Abbreviations : Report Help
Rebecca Rico-Hesse, Tatjana Avsic-Zupanc, Bradley Blitvich, Jens Bukh, Van-Mai Cao-Lormeau, Allison Imrie, Amit Kapoor, Laura D Kramer, Brett D Lindenbach, Peter Simmonds, Donald B. Smith, Pedro Fernando da Costa Vasconcelos
A summary of this ICTV Report chapter has been published as an ICTV Virus Taxonomy Profile article in the Journal of General Virology, and should be cited when referencing this online chapter as follows:
Simmonds, P., Becher, B., Bukh, J., Gould, E.A., Meyers, G., Monath, T., Muerhoff, S., Pletnev, A., Rico-Hesse, R., Smith, D.B., Stapleton, J.T., and ICTV Report Consortium. 2017, ICTV Virus Taxonomy Profile: Flaviviridae, Journal of General Virology, 98:2–3.
The Flaviviridae is a family of small enveloped viruses with positive-sense RNA genomes of approximately 9.0–13 kb. Most infect mammals and birds, and many are host-specific and pathogenic, such as hepatitis C virus (HCV) in the genus Hepacivirus. Most members of the genus Flavivirus are arthropod-borne, and many are important human and veterinary pathogens (e.g., yellow fever virus, dengue virus, West Nile virus).
Table 1.Flaviviridae. Characteristics of the family Flaviviridae.
yellow fever virus-17D (X03700), species Yellow fever virus, genus Flavivirus
Enveloped, 40–60 nm virions with a single core protein (except for genus Pegivirus) and 2 or 3 envelope glycoproteins
9.0–13 kb of positive-sense, non-segmented RNA
Cytoplasmic, in membrane vesicles derived from the endoplasmic reticulum (ER); assembled virions bud into the lumen of the ER and are secreted through the vesicle transport pathway
Directly from genomic RNA containing a type I cap (genus Flavivirus) or an internal ribosome entry site (other genera)
Mammals (all genera); most members of genus Flavivirus are arthropod-borne
Four genera containing 89 species
Flavivirus. Most members of this genus, which includes 53 species, are arthropod-borne viruses, with distinct groups infecting mosquitoes or ticks. Mammals and birds are the usual primary hosts, in which infections range from asymptomatic to severe or fatal haemorrhagic fever or neurological disease. Important human pathogens include yellow fever virus, dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. Other members cause economically important diseases in domestic or wild animals. Additional viruses infect only arthropods or only mammals (e.g., Tamana bat virus).
Pestivirus. Pestiviruses infect pigs and ruminants, including cattle, sheep, goats and wild ruminants, and are transmitted through contact with infected secretions (respiratory droplets, urine or faeces). Infections may be subclinical or cause enteric, haemorrhagic or wasting diseases, including the economically important bovine viral diarrhoea virus and classical swine fever virus. Additional pestiviruses of unknown pathogenicity infect bats and rats.
Hepacivirus. This genus includes hepatitis C virus (HCV), a major human pathogen causing chronic liver disease, including cirrhosis and cancer. Other viruses in the genus are of unknown pathogenicity and infect horses, rodents, bats, cows and primates. Infections are typically persistent and target the liver.
Pegivirus. Members of the genus Pegivirus are associated with persistent infections of a wide range of mammalian species. They have not been clearly associated with disease.
Virions are 40–60 nm in diameter, spherical in shape with a lipid envelope. The capsid is comprised of a single protein and the envelope contains two or three virus-encoded membrane proteins. Specific descriptions of members of the four individual genera are given in the corresponding genus pages.
The virion Mr, buoyant density, sedimentation coefficient and other physicochemical properties differ among the members of the genera and are described separately in the corresponding genus pages.
Genomes are positive-sense ssRNA of approximately 9.2–11.0, 11.3–13.0, 8.9–10.5 and 8.9–11.3 kb for members of the genera Flavivirus, Pestivirus, Hepacivirus and Pegivirus, respectively. All members of the family lack a 3′-terminal poly(A) tract. Only the genomes of members of the genus Flavivirus contain a 5′-terminal type I cap structure, the others possess an internal ribosomal entry site (IRES).
Virions of members of the family have a single, small basic capsid (C) and two (Flavivirus, Hepacivirus and Pegivirus) or three (Pestivirus) membrane-associated envelope proteins. Pegiviruses appear to lack a complete nucleocapsid protein gene. The nonstructural proteins contain sequence motifs characteristic of a serine protease, RNA helicase and RNA-dependent RNA polymerase (RdRP) that are encoded at similar locations along the genome in all genera. Further details of specific functional properties are given in the corresponding sections of the individual genera pages.
Lipids present in virions are derived from host cell membranes and make up 17% of the total virion weight in the case of members of the genus Flavivirus. The lipid content of pestiviruses, hepaciviruses and pegiviruses is unknown.
Virions contain carbohydrates in the form of glycolipids and glycoproteins.
The genomic RNA of all members of the family has a similar organization and is the viral mRNA found in infected cells. It contains a single long open reading frame (ORF) flanked by 5′- and 3′-terminal non-coding regions (NCRs) that form specific secondary structures required for genome replication and translation. Members of the genus Flavivirus, but not pestiviruses, hepaciviruses or pegiviruses produce a unique, subgenomic, small (300–500 nt) non-coding RNA that is derived from the 3′-NCR of genomic RNA (Lin et al., 2004) that is essential for virus replication in cells and modulates pathogenicity in animals. Translation-initiation of genomic RNA is cap-dependent for members of the genus Flavivirus, whereas IRES elements are present in viruses of the other genera. Viral proteins are synthesized as part of a polyprotein that is co- and post-translationally cleaved by viral and cellular proteases. The structural proteins are contained in the N-proximal portion of this polyprotein and the nonstructural proteins in the remainder. The latter include a serine protease, an RNA helicase and the RdRP. Genome replication occurs in the cytoplasm in association with modified cellular membranes via the synthesis of genome-length negative-strand intermediates. Virion assembly, including acquisition of a glycoprotein-containing lipid envelope, occurs by budding through intracellular membranes. Viral particles are transported in cytoplasmic vesicles through the secretory pathway before they are released by exocytosis, as shown for members of the genus Flavivirus and assumed for members of the other genera. In addition, release of infectious RNA via exosomes has recently been demonstrated (Ramakrishnaiah et al., 2013).
The viruses of different genera are antigenically unrelated, but serological cross-reactivity exists among members within each genus.
The biological properties of viruses in the four genera exhibit different characteristics and are described in the corresponding sections of the genus pages.
Flavi: from Latin flavus, “yellow”.
Pesti: from Latin pestis, “plague”.
Hepaci: from Greek hepar, hepatos, “liver” and identifying letter from hepatitis C virus
Pegi: from persistent, and the original names of the GB viruses and hepatitis G, deriving from the initials of the original source, the surgeon “GB”
Phylogenetic relationships of amino acid sequences in a conserved domain of the RdRP show clustering of members of the Flaviviridae into the four currently assigned genera, although there is a closer phylogenetic relationship between members of the Hepacivirus and Pegivirus genera than between others (Figure 1.Flaviviridae). Another exception is the outlier position of Tamana bat virus, currently listed as a potential member of the Flavivirus genus, but sufficiently distinct to potentially merit assignment into a new genus, should further related viruses be found in the future.
Figure 1.Flaviviridae. Phylogeny of conserved amino acid sequences in the RdRP (NS5 or NS5B) of members of the family Flaviviridae. Partial gene sequences between positions 8,040–8,897 (numbered using positions in the HCV sequence, AF011751) from representative isolates of each species and from several related unclassified viruses were aligned as inferred amino acid sequences using MUSCLE (Edgar 2004) and verified by the presence of aligned motifs. An unrooted phylogenetic tree was constructed from the sequence alignment by maximum likelihood using an empirically determined optimal substitution model – Le Gascuel 2008 with a gamma distribution (5 categories) and invariant sites (LG + G+I) computed with the MEGA version 6.1 package (Tamura et al., 2013). Data was bootstrap re-sampled 100 times; values of >=70% are shown next to the branches. This phylogenetic tree and corresponding sequence alignment are available to download from the Resources page.
Members of the Flaviviridae have been placed into RNA virus supergroup II, a group that also includes members of the Tombusviridae (plant), members of the Luteovirus genus in the Luteoviridae (plant), Leviviridae (bacterial virus) and a series of recently described insect-derived flavi-like viruses, many with segmented genomes (Shi et al., 2015). However, the virion structure and other viral structural and nonstructural genes in these other virus groups are distinct and likely non-homologous.
The 5′-end of the genome possesses a type I cap (m7GpppAmp) not seen in viruses of the other genera. Most flaviviruses are transmitted to vertebrate hosts by arthropod vectors, mosquitoes or ticks, in which they replicate actively. Some flaviviruses transmit between rodents or bats without known arthropod vectors.
