The GB viruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the family Flaviviridae

Abstract

In 1967, it was reported that experimental inoculation of serum from a surgeon (G.B.) with acute hepatitis into tamarins resulted in hepatitis. In 1995, two new members of the family Flaviviridae, named GBV-A and GBV-B, were identified in tamarins that developed hepatitis following inoculation with the 11th GB passage. Neither virus infects humans, and a number of GBV-A variants were identified in wild New World monkeys that were captured. Subsequently, a related human virus was identified [named GBV-C or hepatitis G virus (HGV)], and recently a more distantly related virus (named GBV-D) was discovered in bats. Only GBV-B, a second species within the genus Hepacivirus (type species hepatitis C virus), has been shown to cause hepatitis; it causes acute hepatitis in experimentally infected tamarins. The other GB viruses have however not been assigned to a genus within the family Flaviviridae. Based on phylogenetic relationships, genome organization and pathogenic features of the GB viruses, we propose to classify GBV-A-like viruses, GBV-C and GBV-D as members of a fourth genus in the family Flaviviridae, named Pegivirus (pe, persistent; g, GB or G). We also propose renaming 'GB' viruses within the tentative genus Pegivirus to reflect their host origin.

Fig. 1.

Genome organization of the GB viruses and HCV. All four viruses contain a positive-polarity ssRNA genome with a 5′ NTR and 3′ NTR. The genome encodes a polyprotein that is co- and post-translationally cleaved into individual viral proteins. The structural proteins include core (C) and envelope glycoproteins (E1 and E2), and the NS proteins include NS2–NS5B. The presence of a genomic coding region for a C protein has not been identified for GBV-A or GBV-C. Structural proteins are cleaved by cellular signal peptidases (open arrows), and the NS2–NS3 cleavage is accomplished by the NS2–NS3 autoprotease (shaded arrows). The remaining NS proteins are cleaved by the NS3–NS4A protease complex (solid block arrows). The predicted genome organization of GBV-D was based on a polyprotein starting nt 18 of GU566735. *, The predicted sizes of the proteins analogous to the HCV p7 are 21 kDa for GBV-A and 6 kDa for GBV-C. The existence of a GBV-D p7-like protein is not clear from sequence analysis. **, The size of the protein corresponding to the HCV p7 in GBV-B is 13 kDa; this protein could be cleaved into p7 and p6 proteins, of which the p7 protein, but not the p6 protein is critical for viability in vivo. Proposed names for GB viruses are in parentheses.

Fig. 2.

Helicase and RdRp phylogenetic trees of selected members of the family Flaviviridae. UPGMA phylogenetic trees of helicase and RdRp were generated using the alignments shown in Supplementary Figs S1 and S2, respectively. GenBank numbers for all isolates used in these analyses are provided in the legend for Supplementary Fig. S1. The node numbers represent the bootstrap values (expressed as a percentage of all trees) obtained from 2000 replicates. The tree was rooted by using the midpoint of the longest branch. A distance scale in amino acid substitutions per position is shown.

Fig. 3.

Helicase and RdRp phylogenetic trees of selected members of the family Flaviviridae. NJ analyses were performed on the conserved motifs aligned as shown in Supplementary Figs S1 and S2, and their intervening sequences. A distance scale in amino acid substitutions per position is shown.

Fig. 4.

Proposed classification of GB viruses. GBV-B, a member of the genus Hepacivirus with type species HCV, would be renamed GB virus (GBV); this virus is the true GB agent causing acute hepatitis in experimentally infected tamarins. The new genus designation for GBV-A, GBV-C/HGV and GBV-D would be Pegivirus for persistent ‘GB’ or ‘G’ virus. GBV-A and GBV-A-like viruses would become simian Pegivirus (SPgV) and species-specific viruses would have the species name in subscripts. GBV-C (or HGV) would become the human Pegivirus (HPgV), GBV-C_cpz would become SPgV_cpz, and GBV-D would become bat Pegivirus (BPgV). If BPgV isolates found in different bat species segregate by species as with SPgV, the host species will be identified as a subscript. Examples of other viruses within the family Flaviviridae are shown for comparison.