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©2013 Baishideng Publishing Group Co.
World J Gastroenterol. Nov 28, 2013; 19(44): 7910-7921
Published online Nov 28, 2013. doi: 10.3748/wjg.v19.i44.7910
Published online Nov 28, 2013. doi: 10.3748/wjg.v19.i44.7910
Table 1 Summary of in vitro and in vivo models for hepatitis C virus
In vitro and in vivo models | Established year | Advantages | Deficiencies |
In vitro | |||
Cultivation of HCV | 1993-1999 | Achieved cultivation of HCV in human foetal liver cells, human hepatocytes or PBMC. Illustrated HCV is quite species selective and has a narrow range of hosts | Requires specific cellular factors to support viral lifecycle. Primary human and chimpanzee hepatocytes or highly differentiated cells dependent. Most of them have yielded limited success. Poor reproducibility and low levels of HCV replication |
HCV replicon | 1995-2000 | Provided a cell-based model for the study on HCV genome replication | |
HCV VLP | 1998-1999 | Rare evidence to support that HCV structural proteins core, E1, and E2 could form VLP | |
HCVpp | 2003 | Provided a convenient and feasible tool for studies on viral entry, HCV receptor, neutralizing antibody, etc. | |
HCVcc | 2005 | A break through in production of infectious hepatitis C virus in tissue culture | |
In vivo | |||
Chimpanzee | 1979 | The only recognized animal model for HCV study, played a critical role in HCV discovery and play an essential role in defining the natural history of HCV | Chimpanzees differ from humans in their course of infection, that chronic carriers do not develop cirrhosis or fibrosis, limited availability, cost performance, and public resistance |
Tree shrew | 1998 | Might be a succedaneum for chimpanzees | Persistent HCV infection could not be established and only 25% of infected animals developed transient or intermittent viremia. Germ line was not available to a small animal model |
Chimeric human liver mouse | 2001 | Exhibited prolonged infection with high viral titers following inoculation with HCV isolated from human serum. HCV can be transmitted horizontally. Drug evaluation | Since the mice were immunodeficient, they were not appropriate models to study HCV pathogenesis |
Genetically humanized mouse | 2011 | Represents the first immunocompetent mice model for HCV study. Allows for the studies of HCV coreceptor biology in vivo | Operation is difficult |
Table 2 Summary of the properties of hepatitis C virus structural proteins
Core | E1 | E2 | p7 | |
Genome location | 342-914 | 915-1490 | 1491-2579 | 2580-2769 |
Translation processing site | Rough ER | |||
Amino acid composition | 191 | 192 | 363 | 63 |
Molecular weight (kDa) | 21-23 | 33-35 | 70-72 | 7 |
Glycosylation | No | Yes | Yes | No |
Cleavage | ER signal peptidase and SPP | |||
Crystal structure | Not available | Revealed | ||
Functional unit | Dimer | Heterodimer? | Hexamer | |
Common function | Viral particle formation. Core, E1 and E2, together with p7 and NS2, are required for virus assembly (assembly module) | |||
Unique function | Capsid protein, viral particle formation, viral genome recognizing and packaging. Interacts with cLDs in early viral particle formation process. Counters host antiviral factors and involves pathogenesis | Envelope glycoproteins, interact with SRB1, CD81, CLDN1, OCLN, etc. to trigger viral entry. Promote fusion with the endosomal membrane. Counter host immune response via hypervariable regions | Viroporin. Has key roles in organizing the virus assembly complex. p7-NS2 complex interacts with the NS3-4A enzyme to retrieve core protein from cLDs to form viral particle | |
Major scotomas | How do the core form the viral capsid? The signals and processes that mediate RNA packaging are largely unknown. What impeded us to resolve the structure of the viral glycoproteins? What is the real process in HCV entry? How are these receptors and co-receptors temporally and spatially used to ensure the early infection processes? |
Table 3 Summary of the properties of hepatitis C virus non-structural proteins
NS2 | NS3 | NS4A | NS4B | NS5A | NS5B | |
Genome location | 2769-3419 | 3420-5312 | 5313-5474 | 5475-6257 | 6258-7601 | 7602-9378 |
Translation processing site | Rough ER | |||||
