Hepatitis C virus: Wikis

  

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Hepatitis C virus
Electron micrograph of Hepatitis C virus. The bar = 50 nm
Virus classification
Group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Hepacivirus
Type species
Hepatitis C virus
This page is for the virus. For the disease, see Hepatitis C.

Hepatitis C virus (HCV) is a small (55-65 nm in size), enveloped, positive sense single strand RNA virus in the family Flaviviridae. Although Hepatitis A virus, Hepatitis B virus, and Hepatitis C virus have similar names (because they all cause liver inflammation), these are distinctly different viruses both genetically and clinically.

Contents

Structure

Simplified diagram of the structure of the Hepatitis C virus particle

The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope.[1]

Genome

Genome organisation of Hepatitis C virus
Structure of the IRES located in the 5'-UTR of HCV

Hepatitis C virus has a positive sense RNA genome that consists of a single open reading frame of 9600 nucleoside bases.[2] At the 5' and 3' ends of the RNA are the UTR regions, that are not translated into proteins but are important to translation and replication of the viral RNA. The 5' UTR has a ribosome binding site[3] (IRES - Internal ribosome entry site) that starts the translation of a 3000 amino acid containing protein that is later cut by cellular and viral proteases into 10 active structural and non-structural smaller proteins.[4]

The polyprotein is broken into the following proteins [5]:

Replication

A simplified diagram of the HCV replication cycle

Replication of HCV involves several steps. The viruses need a certain environment to be able to replicate, and must therefore first move to such areas.

HCV has a high rate of replication with approximately one trillion particles produced each day in an infected individual. Due to lack of proofreading by the HCV RNA polymerase, HCV also has an exceptionally high mutation rate, a factor that may help it elude the host's immune response.

HCV mainly replicates within hepatocytes in the liver, although there is controversial evidence for replication in lymphocytes or monocytes. By mechanisms of host tropism, the viruses reach these proper locations. Circulating HCV particles bind to receptors on the surfaces of hepatocytes and subsequently enter the cells. Two putative HCV receptors are CD81 and human scavenger receptor class B1 (SR-BI). However, these receptors are found throughout the body. The identification of hepatocyte-specific cofactors that determine observed HCV liver tropism are currently under investigation.

Once inside the hepatocyte, HCV initiates the lytic cycle. It utilizes the intracellular machinery necessary to accomplish its own replication.[6] The HCV genome is translated to produce a single protein of around 3011 amino acids. The polyprotein is then proteolytically processed by viral and cellular proteases to produce three structural (virion-associated) and seven nonstructural (NS) proteins. Alternatively, a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP). HCV encodes two proteases, the NS2 cysteine autoprotease and the NS3-4A serine protease. The NS proteins then recruit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes. RNA replication takes places via the viral RNA-dependent RNA polymerase NS5B, which produces a negative-strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive-strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles are thought to bud into the secretory pathway and are released at the cell surface.

Diagnosis

Diagnosis of HCV can occur via DNA analysis of the 5′-noncoding region (5′-NCR). However results vary according to the HCV genotype and viral load. Non-western HCV genotypes have not been studied as much. In 2009 it was shown that the 3′-X-tail element of the HCV genome is highly conserved across genotypes. It could be tested for $US8.70 within a couple of hours and could also be a valuable tool for screening of blood supplies.[7]

Genotypes

Based on genetic differences between HCV isolates, the hepatitis C virus species is classified into six genotypes (1-6) with several subtypes within each genotype (represented by letters). Subtypes are further broken down into quasispecies based on their genetic diversity. The preponderance and distribution of HCV genotypes varies globally. For example, in North America, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa. Genotype is clinically important in determining potential response to interferon-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to interferon-based treatment than are the other genotypes (2, 3, 5 and 6).[8] Duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks.

Infection with one genotype does not confer immunity against others, and concurrent infection with two strains is possible. In most of these cases, one of the strains removes the other from the host in a short time[9]. This finding opens the door to replace strains non-responsive to medication with others easier to treat.

Host genetic factors influencing treatment response with interferon alpha

For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature [10], showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature [11] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

Vaccination

Unlike hepatitis A and B, there is currently no vaccine to prevent hepatitis C infection.