Virions are 50 nm in diameter and spherical in shape (Figure 1.Flavivirus). Two virus forms can be distinguished. Mature virions contain two virus encoded membrane-associated proteins, E and M. Intracellular immature virions contain the precursor prM, which is proteolytically cleaved into M during maturation (Stadler et al., 1997). In certain instances, partially mature/immature forms are also released from infected cells. The virion structures of dengue virus (DENV) and West Nile virus (WNV) have been determined by X-ray crystallography (Kuhn et al., 2002, Mukhopadhyay et al., 2003). The envelope protein, E, is a dimeric, rod-shaped molecule that is oriented parallel to the membrane and does not form spike-like projections in its neutral pH conformation (Yu et al., 2008). Image reconstructions from cryo-electron micrographs (Figure 1.Flavivirus) have shown that the virion envelope has icosahedral symmetry, in which E protein dimers are organized in a herringbone-like arrangement.
Figure 1.Flavivirus. Three-dimensional cryo-electron microscopic reconstructions of immature (left) and mature (right) particles of an isolate of dengue virus (courtesy of M. Rossmann). Shown is a surface rendering of immature dengue virus at 12.5Å resolution (left) and mature dengue virus at 10Å resolution (right). The viruses are depicted to scale, but not coloured to scale. Triangles outline one icosahedral unit.
Virion Mr has not been precisely determined. Mature virions sediment at about 200S and have a buoyant density of about 1.19 g cm−3 in sucrose (Kokorev et al., 1976). Viruses are stable at slightly alkaline pH 8.0 but are readily inactivated by exposure to acidic pH, temperatures above 40 °C, organic solvents, detergents, ultraviolet light and gamma-irradiation.
The virion RNA of flaviviruses is a positive-sense infectious ssRNA of 9.2–11.0 kb. The 5′-end of the genome possesses a type I cap (m-7GpppAmp) where the A is followed by a highly conserved G nucleotide. The 3′-ends lack a terminal poly(A) tract and terminate with the conserved dinucleotide CU.
Virions contain three structural proteins: capsid (C, 11 kDa), the major envelope protein (E, 50 kDa), , and either prM (26 kDa), in immature virions, or M (8 kDa), in mature virions. The E protein is the viral haemagglutinin, which mediates both receptor binding and acid pH-dependent fusion activity after uptake by receptor-mediated endocytosis. Seven nonstructural proteins are synthesized in infected cells: NS1 (46 kDa), NS2A (22 kDa), NS2B (14 kDa), NS3 (70 kDa), NS4A (16 kDa), NS4B (27 kDa) and NS5 (103 kDa). Some members of the genus harbour sequences that appear to induce a proportion of translating ribosomes to shift -1 nt and continue translating in the new reading frame to produce a 'transframe' fusion protein (Firth and Atkins 2009). When functionally utilized, this is referred to as programmed-1 ribosomal frameshifting (-1 PRF). NS1 has multiple forms and roles, with a cell-associated form functioning in viral RNA replication and a secreted form that regulates complement activation. One such form, a NS1′ protein, is the product of a −1 ribosomal frameshift and plays a role in viral neuroinvasiveness (Melian et al., 2010). The N-terminal one-third of NS1 forms the viral serine protease complex together with NS2B that is involved in processing the polyprotein. The C-terminal portion of NS3 contains an RNA helicase domain involved in RNA replication, as well as an RNA triphosphatase activity that is probably involved in formation of the 5′-terminal cap structure of the viral RNA. NS5 is the largest and most highly conserved protein that acts as the viral RdRP and also possesses methyltransferase activity involved in the modification of the viral cap structure.
Virions contain about 17% lipid by weight; lipids are derived from host cell membranes.
Virions contain about 9% carbohydrate by weight (glycolipids, glycoproteins); their composition and structure are dependent on the host cell (vertebrate or arthropod). N-glycosylation sites are present in the proteins prM (1 to 3 sites), E (0 to 2 sites) and NS1 (1 to 3 sites).
The genomic RNA represents the only viral messenger RNA in infected cells. It consists of a single long ORF of more than 10,000 nt that codes for all structural and nonstructural proteins and is flanked by NCRs at the 5′- and 3′-terminal ends (Figure 2.Flavivirus).
Figure 2.Flavivirus. Flavivirus genome organization (not to scale) and polyprotein processing. The virion RNA is about 11 kb. At the top is the viral genome with the structural and nonstructural protein coding regions and the 5′- and 3′-NCRs. Boxes below the genome indicate viral proteins generated by the proteolytic processing cascade. P, H, and R symbols indicate the localization of the NS3 protease, the NS3 RNA helicase, and the NS5 RdRP domains, respectively.
Both the 5′-NCR and the 3′-NCR contain RNA sequence motifs that are involved in viral RNA translation, replication and possibly packaging. Although RNA secondary structure and function of some elements are conserved, sequence composition, length and exact localization can vary considerably between different members of the genus, in particular between tick-borne and mosquito-borne flaviviruses. In some cases, the 3′-NCR of tick-borne encephalitis virus, for example, contains an internal poly(A) tract. Viral infection induces dramatic rearrangements of cellular membrane structures within the perinuclear endoplasmic reticulum (ER) and causes the formation of ER-derived vesicular packets that most likely represent the sites of viral replication. After translation of the incoming genomic RNA, RNA replication begins with synthesis of complementary negative-strands, which are then used as templates to produce additional genome-length positive-stranded molecules. These are synthesized by a semi-conservative mechanism involving replicative intermediates (containing double-stranded regions as well as nascent single-stranded molecules) and replicative forms (duplex RNA molecules). Translation usually starts at the first AUG of the ORF, but may also occur at a second in-frame AUG located 12 to 14 codons downstream in mosquito-borne flaviviruses. The polyprotein is processed by cellular proteases and the viral NS2B-NS3 serine protease to give rise to the mature structural and nonstructural proteins. Protein topology with respect to the ER and cytoplasm is determined by internal signal and stop-transfer sequences. Virus particles can first be observed in the rough endoplasmic reticulum, which is believed to be the site of virus assembly. These immature virions are then transported through the membrane systems of the host secretory pathway to the cell surface where exocytosis occurs. Shortly before virion release, the prM protein is cleaved by furin or a furin-like cellular protease to generate mature virions. Infected cells also release a non-infectious subviral particle that has a lower sedimentation coefficient than whole virus (70S rather than 200S) and exhibits haemagglutination activity.
All flaviviruses are serologically-related, which can be demonstrated by binding assays such as ELISA and by haemagglutination-inhibition using polyclonal and monoclonal antibodies. Neutralization assays are more discriminating and have been used to identify more closely related Flavivirus serocomplexes (as indicated in Figure 1.Flaviviridae), although not down to the species level. The envelope protein E is the major target for neutralizing antibodies and induces protective immunity. The E protein also induces flavivirus cross-reactive non-neutralizing antibodies. Antigenic sites involved in neutralization have been mapped to each of the three structural domains of the E protein. The prM and NS1 proteins can also induce antibodies that protect infected animals from lethal infection.
Flaviviruses can infect a variety of vertebrate species and in many cases arthropods. Some viruses have a limited vertebrate host range (e.g., only primates), while others can infect and replicate in a wide variety of species (mammals, birds, etc.). The usual route of infection for arthropods is when they feed on a viraemic vertebrate host, but non-viraemic transmission between vectors has also been described for tick-borne flaviviruses. A new group of unclassified viruses in the genus, including cell fusing agent virus, appear only to infect mosquitoes, and several more, highly genetically distinct insect-only flaviviruses have now been identified (Blitvich and Firth 2015).
Most flaviviruses are arthropod-borne viruses with cycles of transmission from hematophagous arthropod vectors to vertebrate hosts. About 50% of known flaviviruses are mosquito-borne, 28% are tick-borne and the remainder transmit between rodents or between bats without known arthropod vectors. For some flaviviruses, the transmission cycle has not yet been identified. In certain instances, flaviviruses can be transmitted to humans by blood products, organ transplantation, non-pasteurized milk or aerosols. Some tick-borne flaviviruses are known to be transmitted directly between ticks by a process known as non-viraemic transmission. In the arthropod vectors, the viruses may also be transmitted trans-ovarially or vertically (mosquitoes, ticks) and transstadially (ticks). The mechanisms of virus transmission involving the insect-only flaviviruses may include vertical transmission, but other mechanisms need to be considered to explain the success with which these viruses have dispersed globally.
Flaviviruses have a world-wide distribution but individual species are restricted to specific endemic or epidemic areas (e.g., yellow fever virus in tropical and subtropical regions of Africa and South America; dengue virus in tropical areas of Asia, Oceania, Africa, Australia and the Americas; Japanese encephalitis virus in Southeast Asia; tick-borne encephalitis virus in Europe and Northern Asia).
More than 50% of known flaviviruses have been associated with human disease, including many important human pathogens such as yellow fever virus, dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. The induced diseases may be associated with symptoms of the central nervous system (e.g., meningitis, encephalitis), fever, arthralgia, rash and haemorrhagic fever. Several flaviviruses are pathogenic for domestic or wild animals (turkey, pig, horse, sheep, dog, grouse, muskrat) and cause economically important diseases.
