|
Type Species |
(HCV) |
Hepaciviruses are transmitted between humans, principally via exposure to contaminated blood or blood products. There is no known invertebrate vector. Hepaciviruses differ from flaviviruses and pestiviruses by their inability to propagate efficiently in cell culture and by the fact that the precursor protein, consisting of nonstructural (NS) proteins 2 and 3 autocatalytically cleaves the NS2-3 junction via a Zn-dependent mechanism.
Virions are about 50 nm in diameter, as determined by filtration and electron microscopy. They are spherical in shape and contain a lipid envelope, as determined by electron microscopy and inactivation by chloroform. The viral core is spherical and about 30 nm in diameter. Detailed structural properties have not been determined.
Physicochemical and Physical Properties
Virion Mr has not been determined. Buoyant density in sucrose is about 1.06 g/cm3 when the virus is recovered from the serum of an acute infection and about 1.15-1.18 g/cm3 when recovered from the serum of a chronically infected patient. The lower density results from the physical association of the virion with serum very-low-density lipoproteins. The higher density results from the binding of serum antibodies to the virion. A buoyant density in sucrose of 1.12 g/cm3 has been measured for Hepatitis C virus (HCV) recovered from cell culture. The S20W is equal to or greater than 150S. The virus is stable in buffer at pH 8.0-8.7. Virions are sensitive to heat, organic solvents and detergents.
Virions contain a single molecule of linear positive sense ssRNA (Fig. 5). The genome length is about 9.6 kb. The 5-NCR contains an internal ribosomal entry site and is about 340 nts in length. The 3-NCR is complex and contains a sequence-variable region (about 50 nts), a polypyrimidine region averaging about 100 nts but variable in length and a highly conserved terminal region (about 100 nts).
The virion consists of at least 3 proteins: the core (nucleocapsid) protein C (p19), and two envelope proteins, E1 (gp31) and E2 (gp70). An additional protein, p7, is incompletely cleaved from a precursor of E2 to yield E2-p7 and p7, but it is not known whether these are virion structural components. The two envelope proteins form heterodimers (probably non-covalently linked) in virions. The recognized nonstructural proteins include NS2, (an Mr 21 103 protein that, before cleavage, is part of a Zn-dependent proteinase that bridges NS2 and NS3 and mediates autocatalytic cleavage of the NS2/NS3 junction), NS3 (an Mr 70 103 protein with serine proteinase, helicase and NTPase acitivities; the proteinase cleaves the remaining junctions between nonstructural proteins), NS4A (an Mr 6 103 cofactor essential for NS3 serine proteinase activity), NS4B (an Mr 27 103 protein of unknown function), NS5A (a serine phosphoprotein of unknown function that exists in Mr 56 and 58 103 forms, depending on the degree of phosphorylation) and NS5B (an Mr 68 103 protein with RNA-dependent RNA polymerase activity).
Lipids have not been demonstrated directly. However, based on observed removal of the viral envelope and loss of infectivity following exposure to solvents or detergents, the presence of lipids is inferred.
Carbohydrates have not been demonstrated directly but the presence of glycosylation sites in the predicted coding sequences of the E1 and E2 genes and the demonstration of carbohydrate associated with the products of these two genes expressed as recombinant proteins is consistent with the presence of carbohydrates in virions.
Genome Organization and Replication
The genome contains a single large ORF encoding a polyprotein of about 3000 amino acids (Fig. 5). The gene order is 5-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-3. All three structural proteins (C, E1, E2), are encoded within the amino-terminal portion of the large ORF. Immediately 3 is a small protein, p7, of unknown function. The recognized nonstructural proteins are encoded in the 3 portion of the ORF. Replication is poorly understood but is believed to occur in association with intracytoplasmic membranes. Replicative forms of viral RNA have been detected in liver tissue. The genomic RNA is translated into a polyprotein that is rapidly processed both co- and post-translationally. Translation initiation occurs via an IRES within the 5-NCR, which also contains several closely spaced AUGs. Translocation of the structural glycoproteins to the endoplasmic reticulum probably occurs via an internal signal sequence. Cleavage of the structural proteins is effected by host cell signal peptidases; viral proteases cleave all non-structural protein junctions. Virus assembly is believed to occur by budding into vesicles.
Virus-specific antibodies to the structural proteins (core, E1 and E2) and to non-structural proteins, (principally NS3, NS4 and NS5) have been detected with recombinant-expressed antigens in individuals infected with HCV. Both linear and conformational epitopes are believed to be involved in the humoral immune response of the host to infection with HCV. Significant genetic heterogeneity throughout the genome is reflected in some serologic heterogeneity in the humoral immune response, especially to the product of the NS4 gene. The most extensive heterogeneity of HCV is found in the N-terminal 27 amino acids of E2 (hypervariable region 1; HVR-1). There is some evidence that HVR-1 is a neutralization epitope of HCV and that neutralization-escape variants of HVR-1 are positively selected by the host’s humoral immune response. Other neutralization epitopes may exist but they have not been defined. Cell-mediated immune responses to all of the HCV proteins have been detected, but their significance is unknown. However, it is believed by some that such responses are associated with amelioration or resolution of infection. Because there is no efficient or standardized cell culture system for the propagation of HCV, it has not been possible to carry out extensive in vitro neutralization assays. However, failure of an HCV infection to protect chimpanzees from reinfection following re-exposure to other HCV strains or even the same HCV strain (and similar results observed in natural infections of humans) suggests that defining serotypes of HCV may be difficult.
Humans are the natural host and apparent reservoir of HCV. The virus can be transmitted experimentally to chimpanzees. No other natural host has been identified.