In a 2006 study, 60 patients received four different doses of an experimental hepatitis C vaccine. All the patients produced antibodies that the researchers believe could protect them from the virus.[12] Nevertheless, as of 2008 vaccines are still being tested.[13][14]

Current research

In 2007 the World Community Grid launched a project where, by computer modelling of the Hepatitis C Virus (and related viruses), thousands of small molecules are screened for their potential anti-viral properties in fighting the Hepatitis C Virus. This is the first project to seek out medicines to attack the virus directly once a person is infected. This is a distributed process project similar to SETI@Home where the general public downloads the World Community Grid agent and the program (along with thousands of other users) screens thousands of molecules while their computer would be otherwise idle. If the user needs to use the computer the program sleeps. There are several different projects running, including a similar one screening for anti-AIDS drugs. The project covering the Hepatitis C Virus is called "Discovering Dengue Drugs – Together," because Dengue virus and HCV belong to the same family, together with West Nile and Yellow fever viruses.[15] The software and information about the project can be found at the World Community Grid web site.[16]

Current research is focused on viral protease inhibitors, with drugs such as Telaprevir, and monoclonal antibodies like MBL-HCV1[17]. Barriers to the study of HCV include the narrow host range of HCV, and the only animal model for HCV study is the chimpanzee. The use of replicons has been successful but these have only been recently discovered.[18] HCV, as with most all RNA viruses, exists as a viral quasispecies, making it very difficult to isolate a single strain or receptor type for study.[19]

See also

References

  1. ^ Op De Beeck A, Dubuisson J (2003). "Topology of hepatitis C virus envelope glycoproteins". Rev. Med. Virol. 13 (4): 233–41. doi:10.1002/rmv.391. PMID 12820185.  
  2. ^ Kato N (2000). "Genome of human hepatitis C virus (HCV): gene organization, sequence diversity, and variation". Microb. Comp. Genomics 5 (3): 129–51. PMID 11252351.  
  3. ^ Jubin R (2001). "Hepatitis C IRES: translating translation into a therapeutic target". Curr. Opin. Mol. Ther. 3 (3): 278–87. PMID 11497352.  
  4. ^ Dubuisson J (2007). "Hepatitis C virus proteins". World J. Gastroenterol. 13 (17): 2406–15. PMID 17552023.  
  5. ^ [1]
  6. ^ Lindenbach B, Rice C (2005). "Unravelling hepatitis C virus replication from genome to function". Nature 436 (7053): 933–8. doi:10.1038/nature04077. PMID 16107832.  
  7. ^ [2]
  8. ^ Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, Halfon P, Inchauspé G, Kuiken C, Maertens G, Mizokami M, Murphy D, Okamoto H, Pawlotsky J, Penin F, Sablon E, Shin-I T, Stuyver L, Thiel H, Viazov S, Weiner A, Widell A (2005). "Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes". Hepatology 42 (4): 962–73. doi:10.1002/hep.20819. PMID 16149085.  
  9. ^ Laskus T, Wang LF, Radkowski M, Vargas H, Nowicki M, Wilkinson J, Rakela J. (2001). "Exposure of hepatitis C virus (HCV) RNA-positive recipients to HCV RNA-positive blood donors results in rapid predominance of a single donor strain and exclusion and/or suppression of the recipient strain". Journal of virology 75 (5): 2059–66. doi:10.1128/JVI.75.5.2059-2066.2001. PMID 11160710.  
  10. ^ Ge D, Fellay J, Thompson AJ, et al. (2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature 461 (7262): 399–401. doi:10.1038/nature08309. PMID 19684573.  
  11. ^ Thomas DL, Thio CL, Martin MP, et al. (2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature. doi:10.1038/nature08463. PMID 19759533.  
  12. ^ Edell, Dean (2006). "Hepatitis C Vaccine Looks Promising". ABC7/KGO-TV. http://abclocal.go.com/kgo/story?section=edell&id=4278043. Retrieved 2006-07-04.  
  13. ^ Strickland GT, El-Kamary SS, Klenerman P, Nicosia A. Hepatitis C vaccine: supply and demand. Lancet Infect Dis. 2008 Jun;8(6):379-86.Click here to read PMID 18501853
  14. ^ HCV Vaccine Development
  15. ^ Website
  16. ^ Website
  17. ^ Infection By Hepatitis C Virus Prevented By Novel Antibody
  18. ^ Meier V, Ramadori G (April 2009). "Hepatitis C virus virology and new treatment targets". Expert Rev Anti Infect Ther 7 (3): 329–50. doi:10.1586/eri.09.12. PMID 19344246. http://www.future-drugs.com/doi/abs/10.1586/eri.09.12?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov. Retrieved 2009-04-16.  
  19. ^ Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. "The way forward in HCV treatment - finding the right path." Nat Rev Drug Discov. 2007 Dec;6(12):991-1000.

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