Finalizing HCV

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    Muhammad Ali Minhas HCV

    Hepatitis C Virus

    (HCV)

    Introduction:Hepatitis is a disease characterized by inflammation of the liver, usually producing

    swelling and, in many cases, permanent damage to liver tissues. A number of different agentscan cause hepatitis, including infectious diseases, chemical poisons, drugs and alcohol. Viralhepatitis refers to a set of at least six viruses that are known to cause hepatitis: hepatitis A(HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), hepatitis E (HEV), andhepatitis G (HGV). Recent scientific evidence also suggests the existence of other, as yetunidentified hepatitis viruses.

    The most common types of viral hepatitis are hepatitis A, B, and hepatitis C. Both hepatitis Band C can lead to serious, permanent liver damage, and in many cases, death.

    There are two primary types of viral hepatitis, food-borne and blood-borne hepatitis. The former,which is spread through contaminated food and water, does not cause chronic liver disease. Bycontrast, blood borne viral hepatitis may lead to long-term, persistent infections and chronic liverdisease that has lethal consequences many years after infection.

    The Hepatitis C Virus:Hepatitis C is an RNA virus - which means that it mutates frequently. Once an infection

    has begun, hepatitis C creates different genetic variations of itself within the body of the host.The mutated forms are frequently different enough from their ancestors that the immune systemcannot recognize them. Thus, even if the immune system begins to succeed against one variation,the mutant strains quickly take over and become new, predominant strains. As a result, thedevelopment of antibodies against HCV does not produce immunity against the disease like itdoes with most other viruses. More than 80% of the individuals infected with HCV will progressto a chronic form of the disease.

    There are six basic genotypes of HCV, with 15 recorded subtypes, which vary inprevalence in different regions of the world. Each of these major genotypes can differsignificantly in their biological effects - in terms of replication, mutation rates, type and severityof liver damage, and detection and treatment options. However, these differences are not yetclearly understood.

    The 21 current variations in genotype, complicated by the constant mutation of the viruswithin infected individuals, represents a major challenge for the development of treatments and

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    vaccinesagainst HCV- and evenfor reliabledetection of

    the virus.There is noguaranteethat atreatment,test, orvaccineagainst onestrain will beeffectiveagainst all of

    them.Moreover, individuals cured of one strain will be prone to reinfection by any of the other strains.

    Anatomy of the Hepatitis C Virus:The structure of the hepatitis C virus is like that of most complex viruses - a core of

    genetic material (RNA), surrounded by a protective shell of protein, and further encased in alipid (fatty) envelope of celluar material. However, the fact that the genetic information of thevirus is stored in RNA, not DNA, has important consequences in the life cycle of the virus, andgives hepatitis C its dangerous ability to mutate.

    All organisms, with the exception of the RNA viruses, store their permanent informationin DNA, using RNA only as a temporary messenger for information. DNA is quite a stablemolecule, not particularly reactive with other molecules, and the processes which reproduce itmake very few mistakes in the process of copying the molecule (between one in 1 million and 1in 10 million). Most of these mistakes are normally corrected even when they do occur. Thismakes DNA an ideal format for the storage of information, for mutations (errors) only rarelyoccur, and most are not significant.

    RNA, by contrast, is a quite reactive molecule, capable of reacting even with itself underthe correct conditions. It also makes frequent mistakes during copying - averaging one mistakeper 10,000 nucleotides each time it is copied. These properties make RNA very poorly suited for

    the storage of information.

    However, these very propeties make RNA ideal for the storage of viral information. Oncethe immune system has learned to recognize an infecting virus and create antibodies against it(developed an immunity), it can quickly destroy it, so the virus can no longer use that host forreproduction. In order to reinfect a host - it must first change its nature enough that the immunesystem will no longer recognize it - in other words, it must mutate.