Species demarcation criteria in the genus include:
Species demarcation considers a combination of each of the criteria listed above. While nucleotide sequence relatedness and the resulting phylogenies are important criteria for species demarcation, the other listed criteria may be particularly useful in the demarcation of genetically closely related viruses. For example far-eastern (FE) strains of tick-borne encephalitis virus exhibit distinct ecological differences when compared with Omsk haemorrhagic fever virus despite the fact that they are genetically relatively closely related. FE strains of tick-borne encephalitis virus are associated predominantly with Ixodes persulcatus ticks in forest environments in far-east Russia, whereas Omsk hemorrhagic fever virus is found in the Steppe regions of western Siberia associated particularly with Dermacentor spp. and to a lesser extent with Ixodes spp. These viruses are also antigenically distinguishable in neutralization tests that employ convalescent sera.
Louping ill virus and tick-borne encephalitis virus provide another example of viruses where, despite their close genetic relationships and similar host ranges, they display different ecologies (moorlands versus forests), pathogenicities (red grouse, sheep/goats versus humans) and geographical distributions (UK versus Europe/Eurasia), thus justifying their classification as members of the distinct species, Louping ill virus and Tick-borne encephalitis virus.
On the other hand, the four dengue virus serotypes all belong to a single species (Dengue virus), despite being phylogenetically and antigenically quite distinct. This is justified by the fact that they co-circulate in the same geographical areas and ecological habitats, and that they exploit identical vectors, exhibit similar life cycles and disease manifestations (Table 1.Flavivirus).
Table 1.Flavivirus. Flaviviruses grouped by vector and host.
Tick-borne, mammalian host
Gadgets Gully virus
Kyasanur Forest disease virus
Alkhumra hemorrhagic fever virus
Louping ill virus
Turkish sheep encephalitis virus subtype
Greek goat encephalitis virus subtype
Omsk hemorrhagic fever virus
deer tick virus
Royal Farm virus
Tick-borne encephalitis virus
Far Eastern subtype
Tick-borne, seabird host
Saumarez Reef virus
Mosquito-borne, Aroa virus group
Mosquito-borne, Dengue virus group
Dengue virus 1
Dengue virus 2
Dengue virus 3
Dengue virus 4
Mosquito-borne, Japanese encephalitis virus group
Japanese encephalitis virus
Murray Valley encephalitis virus
St Louis encephalitis virus
St. Louis encephalitis virus
West Nile virus
Mosquito-borne, Kokobera virus group
Mosquito-borne, Ntaya virus group
Israel turkey meningoencephalitis virus
Mosquito-borne, yellow fever virus group
Yellow fever virus
yellow fever virus
Probably mosquito-borne, Kedougou virus group
Probably mosquito-borne, Edge Hill virus group
Edge Hill virus
Uganda S virus
Unknown vector, Entebbe bat virus group
Entebbe bat virus
Unknown vector, Modoc virus group
Cowbone Ridge virus
Sal Vieja virus
San Perlita virus
Unknown vector, Rio Bravo virus group
Bukalasa bat virus
Carey Island virus
Dakar bat virus
Montana myotis leukoencephalitis virus
Montana myotis leukoencephalitis virus
Phnom Penh bat virus
Batu Cave virus
Rio Bravo virus
Fitzroy River virus
Aedes galloisi flavivirus
cell fusing agent virus
Culex theileri flavivirus
Ecuador Paraiso Escondido virus
Kamiti River virus
Palm Creek virus
Parramatta River virus
Quảng Bình virus
Viruses with no known arthropod vector
Kampung Karu virus
La Tina virus
Long Pine Key virus
Marisma mosquito virus
Tamana bat virus
Segmented flavi-like viruses
Jingmen tick virus
KJ001579; KJ001580; KJ001581; KJ001582
Mogiana tick virus
JX390986; KY523073; JX390985; KY523074
MH158415; MH158416; MH158417; MH158418
Guaico Culex virus
KM461666; KM461667; KM461668; KM461669; KM461670
Shuangao insect virus 7
KR902717; KR902718; KR902719; KR902720
Wuhan flea virus
KR902713; KR902714; KR902715; KR902716
Wuhan aphid virus 1
KR902721; KR902722; KR902723; KR902724
Wuhan aphid virus 2
KR902725; KR902726; KR902727; KR902728
Wuhan cricket virus
KR902709; KR902710; KR902711; KR902712
The best characterised member of the Hepacivirus genus is hepatitis C virus (HCV), classified as a member of the species Hepacivirus C (Smith et al., 2016). HCV infects humans and is an important aetiological agent of chronic hepatitis. A further hepacivirus, GB virus-B (GBV-B), highly divergent in sequence from HCV, was first described in tamarins in 1995 in which it establishes acute infections and liver pathology comparable to that of HCV (Simons et al., 1995b). Several other hepaciviruses have recently been described that infect Old World colobus monkeys, various rodents and bats species, European and African cattle, horses and donkeys (Sibley et al., 2014, Walter et al., 2017, Corman et al., 2015, Baechlein et al., 2015, Kapoor et al., 2011, Burbelo et al., 2012, Kapoor et al., 2013b, Drexler et al., 2013, Firth et al., 2014, Quan et al., 2013). These viruses have been assigned to further hepacivirus species and show distinct host ranges - Hepacivirus A (non-primate hepacivirus, NPHV) infecting horses and possibly dogs, Hepacivirus B (GBV-B) infecting tamarins and potentially other New World primates, Hepacivirus D infecting colobus monkeys, Hepacivirus E, Hepacivirus F, Hepacivirus G, Hepacivirus H, Hepacivirus I and Hepacivirus J infecting various species of rodents, Hepacivirus K, Hepacivirus L and Hepacivirus M infecting bats and Hepacivirus N infecting cows. A currently unclassified, more divergent hepacivirus-like sequence has been assembled from liver tissue of a gracile shark (Wenlin shark virus).
Collectively, these other hepaciviruses are much less well characterised virologically and clinically than HCV (Hepacivirus C) and the descriptions below primarily refer to HCV; any available information on other members is referred to where appropriate.
Hepatitis C virus (HCV) is transmitted between humans, principally via exposure to contaminated blood; the transmission routes of other hepaciviruses are poorly understood but are unlikely to be parenteral. There is no known invertebrate vector for HCV or any other hepacivirus. Hepaciviruses differ from members of the genera Flavivirus and Pestivirus by their limited ability to be propagated in cell culture; only a few adapted strains of HCV, including JFH1, efficiently infect the only susceptible cultured cell line, human hepatoma cell line (Huh7). Cell culture of other hepaciviruses has not been achieved to date. In the HCV precursor protein, the NS2-3 junction is auto-catalytically cleaved by Zn-dependent NS2-3 protease activity; a similar mechanism is likely for other hepaciviruses.
Virions of HCV are about 50 nm in diameter, as determined by filtration and electron microscopy. They are spherical in shape with 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 of HCV or other hepaciviruses have not been determined.
Virion Mr has not been determined. The buoyant density in sucrose of HCV is predominantly about 1.06 g cm−3 for virus recovered from serum during acute infections while more dense forms (ca. 1.15–1.18 g cm−3) predominate when recovered from the serum of chronically infected individuals (Thomssen et al., 1993). Lower density banding results from physical association of the virion with serum very-low-density lipoproteins (VLDLs)(Thomssen et al., 1992). Higher density virions are those bound to serum antibodies. Of these different particle types found in humans, the lowest density particles are the most infectious (paricles < 1.1 g cm-3)(Bradley et al., 1991). A buoyant density range in isosmotic iodixanol gradients of 1.01–1.10 g cm−3 has been measured for HCV recovered from hepatoma cells infected with HCV. The S20,w 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 (Feinstone et al., 1983).
Hepacivirus virions contain a single positive-sense, infectious ssRNA (Figure 1.Hepacivirus). The genome of HCV is about 9.6 kb, while for other hepaciviruses the range is 8.9–10.5 kb. The 5′-NCR of HCV possesses a type IV IRES (Honda et al., 1999) of approximately 340 nt. The divergent GBV-B, a member of Hepacivirus B, has a genome organization similar to HCV, but with a more extensive 5′-NCR (445 nt) also containing a type IV IRES (Muerhoff et al., 1995). Type IV IRESs are similarly present in members of most other hepacivirus species although the rodent hepaciviruses that are members of Hepacivirus F and Hepacivirus J possess an IRES showing sequence homology to those of pegiviruses (Smith et al., 2016, Drexler et al., 2013). The 3′-NCR of HCV contains a sequence-variable region of about 50 nt, a polypyrimidine-rich region (average of 100 nt), and a highly conserved 98 nt 3′-terminal region with three stem-loop RNA secondary structures (Tanaka et al., 1995) The 3′-NCRs of members of other hepacivirus species show little or no conservation in sequence or predicted RNA structure to that of HCV. There are at least two seed sites in the HCV 5′-NCR for the liver abundant microRNA miR-122; this virus-host interaction is required for efficient HCV replication (Jopling et al., 2005). One or two miR-122 seed sites are present in hepaciviruses of other species (Smith et al., 2016).
