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Hepatitis C virus (HCV) is one of the most important Hepaciviruses (family Flaviviridae) and is responsible for the second most common cause of viral hepatitis. The HCV genome is a 9.6-kilobase uncapped linear single-stranded RNA (ssRNA) molecule with positive polarity (Sarnow, 2003). HCV displays a high rate of nucleotide substitutions in the hypervariable region 1 (HVR1) of the envelope gene and exists as a number of distinct quasispecies (Omana, 2006). The HCV genome shows great variability on the basis of which we can identify six major HCV genotypes and several subgenotypes, differing from one other by up to 30% in their nucleotide sequences. Genotype 3a is the most common genotype of HCV in Pakistan.
The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response currently defined as undetectable HCV-RNA in peripheral blood determined with the most sensitive polymerase chain reaction technique 24 weeks after the end of treatment. This goal is practically equivalent with eradication of HCV infection and cure of the underlying HCV induced liver disease (Deutsch and Hadziyannis, 2007). No vaccine is currently available to prevent HCV infection. The currently recommended therapy is pegylated interferon (IFN) in combination with ribavirin. Though remarkable progress has been made in its effectiveness, the therapy is expensive and often associated with side effects that may lead to discontinuation of therapy (Cornberg et al. 2002). In Pakistan about 75% of patients have no therapeutic benefit to current therapies (Mujeeb et al. 1997). Hemolytic anemia, cough, shortness of breath & treatogenicity are the most common adverse effect associated with ribavirin treatment, and muscle aches, fatigue & neuropsychiatric adverse effects of IFN-Î± lead to premature cessation of therapy in 10 to 20% of patients (Stuyver et al. 2002). sustained virological response with standard regimen of interferon alpha-2b in combination with ribavirin, is achievable in only 30-60% of treated patients (Hickman et al. 2006).Moreover development of resistance against currently present antiviral compounds is another problem. Thus due to high prevalence of the disease and the lack of specific anti-HCV drugs for the treatment, by now more efficacious and better tolerated therapies by all patients are urgently needed.
Finding healing powers in plants is an ancient idea. Herbal medicines have been in use for centuries. People on all continents have long applied poultices and imbibed infusions of hundreds, if not thousands, of indigenous plants dating back to prehistory. The origins of some modern medications are actually plants, such as aspirin from white willow bark, digitalis from foxglove, morphine from poppies, warfarin (Coumadin) from sweet clover, and taxol from the Yew tree. Many traditional medicinal plants have been reported to have strong antiviral activity and some of them have already been used to treat animals and people who suffer from viral Infection (Hudson 1990; Venkateswaran et al. 1987; Thyagarajan et al. 1988). Medicinal plants have a variety of chemical constituents, like flavonoids, terpenoids, lignans, sulphides, polyphenolics, coumarins, saponins, furyl compounds, alkaloids, polyines, thiophenes, proteins and peptides, which have the ability to inhibit the replication cycle of various types of DNA or RNA viruses. There are a lot of potentially useful phytochemicals waiting to be evaluated and exploited for therapeutic effect against different virus families. The herbal compound Bing Gan Tang plus IFN-Î± showed a significant effect on the clearance of HCV RNA and ALT normalization compared with IFN- Î± alone(Pei et al. 1996). Compared with vitamins, herbal extract oxymatrine showed a significant effect on clearance of HCV RNA (Li JQ et al. 1998). XCHD, FFHQ and BGL are effective prescriptions of Chinese herbal medicine in treating hepatitis C patients (Jun et al. 2005). Glycyrrhizic acid shows antiviral activity against a number of DNA and RNA viruses possibly due to activation of NFï«B and induction of IL-8 secretion (Mark et al. 2006). Glycyrrhizin (licorice root extract) stimulates endogenous production of interferon (Abe et al. 1994). Silybum marianum, has been shown to be hepatoprotective by a variety of mechanisms in both animal models and clinical studies. It is a potent antioxidant and free radical scavenger and exerts anti-inflammatory and antifibrotic and immunomodulatory effects have also been reported (Fogden and Neuberger, 2003). Several studies have demonstrated that flavonoids have potent anti-tumor and anti-allergic activities as well as promising anti-HIV effects (Kitamura et al., 1998; Nair et al., 2002).
