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Pegiviruses widely infect all human populations and have variously been described as GB virus C (GBV-C) and hepatitis G virus (HGV) (Linnen et al., 1996, Simons et al., 1995a). 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 it infect the surgeon, GB. HPgV has been assigned as a member of the species Pegivirus C (Smith et al., 2016), while a second, more divergent pegivirus group, termed human hepegivirus (HHPgV) or HPgV-2 (Berg et al., 2015, Kapoor et al., 2015) has been assigned to Pegivirus H (Smith et al., 2016). HPgV is transmitted between humans by sexual transmission, exposure to contaminated blood, and mother to child. Horizontal transmission has neither been confirmed nor refuted (Bhattarai and Stapleton 2012). HPgV-2 is likely transmitted via exposure to contaminated blood; however, other modes of transmission have not been extensively studied. Other members of Pegivirus C infect chimpanzees (GBV-Ctro) (Adams et al., 1998, Birkenmeyer et al., 1998) while members of Pegivirus A, Pegivirus B, Pegivirus D, Pegivirus E, Pegivirus F, Pegivirus G, Pegvirus I and Pegivirus K infect Old world monkeys (Sibley et al., 2014, Bailey et al., 2016), Pegivirus As (GBV-A ) infects several New World monkey species ; (Muerhoff et al., 1995, Bukh and Apgar 1997), Pegivirus E (equine pegivirus (Kapoor et al., 2013a) and Pegivirus D (Theiler’s disease associated virus (Chandriani et al., 2013)) infect horses, Pegivirus K infects pigs (Baechlein et al., 2016) and Pegivirus F, Pegivirus G, Pegivirus I and Pegivirus J infect a wide range of rodent and bat species (Kapoor et al., 2013b, Quan et al., 2013, Epstein et al., 2010). There is no known invertebrate vector for known pegiviruses, and like the hepaciviruses, differ from members of the genera Flavivirus and Pestivirus by their limited ability to be propagated in cell culture (Chivero and Stapleton 2015). Cell culture of other pegiviruses has not been achieved to date.
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 proteins found in 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 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. Where known, 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 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 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 and is between 300-550 bases in length. No miR-122 binding sites have been identified in 5’UTR 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 (HPgV-2) classified as 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 to date 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 and quite how pegivirus virions are assembled remains uncertain. However, pegiviruses typically encode shorter although somewhat variable length predicted 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 flaviviruses.
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 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. 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 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).
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). 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 but not by the New World primate virus, GBV-A (Bukh et al., 1998) and rhesus macaques can be infected with baboon SPgV (Bailey et al., 2015).
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. HHPgV / HPgV-2 (Pegivirus H) additionally shows evidence for parenteral routes of transmission with infections detected to date largely confined to IDUs and blood (product) recipients (Berg et al., 2015, Kapoor et al., 2015, Coller et al., 2016, Bonsall et al., 2016). However, 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 HIV-1. Among HIV-infected subjects, co-infection with HPgV does not correlate with HIV transmission risk; however, HCV and HCV-HPgV co-infection were significantly associated with a parenteral mode of HIV acquisition (Bourlet et al., 1999), 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 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 / HPgV-2 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 (Pegivirus D and Pegivirus E) (Lu et al., 2016, Lyons et al., 2014, Kapoor et al., 2013a, de Souza et al., 2015) and pigs (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 it is established that 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 PgV infection in rhesus macaques, PgV replication occurs primarily in the bone marrow (Bailey et al., 2015). The tissue or cellular tropism of pegiviruses infecting other hosts is unknown.
Species in the Pegivirus genus have recently be re-classified based on their genetic divergence (Smith et al., 2016) rather than their host range (Stapleton et al., 2011). As for hepaciviruses, 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 (referred to previously as GBV-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 chosen to match the virus name GBV-C.
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