The HCV virion comprises at least three proteins: the nucleocapsid core protein C (p19-21), and two envelope glycoproteins, E1 (gp31) and E2 (gp70). An additional protein, p7 (believed to have properties of an ion channel protein important in viral assembly) is incompletely cleaved from a precursor of E2 to yield E2-p7 and p7 (Shanmugam and Yi 2013) but it is not known whether these are virion structural components. In GB virus-B, a corresponding protein, p13, is cleaved to p7 and p6 proteins (Takikawa et al., 2006). The two envelope glycoproteins can associate as non-covalent heterodimers; recent data, however, indicate that they are covalently linked in virions (Vieyres et al., 2010). Nonstructural proteins include NS2, a 21 kDa protein that, before cleavage, is part of a Zn-dependent cysteine protease that bridges NS2 and NS3 and mediates autocatalytic cleavage of the NS2/NS3 junction, and is involved with virus assembly and release, NS3, a 70 kDa protein with additional serine protease, helicase and NTPase activities; the NS3 protease cleaves the remaining junctions between nonstructural proteins, NS4A , a 6 kDa cofactor essential for trans NS3 serine protease activity, NS4B, a 27 kDa protein that induces a membranous replication complex at the endoplasmic reticulum, NS5A, a serine phosphoprotein of unknown specific function, but critical for viral replication and assembly, that exists in 56 and 58 kDa forms, depending on the degree of phosphorylation, and NS5B, a 68 kDa protein with RdRP activity.
The genomes of other hepacivirus species show similar organisations to those of HCV and GB virus-B, with predicted cleavage sites in the coding region potentially producing core, E1, E2, p7/p13, NS2, NS3, NS4A, NS4B, NS5A and NS5B proteins homologous to and comparable in size to those of HCV and GB virus-B. One exception is a large insertion of intrinsically disordered amino acid sequence in the NS5A gene of the colobus monkey hepacivirus (Hepacivirus D) (Lauck et al., 2013).
Hepacivirus virions have a lipid bi-layer envelope. Historically, based on the removal of the viral envelope and loss of infectivity of HCV following exposure to solvents or detergents (Feinstone et al., 1983), the presence of lipids was inferred. Recently, it has become apparent that the host lipid metabolism plays a critical role in the virus life cycle of HCV and likely other hepaciviruses.
The E1 and E2 glycoproteins of all hepaciviruses contain numerous N-linked glycosylation sites (1–4 in E1, 2–11 in E2), and carbohydrate is associated with the products of these two genes. E1 and E2 are transmembrane, type I glycoproteins, with C-terminal retention signals that anchor them within the lumen of the endoplasmic reticulum. These signals are apparently masked when budding occurs allowing the virion to move through the secretory pathway. Recent data obtained in culture systems indicate that N-linked glycans of HCV E1 remain in the high-mannose chains lacking complex carbohydrate, whereas those of E2 are modified (Op De Beeck et al., 2004). Glycosylation influences E1–E2 heterodimer formation, folding and assembly and the release of virions (Meunier et al., 1999).
The hepacivirus genome contains a single large ORF encoding a polyprotein of about 3,000 aa (Figure 1.Hepacivirus). The gene order is 5′-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-3′. Immediately downstream of the three structural proteins (C, E1, E2) is a small protein, p7 in HCV, p13 in GB virus-B and comparably small predicted proteins in other hepaciviruses, followed by the nonstructural proteins in the 3′-portion of the ORF. Replication occurs in association with intracytoplasmic membranes. Replicative forms of HCV and of the recently described non-primate hepacivirus (NPHV, Hepacivirus A; (Pfaender et al., 2015)) have been detected in liver tissue. The genomic RNA is translated into a polyprotein that is rapidly processed both co- and post-translationally by host and viral proteases. Translation initiation occurs via an IRES within the 5′-NCR. Translocation of the structural glycoproteins to the endoplasmic reticulum probably occurs via internal signal sequences. Cleavage of the structural proteins is mediated by host cell signal peptidases, and signal peptide peptidase. With the exception of the p7/NS2 signalase cleavage, viral proteases cleave all non-structural protein junctions. Virus assembly is believed to occur by budding into vesicles from the endoplasmic reticulum.
Figure 1.Hepacivirus. Hepacivirus genome organization (not to scale) and polyprotein processing. For members of the species Hepatitis C virus, the RNA is about 9.6 kb. The 5′-NCR is about 340 nt, the 3′-NCR about 250 nt, and the ORF about 9 kb. HCV has a p7 protein between E2 and NS2. The host and viral proteases involved in cleavage of the polyprotein are indicated. The cleavage by host signal peptide peptidase (at the C-terminus of the core protein) is indicated by a green arrow; the cleavages by host signal peptidase (remaining sites) are indicated by filled arrows. The locations of the NS2-3 protease, NS3 protease, NS3 RNA helicase and NS5B RdRP are indicated by P′, P″, H and R, respectively.
Virus-specific antibodies to recombinant-expressed structural proteins of HCV (C, E1 and E2) and nonstructural proteins (principally NS3, NS4 and NS5) have been detected 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. Significant antigenic diversity throughout the genome is reflected in heterogeneity in the humoral immune response. In HCV, high variability is found in the N-terminal 27 aa of E2 (hypervariable region 1; HVR1). The HVR1 contains an HCV neutralization epitope and escape variants of HVR1 are positively selected by the host humoral immune response (Mondelli et al., 2003). Other neutralization epitopes have been identified in E2 outside of HVR1 in E2 and also in E1 (Fafi-Kremer et al., 2012, Edwards et al., 2012, Keck et al., 2004). With the development of intra- and intergenotypic genotype 1-7 JFH1-based recombinant viruses with strain-specific structural proteins, it is now possible to carry out in vitro virus neutralization assays to address the antigenic diversity of HCV (Gottwein et al., 2011). Serological responses to GB virus-B infection are less well-characterized; antibodies to NS3 become detectable after a delay of several weeks in acutely infected tamarins but titres decline rapidly following virus clearance (Beames et al., 2001, Schaluder et al., 1995).
Cell-mediated immune responses to all HCV proteins have been detected (Klenerman and Thimme 2012); it is believed that such responses are associated with amelioration or resolution of infection. T cell responses in marmosets that may similarly correlate with protection from virus challenge have been detected in the NS3 and NS4A proteins of GB virus-B (Woollard et al., 2008).
Humans are the natural host and apparent reservoir of HCV although the virus can be transmitted experimentally to chimpanzees. No other natural host has been identified. The natural host for GB virus-B is not known although it can experimentally infect the New World primate species marmosets and tamarins and the more distantly related owl monkeys (Bukh et al., 2001). Members of other species of hepaciviruses infect a wide range of other mammalian species, both wild and domestic, including colobus monkeys (Sibley et al., 2014), cows (Baechlein et al., 2015), horses (Burbelo et al., 2012), donkeys (Walter et al., 2017) and a range of rodent and bat species (Kapoor et al., 2011, Kapoor et al., 2013b, Drexler et al., 2013, Firth et al., 2014, Quan et al., 2013). The host specificity of these variants for their mammalian hosts is undetermined, although at least one rodent species, the bank vole (Moyodes glareolus) can be infected with two highly divergent hepacivirus variants (RMU10-3382/GER/2010 and NLR07-oct70/NEL/2007)(Drexler et al., 2013) belonging respectively to the species Hepacivirus J and Hepacivirus F. This observation is indicative of a potential degree of cross-species transmission.
HCV 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 by blood and blood products, but other routes of exposure, principally by blood-contaminated syringes, are now the most important recognized risk factors. Sexual and mother-to-child transmission has been documented but is relatively uncommon. Other routes of transmission are suspected for members of other hepacivirus species; in a recent study of thoroughbred horses, evidence for vertical transmission of NPHV was obtained from one of four mares to their foals, while further infections occurred in the post-natal period (Gather et al., 2016).
HCV has a worldwide distribution with about 3% of the world population infected with HCV, equivalent to 170 million chronic infections, with 3–4 million new infections each year. Antibody prevalences are 0.1–2% in developed countries but as high as 20% in some developing countries, possibly reflecting the historic use of contaminated needles and syringes. Horses infected with members of Hepacivirus A have been reported from four continents with viraemia frequencies ranging from 3–10%, indicative of a wide geographical distribution (Burbelo et al., 2012, Pfaender et al., 2015, Lyons et al., 2012, Figueiredo et al., 2015, Lu et al., 2016, Matsuu et al., 2015).
The effects of HCV infection in humans range from subclinical to acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Persistent infection occurs in 60–80% of cases, and in about 20% of the cases the infection progresses over many years to chronic active hepatitis and cirrhosis. Patients with liver cirrhosis have an approximately 5% risk per year of developing hepatocellular carcinoma.
