to the lengthy terminal repeats (LTRs) that are only uncovered in the DNA form of the virus. When the RNA polymerase emphasizes the promoter in the U3 community, it finds the transcription initiation site at the circumference between the U3 and R and starts transcribing at the beginning of the R community. This leads to a faithful copy of the original RNA as the terminal U3 and U5 are lost .
The same problem occurs in hepadnaviruses which also have a DNA form of their genome that is burned to RNA by host cell RNA polymerase II before burning the RNA back to DNA working with reverse transcriptase. However, the mechanism is different; in this case, the DNA form of the virus is smaller than the RNA form, fairly the opposite of what occurs in the retroviruses.
The hepadnaviruses are small DNA viruses and, in contrast to the retroviruses, it is the DNA that is packaged into the viral particle. This DNA is copied to RNA in the infected cell by RNA polymerase II and the resulting RNA is copied back to DNA by reverse transcriptase in the maturing virus particle.
In the viral particle, the DNA is only partially double trapped. The negative strand is complete, though not ligated into a circle. There are free 5? (with an attached reverse transcriptase protein chemical) and 3? ends. The DNA is in the form of a relaxed circle because it is hybridized to a partial copy of the positive strand. The DNA contains two direct repeats (DR1 and DR2). DR1 is close to the 5? end of the negative strand and DR2 is close to the 5? end of the partial positive strand.
On entering the nucleus, the negative strand is ligated to form a covalently closed circle. This is then copied by host RNA polymerase II. The polymerase starts about 6 bases to the left  of the DR1 and proceeds  around the circle past both the initiation site and the DR1 and stops at the termination/poly A site (light blue) that is a little further downstream. The RNA becomes polyadenylated. The RNA copy is therefore larger than the covalently closed circular DNA (compare the situation in retroviruses) because the DR1 region has been duplicated and poly A has been added.
This RNA moves to the cytoplasm where encapsidation by viral proteins occurs. There is an encapsidation signal at the 5? end of the RNA and thus only one RNA molecule is found in each virion (compare the situation in retroviruses). Now, in the virus particle itself, the RNA is copied to DNA using reverse transcriptase. All DNA polymerases need a primer and in the case of the retroviruses this is a host cell tRNA that is packed in the virion. In the hepadnaviruses, the polymerase is packaged in the virion as it is in the retroviruses, though there are fewer polymerase proteins per virus particle in the hepadnaviruses. The reverse transcriptase is itself the primer for the synthesis of the negative DNA strand and it remains attached to the 5? end of the DNA via a tyrosine residue.
The DNA initiates on a hydroxyl group of the tyrosine using, as a template, a region near the 5? end of the RNA (fig 4Ci-3). The polymerase copies through the DR1 near the 5? end of the RNA and terminates at the end of the RNA molecule. Next, a template exchange occurs in which the nascent negative strand DNA moves to the DR1 near the 3? end (fig 4Ci-4). Why this is necessary is obscure since the initiation could have occurred near the 3? DR1. From the 3? DR1, the DNA is extended accompanied by RNase H digestion of the template RNA strand. Synthesis stops when the 5? end of the RNA is reached. The negative strand is now terminally redundant. The RNA is not completely destroyed and the last 15 or so nucleotides remain to serve as a primer for the second (positive) DNA strand synthesis. This is translocated to the DR2 at the 5? end of the first DNA stand . Extension continues to the 5? end of the first DNA strand. There now occurs a switch of template in which the DR1 at the 5? end of the negative strand is replaced by the DR1 at the 3? end so circularizing the template. The reverse transcriptase now copies around the circle for a variable distance to form the DNA that is found in mature virus particles.

Carcinogenesis

It is clear that individuals who are HBsAg positive are at a much higher risk of hepatocellular carcinoma than those who are negative. In patients with chronic hepatitis, there is destruction of hepatocytes as a result of the immune response to the virus. This results in regeneration (by cell division) of liver cells that may ultimately cause the cancer. Although the virus does not integrate during the course of normal replication, parts of the HBV genome are found integrated into the DNA of hepatocellular carcinoma patients. This may result in the activation of a cellular proto-oncogene in much the same way as occurs in some retrovirus-caused cancers; in fact, in most cases of woodchuck hepatocellular carcinoma (a widely used model system), viral DNA is found close to the myc or a similar proto-oncogene. Hepatocellular carcinoma takes many years to develop and this may reflect the rarity of integration in the absence of an integrase enzyme. The tumor that does develop is thus likely to be clone of a single cell where this process has occurred.
An HBV protein called protein X is known to activate the src kinase and this may also underlie HBV carcinogenesis. This protein may also interact with p53, one of the cell’s tumor suppressor genes.

HEPATITIS C VIRUS

Hepatitis C is a flavivirus (of which yellow fever is the prototype) that causes non-A, non-B hepatitis. Flaviviruses are icosahedral, positive strand RNA viruses and gain an envelope from their host cell. The virus particle is about 30 to 60nm across. The genome of 9,600 bases codes for ten proteins. In many ways, the flaviviruses are similar to picornaviruses with the prominent exception that they are enveloped. The viral RNA does not have a 5? cap or 3? poly A tract. Translation of the viral RNA is mediated by the internal ribosome entry site (IRES).
There is one protein product from one open reading frame. The hepatitis C virus polyprotein is cleaved by both a virally-encoded protease activity and a cellular protease. The nascent protein contains a signal sequence that results in the translating ribosome attaching to the cytoplasmic surface of the endoplasmic reticulum. The envelope protein (E) thus crosses and embeds in the membrane and the signal sequence is removed by a cellular signal protease. This results in the remainder of the protein, the core protein, becoming cytoplasmic. It is cut by two viral proteases. The C-terminal domain of NS2 is a cysteine protease and cleaves at the NS2/NS3 junction. Another protease (NS3/4A serine protease) cleaves the remaining junctions.
Thus, the core protein is cut into NS1, NS2, NS3 and NS4 proteins. NS2 and NS4 are then cut again (to give NS2a, NS2b, NS4a and NS4b)
HCV binds to either the CD81 antigen or low density lipoprotein (LDL) receptor on hepatocytes via its E2 glycoprotein. There is also some evidence that it may bind to glycosaminoglycans

HEPATITIS DELTA AGENT

Hepatitis D  is a highly defective virus since it cannot produce infective virions without the help of a co-infecting helper virus. This helper virus is hepatitis B virus that supplies the HBsAg surface protein. In budding out of the cell, HDV acquires a membrane containing HBsAg. HDV is similar to a plant viroid in that it has a small circular RNA genome (1,700 bases) but unlike the plant viroids, the RNA encodes a protein called the delta antigen. This complexes with the RNA. The RNA is single stranded negative sense and is a covalently closed circle. Because of a large amount of base pairing, the RNA takes on a rod-like structure.

HEPATITIS G VIRUS

Hepatitis G virus is a flavivirus, like HCV to which it is closely related. It is associated with some cases of acute or chronic non-A, non-B, non-C, non-D, non-E hepatitis. Although it seems common in human blood, it may not he a significant cause of hepatitis in humans.

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