6.BACKGOUND: Viral hepatitis is caused by at least five distinct viruses. Each belongs to an entirely different family of viruses, and they have very little in common except the target organ that they affect, the liver and the certain degree of shared epidemiology (Purcell et al., 1994). Two of the viruses (HAV and HEV are spread principally by fecal oral means and three (HBV, HCV, and HDV) are spread principally by exposure to blood, although HBV is frequently spread by unprotected sex (Purcell et al., 1994). A new virus HGV was recently discovered and its prevalence and pathogenic role in various liver diseases (hepatitis) have been explained (chow et al., 2002). HCV infection has reached epidemic proportions and becomes a major global health issue and worldwide, the prevalence of chronic HCV infection is estimated to be 3%, varying from 0.1% to 5% depending on geographic region studied (Zein et al., 2000).
The existence of the third type hepatitis was not appreciated until 1975, when the application of recently developed diagnosis tests for hepatitis A and hepatitis B to store samples of prospectively studied cases of transfusion associated hepatitis revealed that the most of the cases were neither hepatitis A nor B (Purcell et al., 1994). The new hepatitis had average incubation period of ~7-10 weeks which is immediate between those of hepatitis A and hepatitis B and similar to mean incubation period of all cases of transfusion associated hepatitis in the 1950's and 1960's, suggesting that NANB (Hussami et al., 2002) hepatitis had also been the principal cause of transfusion associated hepatitis in past (CDC 1963). Although NANB hepatitis was transmitted to chimpanzee in 1978, thus establishing its infectious nature, it was not until 1989 that the virus was identified (Purcell et al., 1994). However, in 1989 a small piece of the viral RNA was reverse-transcribed, cloned and sequenced, and this resulted in the subsequent cloning and sequencing of the entire genome (Choo et al., 1989). The virion was also tentatively visualized by electron microscopy (Takahashi et al., 1992).
Prevalence of HCV:
Although prevalence data are not available from every country, HCV testing using blood donors as a prevalence source may underestimate the real Hepatitis C virus (HCV) continues to be a major disease burden on the world. In 1999, the WHO estimated a worldwide prevalence of about 3% with the virus affecting 170 million people worldwide. The World Health Organization (WHO) developed conservative estimate that 2.3-4.7 million new HCV infections may result from unsafe injections annually (Kane et al., 1999). It was estimated that there were two million HCV infections -40% of all new infections-fromunsafe injection practices in health care setting in the year 2000 (Hauri et al., 2004). Generally, most studies of prevalence use blood donors to report the frequency of HCV usually by anti-HCV antibodies and do not report follow-up prevalence of the virus because donors are generally a highly selected population (Alter et al., 1999). Among Central and South America, a recent community based study in San Juan, Peurto Rico, showed that estimated prevalence of HCV in 2001-2002 was 6.3% (Munoz et al., 1998). In Mexico, the prevalence reported was about 1.2%. Among blood donors in Chile and Brazil, prevalence of HCV Ab was low - 0.3%, 1.14% respectively (Aktar et al., 2004). HCV prevalence studies have come out of Pakistan in the Middle East. 751 out of 16,400 patients (4.57%) were found to +HCV Ab from 1998-2002 with the largest age group from (Simmonds et al., 1996). Among male blood donors in Karachi, Pakistan, the seroprevalence of HCV was 1.8% with a trend of increasing proportion of positive donors from 1998-2002 (Tokita et al., 2004). The prevalence and distribution of HCV genotypes depend on geographical location (Tokita et al., 1995). Three broad patterns of genotype distribution have been identified to date (Pawlotsky et al., 1995). Cell entry