Persistent HCV infection has been linked by epidemiological studies to primary liver cancer, cryptogenic cirrhosis and some forms of autoimmune hepatitis. Extrahepatic manifestations of HCV infection include mixed cryoglobulinemia with associated membrano-proliferative glomerulonephritis and, possibly, porphyria cutanea tarda, Sjögren’s-like syndromes and other autoimmune conditions.
Similarly to HCV infections in humans, GB virus-B causes hepatitis and replicates in the liver of tamarins and owl monkeys, but infection is self-limited and has not been demonstrated in humans or chimpanzees. Only one strain of GB virus-B has been identified to date, in contrast to thousands of often quite divergent variants of HCV. The pathogenicity of other hepaciviruses infecting non-human primates, rodents, bats, cattle, and horses is poorly characterized although the presence of miR-122 seed sites in each species characterised to date predicts widespread hepatotropism among members of this genus (Jopling et al., 2005). Recent evidence suggests that infection of horses with NPHV may be associated with higher rates of spontaneous clearance than observed for HCV in humans (Pfaender et al., 2015, Lyons et al., 2014) and only mild inflammatory liver disease (Pfaender et al., 2015) with minimal elevation of liver enzymes (Lyons et al., 2014). Infection outcomes have been suggested to be dependent on the breed and age of the horse (Ramsay et al., 2015).
HCV has been reported to replicate in several cell lines derived from hepatocytes and lymphocytes, but virus growth has only been sufficient for practical application of these systems in a human hepatoma cell line, Huh7 cells and derivatives thereof. In vivo, HCV replicates in hepatocytes and possibly lymphocytes. The cellular or tissue tropism of other hepaciviruses is poorly characterized although there is evidence that GB virus-B, NPHV, and bovine hepacivirus are hepatotropic; the presence of binding sites for miR-122 (Jopling et al., 2005) in other described hepaciviruses is consistent with widespread hepatotropism, given the restriction of expression of this miRNA to liver tissue.
Species in the Hepacivirus genus have been assigned based on their members’ genetic divergence, where viruses showing greater than 0.25 amino acid p-distances in a conserved region of NS3 (positions 1,123–1,566 as numbered in the HCV genotype 1a H77 reference sequence AF011751), and greater than 0.3 in the NS5B region (amino acid positions 2536–2959) are considered to be members of different species (Smith et al., 2016). Members of different hepacivirus species show characteristically restricted host ranges, typically infecting different host species. There are, however, a few exceptions; the bank vole may be infected by members of both species Hepacivirus F and Hepacivirus J.
This demarcation point places hepaciviruses infecting humans and horses into different species (Hepacivirus A and Hepacivirus C) while assigning the 7 relatively divergent genotypes of HCV described to date (Smith et al., 2014) to a single species. These HCV genotypes differ from each other by about 30–35% at the nt level (Simmonds et al., 2005). Within each genotype, there are a number of subtypes, differing from each other by about 15–25% at the nt level. Although genotypes are distinct genetically, discrimination of subtypes is less clear, particularly in areas of high diversity such as sub-Saharan Africa and Southeast Asia. Because systematic serological typing by virus neutralization has not been performed to date, and because major genotypes do not have any other taxonomic characteristics except, in some cases, geographic distribution and differences in treatment response, it was considered appropriate to classify the seven genotypes of HCV as members of same species (Hepacivirus C).
Although HCV was the first hepacivirus to be discovered and the type species of its genus, it has been assigned to the species Hepacivirus C rather than Hepacivirus A to avoid potential confusion between its name and the letter assigned for its species assignment. Other species are named according to the date of publication of a complete coding sequence with the exception of the assignment of GB virus-B to Hepacivirus B, again to match the virus name and species letter.
Wenling shark virus
Pegiviruses have been detected in a variety of mammalian hosts, with transmission of human pegiviruses occurring by sexual, parenteral and maternal routes. Invertebrate vectors have not been discovered.
Pegiviruses show distant sequence relatedness to other members of the family Flaviviridae, forming a distinct cluster based on phylogenetic analysis of the RdRP (Figure 1.Flaviviridae). In addition to their separate phylogenetic position, they show several differences in genome organization from members of the Hepacivirus, Flavivirus, and Pestivirus genera. Most pegiviruses possess an IRES element that is structurally unrelated to those of hepaciviruses and pestiviruses and they do not encode a protein homologous to the nucleocapsid protein found in members of the other genera (Quan et al., 2013, Muerhoff et al., 1995, Stapleton et al., 2011). Infections with human pegivirus (HPgV) are frequently persistent but, with the exception of an association with non-Hodgkin’s lymphomac (Krajden et al., 2010, Chang et al., 2014), are not associated with the development of any identifiable disease. Pegivirus infections of other mammalian species are persistent and non-pathogenic, apart from the report of Theiler’s disease in horses infected with Theiler’s disease associated virus (Chandriani et al., 2013).
Virions of pegiviruses have not been visualized; the lack of an encoded core protein suggests that they may be structurally distinct from other members of the Flaviviridae. The virion size of HPgV was estimated to be 50–100 nm based on sequential filtration through filters of decreasing pore sizes.
The buoyant density of HPgV from human serum on both sucrose and CsCl density centrifugation ranged from 1.05–1.13 g cm−3 (Xiang et al., 1998, Melvin et al., 1998). Treatment of HPgV with detergent did not recover a denser, non-enveloped form of the virion, consistent with the lack of a viral nucleocapsid (Melvin et al., 1998). In the absence of an established cell culture model for pegiviruses, no information is currently available on their stability or inactivation characteristics.
Pegivirus virions contain a single positive-sense, potentially infectious ssRNA ranging from 8.9–11.3 kb (Figure 1.Pegivirus). The 5′-NCR contains an IRES element of between 300-550 nt. No miR-122 binding sites have been identified in 5′-NCR sequences of HPgV or among members of other pegivirus species (Smith et al., 2016). Most pegiviruses possess an IRES broadly similar in structure but not in sequence to the type I IRES elements of picornaviruses (Quan et al., 2013); however, the more divergent human hepegivirus (HHPgV), a member of Pegivirus H, as well as members of Pegivirus F and Pegivirus J have type IV IRES elements structurally resembling those of hepaciviruses and pestiviruses, but again with almost no sequence identity between them (Kapoor et al., 2015).
Functional studies of most pegivirus proteins have not been performed and information on their likely function in replication and virus assembly has largely been inferred from comparison with homologous genes in hepaciviruses. Most pegiviruses lack or possess no obvious homologue of the core protein of hepaciviruses and other members of the Flaviviridae, so how pegivirus virions are assembled remains uncertain. However, typically pegiviruses are predicted to encode shorter, although somewhat variable length, basic proteins containing multiple arginine and leucine amino acids immediately upstream of the signalase site before E1; these may play some role in RNA packaging during virion assembly. E1 and E2 proteins are believed to be envelope glycoproteins, while NS3 and NS5B contain motifs common to helicase and polymerase proteins in viruses of other genera of the Flaviviridae (reviewed in (Stapleton et al., 2011)). The NS3-4A region has been shown to be proteolytically active for processing the nonstructural region of the human pegivirus polyprotein (Belyaev et al., 1998).
The virion structure of pegiviruses is unknown, but the presence of predicted hydrophobic transmembrane regions in the E1 and E2 glycoproteins is consistent with the presence of viral envelope, likely derived by budding of pegiviruses from infected cells, analogously to other members of the family Flaviviridae.
The E1 and E2 glycoproteins have variable numbers of potential N-linked glycosylation sites, with members of the more divergent species Pegivirus F, Pegivirus H, and Pegivirus J possessing a larger number of sites, a feature more typical of hepaciviruses (Kapoor et al., 2015).
In common with other members of the Flaviviridae, the genome contains a single ORF. Structural proteins are processed by cellular proteases, while the NS3-4A viral protease cleaves the nonstructural region of the polyprotein in the same gene order as hepaciviruses (Figure 1.Pegivirus).
Figure 1.Pegivirus. Genome organization of pegiviruses. Pegivirus genomes range from approximately 8.9–11.3 kb; those with longer genomes code for additional predicted structural proteins, X and Y (lower diagram). The genome encodes a polyprotein that is co- and post-translationally cleaved into individual viral proteins. Structural proteins common to all pegiviruses are the envelope glycoproteins (E1 and E2), and non-structural proteins are NS2–NS5B. No protein homologous to the core protein of other members of the Flaviviridae has been identified in pegiviruses although some possess a predicted, basic protein upstream of E1 of unknown function (Y). Several pegiviruses also have a predicted additional glycoprotein downstream of E2 (X). Cleavage of structural proteins by cellular signal peptidases, of NS2/NS3 by the NS2–NS3 autoprotease and of the remaining NS proteins by the NS3–NS4A protease complex is comparable to hepaciviruses. All pegiviruses possess a long 5ʹ-noncoding region with predicted IRES function; most pegiviruses have a type I picornavirus-like IRES while others have a type IV IRES type structurally related to those of hepaciviruses and pestiviruses.
