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Pegiviruses have been identified in humans (human pegivirus [HPgV]; originally described as GBV-C or hepatitis G virus; HGV) (Linnen et al., 1996, Simons et al., 1995), non-human primates (simian pegiviruses [SPgV]) including chimpanzees (GBV-Ctro) (Adams et al., 1998), Old world monkeys (Sibley et al., 2014) and several New World monkey species (GBV-A; (Muerhoff et al., 1995)), horses (equine pegivirus (Kapoor et al., 2013); Theiler’s disease associated virus (Chandriani et al., 2013)), rodents and bats (GBV-D and others)(Kapoor et al., 2013, Quan et al., 2013, Epstein et al., 2010). 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 and other Flaviviridae 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 of members of other genera in the Flaviviridae (Quan et al., 2013, Muerhoff et al., 1995, Stapleton et al., 2011). Infections with HpgV are frequently persistent but are not associated with development of any identifiable disease. Where known, infections of other mammalian species are also frequently 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 to date; 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 or animal 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 elements and is between 300-550 bases in length. No miR-122 binding sites have been identified in pegivirus RNA. 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, members of the divergent group 2 pegiviruses have a type IV IRES element structurally resembling those of hepaciviruses and pestiviruses but with almost no sequence identity (Kapoor et al., 2015).
Functional studies of most pegivirus proteins have not been performed to date and information on their likely function in replication and virus assembly has largely been inferred from comparison with homologous genes in hepaciviruses. Thus, the 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.
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 flaviviruses.
The E1 and E2 glycoproteins have variable numbers of potential N-linked glycosylation sites, with members of group 2 pegiviruses possessing a number of sites comparable to that 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. Genome sizes of known pegiviruses range from approximately 8900-11300 bases; 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 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, NS2/NS3 by the NS2–NS3 autoprotease and the remaining NS proteins by the NS3–NS4A protease complex is comparable to hepaciviruses. All pegiviruses possess long 5’untranslated 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).
HPgV variants can be detected in a wide range of mammalian species (humans, non-human primates and a range of rodent and bat species). 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 (Bukh et al., 1998).
HPgV can be transmitted by blood transfusion and 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. However, 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 HIV-1, indicating the likelihood of sexual routes of transmission.
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 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 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 it is established that experimental infection of New World primates with simian pegiviruses does not induce liver disease.
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). The tissue or cellular tropism of pegiviruses infecting other hosts is unknown.
The species, Pegivirus A and Pegivirus B form separate phylogenetic groups; the aligned polyprotein sequences from different Pegivirus A and Pegivirus B isolates show >55% sequence divergence from each other, although this threshold may be subject to revision to accommodate the large number of further pegiviruses that have recently been genetically characterized (Figure 1.Flaviviridae). Members of the Pegivirus A and Pegivirus B species infect primates and bats although, currently, host range is not a primary criteria for species assignment.
SpeciesVirus name(s)Exemplar isolateExemplar accession numberExemplar RefSeq numberAvailable sequenceOther isolatesOther isolate accession numbersVirus abbreviationIsolate abbreviationPegivirus Asimian pegivirusA/T1053U22303Complete coding genomeGBVPegivirus Asimian pegivirusAlabU94421SPgVPegivirus BGB virus-D; bat pegivirusD/68GU566734NC_030291Complete genomeGBVPegivirus BGB virus-D; bat pegivirusD/93GU566735GBV
The genus Pegivirus currently comprises two species, Pegivirus A and Pegivirus B although these two groups are just two of many lineages described for this genus (Figure 1.Flaviviridae). As shown, human pegiviruses are classified within Pegivirus A but they can be further classified into six genetic groups (termed genotypes; see table above for representative isolates), based upon the genome-wide heterogeneity of isolates recovered throughout the world.
A wide range of genetically diverse viruses that group phylogenetically with Pegivirus A and Pegivirus B isolates (Figure 1.Flaviviridae) represent further candidate species within the Pegivirus genus. The ICTV Executive committee has recently approved proposals for the creation of additional species in the genus as described in (Smith et al., 2016). The chapter will be updated to include these new assignments once the proposals are ratified by the ICTV (estimated March 2017).
simian pegivirus- krtg/RT06
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