HCV

In terms of genome organization, HCV is a member of the Flaviviridae and has now been placed in a new monotypic genus in this family:

Flaviviridae	Flavivirus	Yellow fever virus
	Pestivirus	Bovine diarrhoea virus 1
	*Hepacivirus*	*Hepatitis C virus*

The genome contains a single long open reading frame which encodes a polyprotein of about 3000 amino acids. There is a non-coding region (NCR) of 324-341 nucleotides at the 5' end and a 3' NCR of variable length including a poly(U) tract. The 5' NCR contains an IRES apparently similar in function (but not structure) to that of picornaviruses.

The nucleotide sequence of HCV is highly variable, the most divergent isolates sharing only 60% nucleotide sequence homology. Isolates from all over the world have now been grouped into 6 main types, each with several subtypes, based on sequence data (Simmonds et al, Hepatology 21: 570-83, 1995). Types 1-3 account for almost all infections in Europe, type 4 is prevalent in Egypt and Zaire, type 5 in South Africa & type 6 in Hong Kong. It is not yet clear whether immunity to one type prevents subsequent infection with another, but there is some evidence that various genome types differ in their biological properties.

HCV infection occurs in approximately 0.1% of the UK population (inferred from the level of infection seen in UK blood donors), although rates of infection in other parts of the world are much higher. Chronic HCV infection affects an estimated 170 million individuals worldwide, with most countries reporting a prevalence of 1.0% to 4.9%. Currently, approximately 40% to 60% of chronic liver disease is attributable to HCV. Since autumn 1991 the BTS has screened all donated blood for HCV. Several diagnostic tests have been developed, serological (used for screening blood donations) - using recombinant antigens, and molecular (PCR - being used to determine the extent of virus variation). The parenteral (blood-borne) route of infection seems to be most prevalent, with high rates of infection seen in intravenous drug abusers, haemophiliacs and recipients of unscreened blood transfusions. The possibility of sexual transmission cannot be eliminated, but if it occurs, the risk seems to be very low. Vertical transmission of HCV seems to occur with at a rate of 5-10%. Much of this risk can be lowered by caesarean section. Infection in utero, if it occurs, seems to be rare. However, breast feeding does not appear to be a significant risk factor. It has been estimated that 2.2% of the world's population, ~130 million people, are infected with hepatitis C.

Pathogenesis:

It is generally believed that the majority of cases of HCV infection give rise to an acute illness - up to 80% may develop into chronic hepatitis. Almost all patients develop a vigorous antibody and cell-mediated immune response which fails to clear the infection but may contribute towards liver damage. Most flavivirus infections are cytopathic, but this has not been directly tested in the case of HCV since the virus cannot be cultured. Spontaneous resolution of chronic liver disease is very rare (<2%) and patients with chronic disease are at risk of developing hepatocellular carcinoma (HCC). However, some studies have suggested that infection may have a more benign outcome, at least in some populations. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 2004 12: 96-102. Acute HCV infection tends to follow this course:

As with HBV, chronic HCV infection is a major risk factor for HCC (30% of UK HCC patients?). >80% of the world's 530000 cases of liver cancer per year are caused by viral hepatitis infection, with ~60% associated with HBV and ~40% with HCV. Time from HCV transmission to development of cancer ranges from 10 to 50 years (median 30 years). There is a strong association between chronic HCV infection, cirrhosis, and hepatocarcinogenesis (Haydon et al Gut 40: 128-132, 1997; Degos et al Gut 47: 131-136, 2000). The duration from the onset of acute hepatitis until the time of diagnosis of cirrhosis of the liver and of HCC is about 20 and 30 years, respectively. The acute phase lasts from the onset of disease until 2-3 years thereafter, and the silent phase which follows lasts for 10-15 years:

Since relatively little is known about the biology of HCV (In vitro replication models for the hepatitis C virus. J Viral Hepat. 2007 14: 2-10; Replication of hepatitis C virus. 2007 Nature Reviews Microbiology 5: 453), it is presently unclear how this RNA virus establishes a persistent infection. However, it is known that there is a very rapid turnover of plasma virus in patients, with particle half-lives of 100-182 min. Recently it has been suggested that subversion of the humoral immune response, specifically neutralizing antibody production, may allow HCV to persist. Persistent infection appears to be due to weak CD4⁺ and CD8⁺ T-cell responses during acute infection, which fail to control viral replication.

Spengler U, Nattermann J. Immunopathogenesis in hepatitis C virus cirrhosis. Clin Sci 2007 112:141-155. Since HCV itself is not cytopathic, liver damage in chronic HCV infection is commonly attributed to immune-mediated mechanisms. HCV proteins interact with several pathways in the host's immune response and disrupt pathogen-associated pattern recognition pathways, interfere with cellular immunoregulation and subvert the activity of NK cells as well as CD4(+) and CD8(+) T-cells. Finally, HCV-specific T-cells become increasingly unresponsive and apparently disappear, owing to possible mechanisms such as escape mutations in critical viral epitopes, lack of sufficient help, clonal anergy or expansion of regulatory T-cells. The role of neutralizing antibodies remains uncertain, although it is still possible that humoral immunity contributes to bystander damage of virally coated cells via antibody-dependent cellular cytotoxicity.