Pegivirus antigenicity is poorly characterized in the absence of in vitro neutralization assays or experimental animal models. Antibody to the E2 glycoprotein of HPgV can be detected in humans and is associated with clearance of viraemia (Feucht et al., 1997, Tacke et al., 1997). These E2 antibodies reduce the rate of re-infection following liver transplantation (Tillmann et al., 1998). Recent data show the immune modulating effects of E2 protein on T cell activation and NK cell signalling, which may contribute to the absence of serological reactivity to other HPgV proteins (Chivero et al., 2015).
Pegiviruses can be detected in a wide range of mammalian species (humans, non-human primates, pigs, horses and a range of rodent and bat species). Members of Pegivirus A infect New World monkeys (Muerhoff et al., 1995, Bukh and Apgar 1997) and bats, while members of Pegivirus C infect humans, chimpanzees (Adams et al., 1998, Birkenmeyer et al., 1998) and Old World monkeys (Sibley et al., 2014, Bailey et al., 2016). Members of Pegivirus E (equine pegivirus (Kapoor et al., 2013a) and Pegivirus D (Theiler’s disease associated virus (Chandriani et al., 2013)) infect horses, members of Pegivirus K infect pigs (Baechlein et al., 2016) and members of Pegivirus B, Pegivirus F, Pegivirus G, Pegivirus I and Pegivirus J infect a wide range of bat and rodent species (Kapoor et al., 2013b, Quan et al., 2013, Epstein et al., 2010)(Epstein et al., 2010; Kapoor et al., 2013b; Quan et al., 2013).
Very limited information is available on the potential of pegiviruses to transmit between different host species. However, chimpanzees can be experimentally infected by inoculation with HPgV (Pegivirus C) but not by the New World primate virus, GBV-A (Pegivirus A) (Bukh et al., 1998) and rhesus macaques can be infected with a baboon isolate of Pegivirus C (Bailey et al., 2015).
HPgV is transmitted between humans by sexual transmission, exposure to contaminated blood, and from mother to child. Horizontal transmission has neither been confirmed nor refuted (Bhattarai and Stapleton 2012). HPgV viraemia frequencies are higher in injecting drug users and in haemophiliacs with a history of exposure to non-virally inactivated clotting factor concentrates, indicating an efficient parenteral route of transmission. HPgV viraemia frequencies are also higher in people with sexually transmitted diseases and without a history of parenteral exposure (Scallan et al., 1998); human pegivirus infection is also a frequent co-infection with human immunodefiency virus 1 (HIV-1). Among HIV-infected subjects, co-infection with HPgV does not correlate with HIV transmission risk; however, hepatitis C virus (HCV) and HCV-HPgV co-infection are significantly associated with a parenteral mode of HIV acquisition (Bourlet et al., 1999), indicating the likelihood of sexual routes of transmission.
HHPgV (Pegivirus H) additionally shows evidence for parenteral routes of transmission with infections largely confined to intravenous drug users and recipients of blood or blood products (Kapoor et al., 2015, Coller et al., 2016, Bonsall et al., 2016, Berg et al., 2015); however, other modes of transmission have not been extensively studied.
Infection of humans with HPgV occurs worldwide and it is likely that it is ubiquitous in human populations. Prevalence studies in developed countries indicate between 1–4 % of healthy blood donors are viraemic for HPgV and another 5–13 % have anti-E2 antibodies, indicating prior infection. Rates of infection with HPgV in developing countries are higher, with viraemia frequencies in the general population frequently exceeding 10%. Infection frequencies of pegiviruses infecting non-human hosts are incompletely described. Infections with HHPgV appear to be confined to those with parenteral exposure, more reminiscent of HCV. Relatively low frequencies (1%–2%) of viraemia of other pegiviruses have been described in horses for members of Pegivirus D and Pegivirus E (Lu et al., 2016, Lyons et al., 2014, Kapoor et al., 2013a, de Souza et al., 2015) and pigs for members of Pegivirus K) (Baechlein et al., 2016).
Infections with HPgV in humans are considered non-pathogenic, to the extent that viraemic blood donations are not excluded from transfusion. The pathogenicity of pegiviruses infecting other hosts is unknown although experimental infection of New World primates with simian pegiviruses does not induce liver disease. However, it has been reported that infection of horses with members of Pegivirus D is associated with Theiler’s disease in horses (Chandriani et al., 2013).
Pegiviruses infecting humans or new world primates cannot be readily detected in the liver of infected hosts, whereas they are present at higher viral loads in circulating lymphocytes, including T and B lymphocytes (Kobayashi et al., 1999, Tucker et al., 2000). However, based on autopsy studies in humans (Tucker et al., 2000, Radkowski et al., 1999), and the animal model of nonhuman pegivirus infection in rhesus macaques, pegivirus replication occurs primarily in the bone marrow (Bailey et al., 2015). The tissue or cellular tropism of pegiviruses infecting other hosts is unknown. Like the hepaciviruses, pegiviruses differ from members of the genera Flavivirus and Pestivirus by their limited ability to be propagated in cell culture (Chivero and Stapleton 2015).
Species in the Pegivirus genus are now classified based on their genetic divergence (Smith et al., 2016) rather than their host range (Stapleton et al., 2011). Assignment thresholds are based on amino acid sequence divergence in conserved regions of NS3 and NS5B; pegiviruses showing greater than 0.31 amino acid p-distances in a conserved region of NS3 (positions 888–1635 as numbered in the HPgV reference sequence U22303), and greater than 0.31–0.36 in the NS5B region (amino acid positions 2398–2916) are considered to be separate species (Smith et al., 2016). In general, members of different pegivirus species infect different hosts with the notable exception of Pegivirus A, into which are assigned pegiviruses infecting New world primates (GB virus-A) and African bats.
Pegivirus species names have been assigned in alphabetical sequence largely based on their order of discovery, the exception being Pegivirus C which was chosen to match the virus name GB virus C (GBV-C). Isolates of this species are also known as hepatitis G virus (HGV) (Linnen et al., 1996, Simons et al., 1995a), although more recently the name human pegivirus (HPgV) has been proposed and adopted as there is now no evidence that infections are associated with hepatitis (Stapleton et al., 2011), nor did this virus infect the surgeon, GB, from whom infective material was passaged in primates and the virus first described. A second, more divergent group of pegiviruses, termed human hepegivirus (HHPgV) or HPgV-2 (Kapoor et al., 2015, Berg et al., 2015) has been assigned to Pegivirus H (Smith et al., 2016).
Compared to the other viruses in the Flaviviridae, pestiviruses encode two unique gene products, namely Npro and Erns (Tautz et al., 2015). The first protein of the ORF, nonstructural protein Npro, which possesses an autoproteolytic activity and is responsible for its release from the nascent polyprotein (Gottipati et al., 2014, Rumenapf et al., 1998, Stark et al., 1993), is not essential for virus replication in cell culture (Tratschin et al., 1998). One of the three viral envelope glycoproteins, Erns, possesses an intrinsic RNase activity (Krey et al., 2012, Schneider et al., 1993). Both of these unique proteins of the pestiviruses are involved in repression of the host type I IFN response (Schweizer and Peterhans 2001, Meyers et al., 2007, Ruggli et al., 2005, Ruggli et al., 2009, Python et al., 2013, Zurcher et al., 2014, Hilton et al., 2006, La Rocca et al., 2005). Two biotypes of pestiviruses, cytopathogenic (cp) and non-cytopathogenic (noncp) viruses, are distinguished by their ability to cause cytopathic effects in cell culture (Tautz et al., 2015, Becher and Tautz 2011).
Virions are 40–60 nm in diameter and spherical in shape (Figure 1.Pestivirus) (Laude 1979). The virion envelope has 10–12 nm ring-like subunits on its surface. The structure and symmetry of the core have not been characterized.
Figure 1.Pestivirus. Negative-contrast electron micrograph of particles of an isolate of bovine viral diarrhea virus 1. The bar represents 100 nm. (From M. König, with permission.)
Virion Mr has not been determined precisely. Buoyant density in sucrose is 1.10–1.15 g cm−3; S20,W is 140–150S (Laude 1979, Maurer et al., 2004). Virion infectivity is stable over a relatively broad pH range, but unstable at temperatures above 40 °C. Organic solvents and detergents rapidly inactivate these viruses (Depner et al., 1992).