Hepatitis C virus (HCV) entry is the first step of interactions between virus and the target cell that is required for initiation of infection. The data that have recently been reported suggest that HCV entry is a slow and complex multistep process. Several host cell surface molecules including glycosaminoglycans, CD81, scavenger receptor class B type I (SR-BI), members of the claudin family (CLDN1, 6 and 9) and mannose-binding lectins DC-SIGN and L-SIGN have been identified as putative HCV receptors or co-receptors (Figure 2) [71, 72]. GAGs and the LDL-R may facilitate initial attachment to the host cell. This interaction is probably mediated by the lipoproteins associated with HCV virions. However, one cannot exclude direct contact between HCV envelope proteins and these cellular proteins. After the initial binding step, the particle likely interacts with SR-BI and CD81. HCV E2 binds with high affinity to the large external loop of CD81 and CLDN1 acts at a late stage of the entry process . These receptors have been shown to play an important role for viral entry. Several human cell lines expressing all known entry factors but are non-permissive for HCV entry. This finding suggests that the existence of additional cellular factors which modulating viral entry. In recent years, several host restriction factors that protect cells from viral infection have been identified such as EW1-2wint [73, 74]. EW1-2wint is a CD81 associated protein which is able to inhibit HCV entry into target cells by blocking the interactions between HCV glycoproteins and CD81. EWI-2wint may interfere with actin polymerization during viral entry or block signaling pathways necessary for viral entry .
Figure 2: HCV recepters for cell entry
Viral RNA Transcription, replication and Translation
The virus linked to its receptor complex, internalize and then nucleocapsid is released into the cytoplasm. The virus is decapsidated, and the genomic HCV RNA is used both for polyprotein translation and replication in the cytoplasm. Being a positive sense RNA, viral RNA act as mRNA and is therefore directly translated. Translation of HCV RNA is not cap dependent like other cellular RNAs in which cap bind to ribosomal machinery for translation. Translation of HCV RNA is initiated by binding the 5/-IRES to ribosome. Translation of HCV RNA occurs at rough endoplasmic reticulum and produces single polyprotein which cleave by co and post-translationally by cellular and viral proteases, to produce structural and non structural proteins. Hepatitis C virus like other single stranded viruses of positive polarity induces alteration in membrane. These changes in the membrane termed as membraneous web [76, 77]. NS5B RNA-dependent RNA polymerase replicates the genome by the synthesis of negative strand RNA. This negative strand RNA serves as a template for the synthesis of positive strand RNA. Replication and post-translational processing appear to take place in a membranous web made of the non-structural proteins and host cell proteins called "replication complex", located in close contact with perinuclear membranes. Genome encapsidation appears to take place in the endoplasmic reticulum and nucleocapsids are enveloped and matured into the Golgi apparatus before newly produced virions are released in the pericellular space by exocytosis (Figure 3) .
Figure 3: Diagrammatic representation of HCV life cycle
Infection with HCV is unique as majority of the patients remain asymptomatic, with fluctuating liver enzyme levels. Thus, rather than developing novel therapeutic strategies, development of a vaccine that can prevent the viral infection should be of paramount importance HCV has a high mutation rate, development of an effective vaccine represents a challenge to human kind. It may be noted at this stage that binding of the virus to the cellular receptor requires glycosylation of the viral proteins and involves a carbohydrate moiety during this process. Thus targeting potential N-linked glycosylation sites on the viral structural proteins, particularly the envelope proteins, makes for an effective strategy against the virus. ( Rumennapf et al., 1999). In addition to this, many members of the Flaviviridae family, to which HCV also belongs, may enter the cell by binding to low-density lipoprotein (LDL) receptors. Recently, (Agnello et al., ) have demonstrated a direct correlation between the level of cell surface-expressed LDL receptor and the number of HCVRNA positive cells. Furthermore, HCV particles are observed to be associated with beta-lipoproteins (Thomssen et al., 1992). Taken together, these results also suggest LDL-receptors as possible sites of entry of the virus into the cells. However, it remains to be seen whether interaction of HCV with LDL-receptor or CD81 leads to a productive infection. Recently, a cell culture model for HCV replication has been reported. ( Lohamn et al., 1999).