Hepatitis C virus is transmitted almost exclusively by parenteral exposure to blood, blood products and objects contaminated with blood. Effective screening of blood donors and implementation of inactivation procedures have virtually eliminated the transmission of HCV via blood and blood products, but other routes of exposure, principally via blood-contaminated syringes, are now the most important recognized risk factors in developed countries. Sexual and perinatal transmission have been reported but appear to be relatively uncommon.
Hepatitis C virus has a worldwide distribution. Antibody-based epidemiologic studies suggest that about 0.1-2% of the populations of developed countries may be infected with HCV but antibody prevalence as high as 20% has been detected in some developing countries. The high prevalence of antibody to HCV is thought to be the result of using contaminated needles and syringes in such countries. Overall, it has been estimated that about 3% of the world population has been infected with HCV, resulting in about 170 million chronically infected individuals.
Infections range from subclinical to (rarely) fulminant disease. Persistence of the virus occurs in about 80% of HCV infections. Of these, about 20% progress to chronic active hepatitis and cirrhosis. Persistent HCV infection has been epidemiologically linked to primary liver cancer, cryptogenic cirrhosis and some forms of auto-immune hepatitis. Extra-hepatic manifestations of HCV infection include mixed cryoglobulinemia with associated membranoproliferative glomerulonephritis and possibly, porphyria cutanea tarda, Sjögren’s-like syndrome and other autoimmune conditions.
Hepatitis C virus has been reported to replicate in several cell lines derived from hepatocytes and lymphocytes but virus growth has not been sufficient for practical application of these systems. In vivo, HCV replicates in hepatocytes in the apparent absence of cytopathogenic effects. Genomic RNA of HCV has also been identified in peripheral blood mononuclear cells but the significance of this is unknown.
List of Species Demarcation Criteria in the Genus
Hepatitis C virus can be classified into six genetic groups, based upon the genome-wide heterogeneity of isolates recovered throughout the world. These have been called HCV genotypes 1-6; genotypes differ from each other by about 25-35% at the nucleotide level. Genotypes 7-11 have been described but more extensive genetic analysis has placed genotypes 7, 8, 9 and 11 within genotype 6 and genotype 10 within genotype 3. The six genotypes have been further subdivided into over 100 subtypes. These differ from each other by about 15-25% at the nucleotide level. Although the genotypes are more or less distinct, discrimination of subtypes is less clear, owing to overlap in the degree of heterogeneity. It has been proposed that the major genotypes of HCV be classified as genetic groups 1-6. Because serotyping of HCV isolates is not possible at present and because major genotypes do not have any other taxonomic characteristics except, in some cases, geographic distribution, the six genetic groups of HCV currently comprise one species.
A number of genotypic clusters are recognized for Hepatitis C virus (HCV). Examples are listed below.
Official virus species names are in italics. Tentative virus species names, alternative names ( ), strains or serotypes are not italicized. Virus names, genome sequence accession numbers [ ], and assigned abbreviations ( ) are:
|
Hepatitis C virus |
(HCV) | ||
|
HCV cluster 1 |
genotype 1a |
[M62321] |
(HCV-1) |
|
genotype 1b |
[D90208] |
(HCV-J) | |
|
HCV cluster 2 |
genotype 2a |
[D00944] |
(HCV-J6) |
|
genotype 2b |
[D01221] |
(HCV-J8) | |
|
HCV cluster 3 |
genotype 3a |
[D17763] |
(HCV-NZL1) |
|
genotype 10a |
[D63821] |
(HCV-JK049) | |
|
HCV cluster 4 |
genotype 4a |
[Y11604] |
(HCV-ED43) |
|
HCV cluster 5 |
genotype 5a |
[Y13184] |
(HCV-EVH1480) |
|
HCV cluster 6 |
genotype 6a |
[Y12083] |
(HCV-EUHK2) |
|
genotype 11a |
[D63822] |
(HCV-JK046) | |
Tentative Species in the Genus
None reported.
Unassigned Species in the Family
Three distinct groups of viruses tentatively have been assigned to the family Flaviviridae, based upon their genomic organization and genetic similarity to recognized members of the family.
|
Type Species |
GB virus A |
[U22303] |
(GBV-A) |
|
GBV-A-like agents |
[U94421] |
(GBV-A-like agents) |
GBV-A and GBV-A-like agents are a group of related viruses that have been identified in at least six species of New World monkeys. They do not cause hepatitis in the unique host species of each virus nor in other susceptible species. Their organ site of replication has not been identified and, although the viruses are transmissible via blood, their natural route of transmission is unknown. These viruses share an overall genomic organization and distant genetic similarity with hepaciviruses but differ in that they appear to lack a complete capsid protein gene and the organization of their 3-NCR is less complex than that of the hepaciviruses.
|
Type Species |
GB virus B |
[U22304] |
(GBV-B) |
GBV-B was recovered from a tamarin monkey but its passage history suggests that it could be of human origin. It is transmissible by blood and causes hepatitis in several species of New World monkeys. Both in genomic organization and sequence similarity, GBV-B most closely resembles the hepaciviruses.
|
Type Species |
GB virus C/Hepatitis G virus |
[U36380] |
(GBV-C) |
|
[044402] |
(HGV-1) |
GBV-C/HGV is a genetically heterogeneous virus of human origin. It is transmitted via blood and blood products but other routes of transmission may exist. Although originally described as a hepatitis virus, (therefore the alternate name: Hepatitis G virus), its pathogenicity and its organ site of replication remain controversial. Although distinct, GBV-C is most closely related to the GBV-A group of viruses, both in genomic organization and genetic relatedness.
Phylogenetic Relationships within the Family
Not available.
None reported.
Flavi: from Latin flavus, ”yellow”.
Hepato: from Greek hepar, hepatos, ”liver”.
Pesti: from Latin pestis, ”plague”.
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