The virion RNA is a positive-sense, infectious molecule of ssRNA of 11.3–13.0 kb encoding a single ORF (Becher et al., 2014, Becher et al., 1998, Collett et al., 1988, Meyers et al., 1989). The 5′-NCR contains an IRES and is about 370–385 nt (Poole et al., 1995). The 3′-NCR, of about 185–273 nt, is complex and contains a region with variable sequences and a highly conserved terminal region (Pankraz et al., 2005, Yu et al., 1999). For some cp pestivirus strains, a small and variable segment of host cell or viral nucleic acid is integrated into particular regions (often within NS2 or directly upstream of NS3) of the viral genome, sometimes accompanied by viral gene duplications or deletions (Tautz et al., 2015, Becher and Tautz 2011). Other cp pestiviruses contain only viral gene duplications involving all or part of the Npro and NS3 to NS4B protein-coding regions, resulting in genomic RNA of up to about 16.5 kb. In all cases, the single large ORF is maintained. Finally, cp viruses may also arise by deletion of large portions of their genomes. Such defective genomes can be rescued by co-infecting intact helper viruses (Tautz et al., 2015, Becher and Tautz 2011, Abbas et al., 2013).
Virions contain four structural proteins: a basic nucleocapsid core protein, C (14 kDa) and three envelope glycoproteins, Erns (gp44/48), E1 (gp33) and E2 (gp55). All three glycoproteins exist as intermolecular disulfide-linked complexes: Erns homodimers, E1-E2 heterodimers and E2 homodimers (Rumenapf et al., 1991, Thiel et al., 1991, Weiland et al., 1992, Weiland et al., 1990). The Erns protein possesses an intrinsic RNase activity. Pestiviruses encode eight nonstructural (NS) proteins among which Npro (23 kDa), p7 (7 kDa) and NS2 (40 kDa) are not necessary for RNA replication (Behrens et al., 1998, Tautz et al., 1999). Npro is a proteinase that auto-catalytically releases itself from the nascent polyprotein. Nonstructural protein p7 is presumed to have a role in virus maturation (Harada et al., 2000, Elbers et al., 1996). NS2-3 (120 kDa) is a multifunctional protein of which the N-terminal 40% (NS2) is hydrophobic and contains a zinc finger motif that binds divalent metal ions (De Moerlooze et al., 1990, Lackner et al., 2006). NS2 is a cysteine protease that is responsible for processing of NS2-3 to give rise to NS2 and NS3 (Lackner et al., 2006). NS3 (80 kDa) acts as both a serine protease involved in polyprotein processing and an RNA helicase/NTPase involved in RNA replication (Tautz et al., 1997, Tautz et al., 2000, Warrener and Collett 1995, Wiskerchen and Collett 1991). NS2-3 is found after infection with all pestiviruses. In cells infected with cp pestiviruses, large amounts of NS3 can be detected. For noncp bovine viral diarrhea virus (BVDV), noncp Border disease virus (BDV) and classical swine fever virus (CSFV) strains, efficient NS2-3 cleavage is limited to the first eight hours of infection and at later time points the cleavage products NS2 and NS3 are difficult to detect (Lackner et al., 2004). The NS4A (7 kDa) protein acts as a cofactor to the NS3 protease activity (Tautz et al., 2000). The role of NS4B (33 kDa) is unknown. NS5A (58 kDa) represents a phosphorylated protein and also plays still to be further characterized roles in RNA replication and virion morphogenesis (Chen et al., 2012, Isken et al., 2014, Tellinghuisen et al., 2006, Xiao et al., 2009). NS5B (75 kDa) possesses RdRP activity (Zhong et al., 1998, Steffens et al., 1999, Choi et al., 2006).
The viruses are enveloped, but no reports have described the lipid composition.
All virus envelope glycoproteins contain N-linked glycans (Thiel et al., 1991).
The genomic RNA contains a single large ORF encoding a polyprotein of about 3,900 aa that is preceded by a 5′-NCR of 370–385 nt and followed by a 3′-NCR of 185–273 nt. The gene order is 5′-Npro-C-Erns-E1-E2-p7-NS2-3(NS2-NS3)-NS4A-NS4B-NS5A-NS5B-3′ (Figure 2.Pestivirus) (Tautz et al., 2015, Abbas et al., 2013).
Figure 2.Pestivirus. Pestivirus genome organization (not to scale) and polyprotein processing. The RNA is 11.3–13.0 kb, comprising a 5′-NCR of 370–385 nt, the single ORF of about 11.7 kb and the 3′-NCR of 185–273 nt. Virus nonstructural proteins are indicated as NS. The symbols P′, P″, P′″, H and R indicate the localization of the Npro protease, the NS2 protease, the NS3 protease, the NS3 RNA helicase and the NS5B RdRP, respectively. The proteases and proteolytic steps involved in the generation of individual proteins are indicated. In noncp BVDV viruses, NS2-3 cleavage is detectable early after infection whereas in cp BVDV viruses both NS2-3 and NS3 are produced continuously.
Pestivirus replication is initiated by receptor-mediated endocytosis involving more than one cell surface molecule and the viral glycoproteins Erns and E2. CD46 has been shown to function as a cellular receptor for BVDV but is not by itself sufficient to mediate infection (Maurer et al., 2004, Krey et al., 2006a, Krey et al., 2006b, Krey et al., 2005). After endocytosis and uncoating, the genome RNA serves as mRNA; there are no subgenomic mRNA molecules. Translation initiation occurs by a cap-independent internal initiation mechanism involving a type IV IRES within the 5′-NCR of the RNA (Lozano and Martinez-Salas 2015). Polyprotein processing occurs co- and post-translationally by both cellular and viral proteases (Tautz et al., 2015). Nonstructural protein Npro, the first protein of the ORF, auto-proteolytically removes itself from the nascent polyprotein by cleavage at the Npro/C site. Downstream cleavages that produce structural proteins C, Erns, E1 and E2 as well as p7 are mediated by cellular signal peptide peptidase and signal peptidase(s) (Elbers et al., 1996, Bintintan and Meyers 2010, Heimann et al., 2006, Rumenapf et al., 1993). Glycoprotein translocation to the endoplasmic reticulum occurs by an internal signal sequence, within the C-terminal region of the C protein. Cleavage between E2 and p7 is not complete, leading to two intracellular forms of E2 with different C-termini (Elbers et al., 1996). Depending on the pestivirus biotype, NS2-3 either remains mostly intact or is found at reduced levels together with high amounts of its N- and C-terminal products NS2 and NS3 (Lackner et al., 2004). The increased generation of NS3 in cp pestiviruses is in most cases due to gene insertion, deletion, duplications or rearrangements (Tautz et al., 2015, Becher and Tautz 2011). The NS3/NS2-3 serine protease activity is responsible for all processing events downstream of NS3. NS4A facilitates cleavages by the NS3 protease of sites 4B/5A and 5A/5B (Tautz et al., 2015).
RNA replication probably occurs in association with intracytoplasmic membranes, presumably in a replication complex composed of viral RNA and viral nonstructural proteins. Nonstructural proteins NS3, 4A, 4B, 5A and 5B are necessary for RNA replication; only NS5A can be provided in trans (Grassmann et al., 2001). Replicative forms of viral RNA have been detected (Gong et al., 1996). The ratio of positive- to negative-sense RNA in cells 12 hours post-infection is about 10. RNA synthesis is resistant to actinomycin D. Virus maturation and release is poorly understood. Budding of virions occurs at ER membranes. Pestivirus particles have been shown in intracellular vesicles and the Golgi complex and during exocytosis (Schmeiser et al., 2014). Considerable amounts of infectious virus remain cell-associated. Host cell RNA and protein synthesis continues throughout infection.
Pestiviruses are antigenically related and cross-reactive epitopes have been documented for all species investigated (Tautz et al., 2015, Moennig et al., 1987). Separate antigenic determinants defined by monoclonal antibodies have also been identified. Antigenic variation is particularly pronounced among isolates of BVDV and BDV (Becher et al., 2003, Postel et al., 2015). The N-terminal portion of E2 contains an antigenically hypervariable region (van Rijn et al., 1994, van Rijn et al., 1992). Monoclonal antibody binding patterns are generally consistent with the genetic relatedness of viruses.
Infected animals mount potent antibody responses to two structural glycoproteins (Erns, E2) and to the NS2-3/NS3 protein, while antibody responses to other virus-encoded polypeptides are weak or not detectable. Erns and E2 are able to induce protection independently and monoclonal antibodies reactive with these proteins can neutralize virus infectivity (Weiland et al., 1992, Weiland et al., 1990, Hulst et al., 1993, van Zijl et al., 1991, Reimann et al., 2004).
Pestiviruses infect pigs and ruminants, including cattle, sheep, goats and wild ruminants (Becher et al., 1997, Vilcek and Nettleton 2006). Moreover, pestivirus sequences have been detected in samples from bats and rats by next generation sequencing, but infectious pestiviruses have not yet been isolated from these host species (Firth et al., 2014, Postel et al., 2015, Harasawa et al., 2000, Schirrmeier et al., 2004, Vilcek et al., 2005, Kirkland et al., 2007, Wu et al., 2012, Hause et al., 2015, Postel et al., 2016). There are no invertebrate hosts. Transmission occurs by direct and indirect contact (e.g., nasal or urine secretion, faeces, contaminated food, etc.) and transplacentally. Infections may be subclinical or produce a range of clinical conditions including acute diarrhea, acute hemorrhagic syndrome, acute fatal disease, and a wasting disease. Transplacental infection can result in foetal death, congenital abnormalities, or lifelong persistent infection (Moennig and Plagemann 1992). Fatal mucosal disease can occur in cattle persistently infected with noncp viruses when a cp virus is generated by mutation or introduced by superinfection (Meyers and Thiel 1996). Pestivirus infections of livestock are economically important worldwide (Moennig and Becher 2015, Houe 2003).