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    Hepatitis C virus. Structure of the viral capsid is clearly visible

    The unstable nature of the RNA molecule provides this mutagenic factor, allowing theHepatitis C virus to develop new genetic variations of itself. As discussed earlier, the mutatedforms are frequently different enough from their ancestors that the immune system cannotrecognize them, so if the immune system begins to succeed against one variation, the mutantstrains quickly take over and become new, predominant strains. Because each surviving virusreproduces itself thousands of times, mutations in the RNA sequence occur frequently, allowingit to evolve faster than any other type of living organism. This evolution is known as antigenicdrift. Mutations occur randomly across the entire length of the viral RNA, and so of course mostare not beneficial, producing viruses which lack a needed protein or are otherwise disadvantaged.However, because of the enormous number of offspring produced by each virus, even a high rateof mutation does not threaten the survival of the virus - and when advantageous mutations dooccur, they are rapidly selected for and reproduced.

    Hepatitis C, as an RNA virus, has apowerful reproductive strategy. Because itstores its information in a "sense" strand ofRNA, the viral RNA itself can be directlyread by the host cell's ribosomes,functioning like the normal mRNA presentin the cell. The virus thus needs no specialabilities of its own - it uses the cell's ownribosomes to produce everything it needsfor its takeover of the cell's processes andreproduction. This means hepatitis C

    requires only a small amount of RNA to encode its core information, and thus has lots of room

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    for genetic variation within the non-essential portions of its RNA. This also gives it fewercommon characteristics that can be readily identified by the immune system - or, for that matter,exploited by scientists working to create a treatment.

    Genome of HCV:Hepatitis C virus has a positive sense single-stranded RNA genome. The genome consists

    of a single open reading frame that is 9600 nucleotide bases long. This single open reading frameis translated to produce a single protein product, which is then further processed to producesmaller active proteins.

    At the 5' and 3' ends of the RNA are the UTR, which are not translated into proteins butare important to translation and replication of the viral RNA. The 5' UTR has a ribosome bindingsite (IRES - Internal ribosome entry site) that starts the translation of a very long proteincontaining about 3,000 amino acids. This large pre-protein is later cut by cellular and viral

    proteases into the 10 smaller proteins that allow viral replication within the host cell, or assembleinto the mature viral particles.

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    Structural proteins made by the hepatitis C virus include Core protein, E1 and E2; nonstructuralproteins include NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.

    The Life Cycle of Hepatitis C:1) The hepatitis C virus must attach to and infect liver cells in order to carry out its life

    cycle and reproduce - this is why it is associated with liver disease. While little isknown about the exact natural processes of hepatitis C, like other viruses, it mustcomplete eight key steps to carry out its life cycle:

    2) The virus locates and attaches itself to a liver cell. Hepatitis C uses particular proteinspresent on its protective lipid coat to attach to a receptor site (a recognizable structureon the surface of the liver cell).

    3) The virus's protein core penetrates the plasma membrane and enters the cell. Toaccomplish this, hepatitis C utlilizes its protective lipid (fatty) coat, merging its lipidcoat with the cells outer membrane (the coat is in fact composed of a fragment ofanother liver cell's plasma membrane). Once the lipid coat has successfully fused tothe plasma membrane, the membrane engulfs the virus - and the viral core is insidethe cell.

    4) The protein coat dissolves to release the viral RNA in the cell. This may beaccomplished during penetration of the cell membrane (it is broken open when it isreleased into the cytoplasm), or special enzymes present in liver cells may be used todissolve the casing.

    5) The viral RNA then coopts the cell's ribosomes, and begins the production ofmaterials necessary for viral reproduction. Because hepatitis C stores its informationin a "sense" strand of RNA, the viral RNA itself can be directly read by the host cell'sribosomes, functioning like the normal mRNA present in the cell. As it beginsproducing the materials coded in its RNA, the virus also probably shuts down most of

    the normal functions of the cell, conserving its energy for the production of viralmaterial,

    6) although it occasionally appears that hepatitis C will stimulate the cell to reproduce(presumably to create more cells that can produce viruse