GB virus B infection of the common marmoset (Callithrix jacchus) and associated liver pathology

Abstract

GB virus B (GBV-B) is a flavivirus that is related closely to hepatitis C virus (HCV) and induces an acute hepatitis when inoculated into several species of New World primates. Common marmosets (Callithrix jacchus) are a widely available, non-endangered primate species that is susceptible to GBV-B infection and develops a characteristic acute hepatitis. Here, animals were found to be susceptible to serially passaged serum and GBV-B transcripts. Hepatic pathology and peripheral viraemia could be quantified biochemically, immunophenotypically and morphologically, and persisted for periods of up to 6 months in some animals. Hepatitis was characterized by a marked influx of CD3 + CD8 + T lymphocytes and CD20 + B cells within the first 2 months of primary infection. The results of this study document the marmoset as another small, non-human primate species in which the pathogenesis of GBV-B can be studied and used as a surrogate model of HCV infection for investigation of pathogenesis and antiviral drug development.

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

“…Hepacivirus infection induces a potent T cell response, and CD4 ϩ T cells upregulate PD-1 acutely after GBV-B infection, which is indicative of activation; a similar PD-1 ϩ T cell activation is observed in early HCV infection (15)(16)(17)(18). Acute GBV-B infection is also characterized by an influx of CD8 T cells into the liver (9), and clearance of GBV-B has previously been associated with strong responses against the NS3 protein (14). Anti-NS3 responses may also be protective and important for clearance of HCV (19)(20)(21).…”

“…Virus inoculum. All marmosets were inoculated intravenously with 1.0 ϫ 10 3 to 4.0 ϫ 10 3 virus copy equivalents from one of two plasmaderived challenge stocks of related GBV-B isolates: (i) an uncloned GBV-B stock derived at the Southwest National Primate Research Center (SNPRC) (a kind gift from Robert Lanford) (40) and (ii) an uncloned GBV-B stock derived at the New England Primate Research Center (NEPRC) (9).…”

“…Virus quantification was performed by quantitative reverse transcription-PCR (RT-PCR), using a modified assay as previously described (9). Briefly, cell-free plasma samples were processed to yield RNA by use of a QIAamp viral RNA minikit (Qiagen), and viral RNA was converted to cDNA by use of a high-capacity reverse transcription kit (Life Technologies).…”

“…Although limitations in access to acute or tissue samples make understanding early hepacivirus pathology and immunology challenging, other related hepaciviruses recapitulate many features of HCV. The most closely phylogenetically related virus, GB virus B (GBV-B), has a nearly identical genome organization (5,6), and it is almost always cleared by the immune system (7)(8)(9). Most GBV-B infection studies are conducted using common marmosets, and the virus has previously been demonstrated to induce hepatitis and a T cell response very similar to those with HCV (5,(10)(11)(12)(13)(14).…”

A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

“…It shares the hepatotropism of HCV. Although GBV-B has been reported to lead to persistent infections in some cases in tamarins (Saguinus species) (Martin et al, 2003;Nam et al, 2004), unlike the human virus, GBV-B primarily causes an acute, resolving hepatitis in tamarins and other New World monkeys such as common marmosets (Callithrix jacchus) (Bukh et al, 2001;Jacob et al, 2004;Lanford et al, 2003). In contrast, HCV is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, affecting an estimated 3 % of the world's population.…”