The HCV core protein binds to and represses transcription from the p53 promoter, thus blocking p53 synthesis. This may play a role in survival of hepatocarcinoma cells transformed by HCV. Transgenic mice expressing the core protein develop HCC due to the formation of intracellular reactive oxygen species caused by mitochondrial injury.

Therapy:

Recurrent HCV infection occurs in >90% infected liver transplant recipients, although not all patients develop subsequent liver disease. At the present time, the only therapy with any demonstrated efficacy against HCV-induced liver disease involves the use of α-IFN, but this approach is not entirely successful. Even in the best trials reported, only 40-50% of chronic suffers respond and 50% of these individuals relapse when treatment is stopped and there is evidence that α-IFN treatment is much less effective against some HCV genotypes than others. The development of vaccines, although proceeding, has been slowed by the extreme antigenic variability of the virus. Even when available, vaccines will not alleviate the problems faced by millions of chronic HCV carriers worldwide.

IFN therapy is expensive due to the high cost of recombinant human interferons, the large doses and lengthy course of administration necessary to achieve maximum response rates in recipients. Typical therapeutic regimes may be 3 million units IFN administered by injection three times a week for six months. However, recent studies suggest that 3-6 million units IFN three times a week for one year or even longer may be necessary to achieve maximum response rates (Chemello et al. Hepatology 22: 700-706, 1995)(Hakozaki et al. Am.J.Gastroenterol, 90: 1246-1249, 1995). The cost of the treatment effectively rations the number of patients able to receive this therapy. There are data from early studies which suggest that sustained response rates are enhanced if ribavirin, a broad spectrum antiviral agent, is administered in combination with IFN. Recent studies suggest that ribavirin may modulate the T helper Th₁/Th₂ subset balance in HCV infection rather than acting directly on the virus (Hultgren et al, J.Gen.Virol. 1998, 79: 2381-2391).

A combination of interferon-2β and ribavirin is currently recommended as the treatment of choice for patients considered to be at greatest risk of disease progression (those with moderate to severe fibrosis and/or inflammation and those with compensated cirrhosis). This combination therapy increases the sustained response rate (no detectable HCV RNA 6 months after completion of treatment) compared with interferon monotherapy in both previously untreated patients and those who have relapsed following a previous course of interferon therapy. A new pegylated formulation of interferon-2β in combination with ribavirin looks likely to supersede standard interferon-2b/ribavirin combination therapy following recent approvals in Europe and the US. The pegylated interferon formulation increases the half-life of interferon and has the advantage of less frequent administration. In previously untreated patients, pegylated interferon-2β/ribavirin combination showed a greater sustained response rates than standard interferon-2β/ribavirin in a large randomised trial.

Vaccine Development for Hepatitis C

Compared with other types of viral hepatitis such as hepatitis A and hepatitis B, development of vaccines against HCV infection has also been difficult. Some of the reasons for this is that HCV seems to elicit a weak immune response which does not protect against infection, and the considerable genetic and antigenic variability of the virus. In these respects, HCV is reminiscent of HIV.
Nevertheless, some progress has been made and HCV vaccine candidates are being tested in humans. One of these consists of a recombinant form of the HCV envelope proteins (E1 and E2) expressed in mammalian cells. This vaccine has been shown to offer partial protection to chimpanzees, specifically, in protecting them from becoming chronically infected. Other candidate vaccines are composed of proteins from the nonstructural region of the HCV genome, which stimulating more of a cellular rather than a humoral immune response. Finally, some therapeutic vaccines are being tested for their possible value in the treatment of chronic HCV infection.
Although some progress has been made in attempts to prevent HCV infection, a truly effective vaccine still appears to be a considerable way off.Most antibodies to HCV do not play a major role in clearance of infection, although neutralising antibodies do exist. However, these tend to be strain-specific and are ineffective against emerging strains, allowing infection to persist. Formidable obstacles remain to be overcome before a generally useful HCV vaccine is available. Thus there is clearly a desperate need for effective antiviral therapy to complement future vaccination programmes when these become available and to mitigate the effects of long-term HCV infection. However, our inability to propagate HCV in any tissue-culture system and due to the lack of any other animal model than the chimpanzee has confounded the development of antiviral compounds active against this agent.

	Bestsellers - Music - DVDs - Videos - Electronics Search for ... (keywords):
	Search for ... (keywords): Bestsellers - Music - DVDs - Videos - Electronics

Hepatitis C Virus (HCV)

Pathogenesis:

Therapy:

Vaccine Development for Hepatitis C