Experimental infection models have not been established for bovine or ovine pestiviruses outside their natural mammalian hosts; CSFV can be adapted to propagate in rabbits (Tautz et al., 2015). Cells derived from natural host species (bovine, porcine, ovine) support virus replication. Most virus isolates are noncp and can establish persistent infections in cell culture. Infectious noncp BVDV is often present in bovine serum products used for cell culture (Buttner et al., 1997). Cp pestiviruses induce extensive cytopathology and apoptosis, and form virus plaques under appropriate conditions (Hilbe et al., 2013, Birk et al., 2008, Grummer et al., 2002, Jordan et al., 2002). No hemagglutinating activity has been found associated with pestiviruses.
Pestiviruses have been assigned to eleven different species based on phylogenetic analysis of conserved amino acid sequences in the regions 189–418, 1,547–2,321, 2,397–2,688 and 3,312– 3,837 (numbered according to the first amino acid of the polyprotein if BVDV-1 Sd-1, M96751) (Figure 3.Pestivirus) (Smith et al., 2017). Pestivirus species are named according to the format Pestivirus A, Pestivirus B, etc. replacing the previous names as follows: Pestivirus A replaces Bovine viral diarrhea virus 1, Pestivirus B replaces Bovine viral diarrhea virus 2, Pestivirus C replaces Classical swine fever virus and Pestivirus D replaces Border disease virus. Additional species in the genus include Pestivirus E (pronghorn antelope virus), Pestivirus F (porcine pestivirus, Bungowannah virus), Pestivirus G (giraffe pestivirus), Pestivirus H (Hobi-like pestivirus, atypical ruminant pestivirus), Pestivirus I (Aydin-like pestivirus, sheep pestivirus), Pestivirus J (rat pestivirus) and Pestivirus K (atypical porcine pestivirus) (Firth et al., 2014, Postel et al., 2015, Hause et al., 2015, Postel et al., 2016). Convalescent animal sera generated against members of a given species (e.g., Pestivirus A) generally show a several-fold higher neutralization titre against viruses of the same species than against viruses from the other species (Becher et al., 2003, Postel et al., 2015). Finally, differences in host of origin and disease can assist in species demarcation.
Figure 3.Pestivirus. Phylogenetic tree of pestivirus amino acid positions 3,312–3,899. Maximum likelihood distances were calculated using a JTT+G model in MEGA 6 (Tamura et al., 2013) using up to 15 of the most divergent sequences for each species, with elimination of sequences <1 % divergent. Branches supported by >70 % of bootstrap replicates are indicated. Virus names and species assignments are indicated to the right. This phylogenetic tree and corresponding sequence alignment are available to download from the Resources page.
For example, Pestivirus A and Pestivirus C are considered different species because their members have: (i) amino acid sequences that are phylogenetically distinct in three different subgenomic regions (ii) at least 10-fold difference in neutralization titre in cross-neutralization tests with polyclonal immune sera, and (iii) host range, in that under natural conditions members of Pestivirus C infect only pigs while members of Pestivirus A infect ruminants as well as pigs.
Members of the species Pestivirus A can be further subdivided into at least seventeen genotypes, while three genotypes (CSFV-1, CSFV-2, and CSFV-3) are recognized among members of Pestivirus C (Yesilbag et al., 2014, Postel et al., 2012). Genotypes of these Pestivirus species can be further divided into subgroups.
Proposals for additional pestivirus species should be based on the complete genome sequence of at least one virus isolate, while data on antigenic relatedness and host range should also be considered. An incomplete genome sequence of an isolate from a bat (JQ814854) therefore remains unclassified.
Rebecca Rico-Hesse*Flavivirdae Study Group ChairDepartment of Molecular Virology & MicrobiologyBaylor College of MedicineOne Baylor PlazaHouston, TX 77030USATel: 1-713-798-3010E-mail: firstname.lastname@example.org
Tatjana Avsic-ZupancUniversity of Ljubljana | Faculty of MedicineINSTITUT OF MICROBIOLOGY AND IMMUNOLOGYZaloška 4,1000 LjubljanaSloveniaE-mail: email@example.com
Bradley BlitvichCollege of Veterinary Medicine1800 Christensen DriveAmes, Iowa 50011-1134Tel: 515-294-1242E-mail: firstname.lastname@example.org
Jens BukhCopenhagen Hepatitis C Program (CO-HEP)Department of Infectious Diseases and Clinical Research CentreCopenhagen University Hospital, Hvidovre, andDepartment of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of CopenhagenKettegaard Alle 30, DK-2650 HvidovreDenmarkTel: +45-23-41-89-69E-mail: email@example.com
Van-Mai Cao-LormeauInstitut Louis MalardéPO Box 3098713 PapeeteTahitiFrench PolynesiaE-mail: firstname.lastname@example.org
Allison ImrieFaculty of Health and Medical SciencesUniversity of Western AustraliaCrawley, WAAustraliaE-mail: email@example.com
Amit KapoorCenter for Vaccines and ImmunityThe Ohio State University700 Children's Drive Room WA4015ColumbusOH 43205USAE-mail: Kapoor.firstname.lastname@example.org
Laura D KramerNYS Department of Health, Wadsworth CenterEmpire State PlazaP.O. Box 509AlbanyNew York 12201-0509USATel: 518 485-6632E-mail: email@example.com
Brett D LindenbachMicrobial PathogenesisDepartment of Microbial Pathogenesis295 Congress AveNew Haven,CT 06536-0812USATel: 203.785.4705E-mail: firstname.lastname@example.org
Peter Simmonds[Previous Flavivirdae Study Group Chair]Nuffield Department of MedicineUniversity of OxfordPeter Medawar BuildingSouth Parks RoadOxford, OX1 3SYUnited KingdomTel: +44 (0) 1865 281 233E-mail: Peter.Simmonds@ndm.ox.ac.uk
Donald B. SmithCentre for Immunity, Infection and EvolutionUniversity of EdinburghWest Mains Road,Edinburgh, EH9 3FLUnited KingdomTel: +44-131-650-7331E-mail: D.B.Smith@ed.ac.uk
Pedro Fernando da Costa VasconcelosSeção de Arbovirologia e Febres HemorrágicasInstituto Evandro ChagasAnanindeua,ParaBrazilE-mail: email@example.com
* to whom correspondence should be addressed
Authors of a previous version of this Report:
Paul BecherInstitute of VirologyDepartment of Infectious DiseasesUniversity of Veterinary Medicine HannoverBuenteweg 17D-30559 HannoverGermanyTel: +49-511-953-8840E-mail: firstname.lastname@example.org
Ernest GouldUnité des Virus EmergentsFaculté de Médecine Timone5ème étage Aile Bleu27, Bd Jean Moulin13385 Marseille Cedex 05Tel: +44-7806-939165E-mail: email@example.com
Gregor MeyersFriedrich Loeffler InstituteSüdufer 10D-17493 Greifswald-RiemsGermanyTel: +49-3835-171156E-mail: Gregor.Meyers@fli.bund.de
Thomas P. MonathBioProtection Systems/NewLink Genetics Corp.94 Jackson Rd. Suite 108Devens MA 01434USAPhoine: +1 firstname.lastname@example.org
A. Scott Muerhoff Abbott Laboratories100 Abbott Park RoadDept. 09QS, AP20-4Abbott Park, IL 60064-6015USATel: +1-224-668-1077E-mail: email@example.com
Alexander G. PletnevLaboratory of Infectious DiseasesNational Institute of Allergy and Infectious DiseasesNational Institutes of Health33 North DriveBethesda, MD 20892United States of AmericaTel: +1-301-402-7754E-mail: firstname.lastname@example.org
Jack T. StapletonDepartments of Internal Medicine and MicrobiologyUniversity of Iowa, SW54, GH200 Hawkins Drive, UIHCIowa City, IA 52242USATel: +1-319-356-3168E-mail: email@example.com
The chapter in the Ninth ICTV Report, which served as the template for this chapter, was contributed by Simmonds, P., Becher, P., Collett, M.S., Gould, E.A., Heinz, F.X., Meyers, G., Monath, T., Pletnev, A., Rice, C.M., Stiasny, K., Thiel, H.-J., Weiner, A. and Bukh, J.
ICTV Flaviviridae Study Group (dengue virus and hepatitis C virus subtypes):
Tree file (newick format)
Alignment file (FASTA format)
Alignment file - amino acid (FASTA format)
Alignment file - nucleotide (FASTA format)
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