Amino acid composition | 810-1026 | 1027-1657 | 1658-1711 | 1712-1972 | 1973-2420 | 2421-3012 |
Molecular weight (kDa) | 21-23 | 70 | 8 | 27 | 56-58 | 65-68 |
Cleavage | Viral cysteine protease NS2-3 and the serine-type protease activity of the viral NS3-NS4A complex | |||||
Crystal structure | C-terminal (aa904-1026) was solved | Revealed | Revealed | Not available | Revealed | Revealed |
Functional unit | Homodimer | Monomer or oligomer | Monomer | Oligomer | Homodimer | Monomer |
Common function | Replication module | |||||
Unique function | A metal-dependent proteinase, many functions dependent on the interaction with P7 and NS3. Participation in proteolytic cleavage at the NS2-NS3 junction of the polyprotein. Both the TMDs and protease domain of NS2 are required for the production of virus particles | The DAA targeting protein. NS3 was anchored in ER membrane by cofactor NS4A. NS3-4A complex has serine-type protease activity and NTPase/RNA helicase activities. Nonspecific cleavage of two critical interferon induction proteins: MAVS and TRIF | The central portion of NS4A, residues 21-32, intercalates into NS3 and activates the protease activity by stabilizing this protease subdomain and contributing to the substrate recognition site. The C-terminal acidic portion of NS4A interacts with the NS3 helicase and other HCV proteins and contributes to RNA replication as well as assembly | A master organizer of replication complex formation. NTPase activity? RNA binding? | Produced as multiple phospho-variants. RNA-binding phosphoprotein involved in RNA replication. Phosphorylation of a specific serine residue within the C-terminus by CKIIα is essential for virus assembly. The interaction of NS5A with the cLD-bound core protein is the key steps in HCV assembly | RNA-dependent RNA polymerase |
Major scotomas | How HCV particles are organized? What is the accurate duty of each nonstructural protein in viral lifecycle? How do the nonstructural proteins utilize host cellular factors for its own survival? Why HCV lifecycle is tightly associated with components of LDLs and VLDLs? |
Table 4 Epidemiological features of hepatitis C virus infection
Epidemiological index | Current consensus |
Source of infection | Chronic HCV carriers |
Route of transmission | HCV transmission occurs primarily through exposure to infected blood. Past: Receiving infected blood or organ transplantation, from accidental exposure to infected blood, and sexual transmission in persons with high risk behaviours. Present: HCV is usually spread by sharing infected needles with a chronic HCV carrier, and some people acquire the infection through nonparenteral means that have not been fully defined. |
Susceptible population | General population |
Incubation period | Average 6-10 wk |
Prevalence and incidence | 3% of the world’s population have HCV |
Rate of chronic infection | Up to more than 80% |
Outcome of chronic infection | 10%-20% of chronic HCV carriers may develop into cirrhosis and liver failure. 1%-5% of chronic HCV carriers are associated with the development of hepatocellular carcinoma |
Molecular epidemiology | HCV is classified into eleven major genotypes (designated as 1-11), many subtypes (designated a, b, c, etc.), and about 100 different strains (numbered 1, 2, 3, etc.) based on the genomic sequence heterogeneity. Genotypes 1-3 have a worldwide distribution. Types 1a and 1b are the most common, accounting for about 60% of global infections. Type 2 is less frequently represented than type 1. Type 3 is endemic in southeast Asia and is variably distributed in different countries. Genotype 4 is principally found in the Middle East, Egypt, and central Africa. Type 5 is almost exclusively found in South Africa, and genotypes 6-11 are distributed in Asia. |
Stability | HCV is inactivated by exposure to lipid solvents or detergents, heating at 60 °C for 10 h or 100 °C for 2 min in aqueous solution, formaldehyde (1:2000) at 37 °C for 72 h, β-propriolactone and UV irradiation. |
Vaccine | Not available |
- Citation: Wang Y. Scotomas in molecular virology and epidemiology of hepatitis C virus. World J Gastroenterol 2013; 19(44): 7910-7921
- URL: https://www.wjgnet.com/1007-9327/full/v19/i44/7910.htm
- DOI: https://dx.doi.org/10.3748/wjg.v19.i44.7910