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

Abstract

Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R ‫؍‬ 0.698; P ‫؍‬ 0.015) and liver (R ‫؍‬ 0.567; P ‫؍‬ 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-␥) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection. IMPORTANCEHepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study. H epatitis C virus (HCV) infection has become a global health epidemic, with the virus infecting more than 170 million people worldwide (1) and resulting in 350,000 HCV-related liver disease deaths each year (2). HCV infection results in the following two disparate manifestations: (i) an acute, self-resolving infection and (ii) a chron...

Hepatic immunopathology during occult hepacivirus re-infection

“…Our previous study of acute and chronic GBV-B infection suggested immune activation induces significant acute liver pathology in marmosets (Manickam et al, 2016). Strikingly, in this reinfection study, pathological manifestations were observed in the livers of re-infected animals despite only very low levels of virus replication.…”

“…Following primary infection, all animals rapidly developed viremia with variable clearance (Fig 1) (Manickam et al, 2016). Prior to re-challenge, all animals were confirmed to be aviremic on day 300 relative to primary infection (heretofore day 0 of re-infection) (Fig 1A).…”

“…Additionally, moderate fibrotic changes characterized by deposition of trichome positive sinusoidal connective tissue were observed in 01–10 and at mild levels in 08–10 (Fig 3B). The animals were scored in comparison to normal animals as reported previously (Manickam et al, 2016). …”

“…In reinfected chimpanzees, rapid viral clearance was associated with proliferating CD4 + and CD8 + T cell responses after re-challenge (Bassett et al, 2001; Major et al, 2002; Nascimbeni et al, 2003; Prince et al, 2005; Zubkova et al, 2014). While chimpanzees are now rarely used in biomedical research, new world primates infected with GBV-B are commonly used as surrogate animal models for HCV (Akari et al, 2009; Beames et al, 2001; Bright et al, 2004; Jacob et al, 2004; Manickam et al, 2016). GBV-B belongs to the same family Flaviviridae and genus Hepacivirus and is closely related to HCV (Deinhardt et al, 1967; Karayiannis and McGarvey, 1995; Muerhoff et al, 1995; Tabor et al, 1980).…”

“…GBV-B belongs to the same family Flaviviridae and genus Hepacivirus and is closely related to HCV (Deinhardt et al, 1967; Karayiannis and McGarvey, 1995; Muerhoff et al, 1995; Tabor et al, 1980). Viremia in primary GBV-B infection clears within 2-to-3 months of infection (Bright et al, 2004; Bukh et al, 1999; Manickam et al, 2016). Several studies have shown viral immunity in primary infection, but there are only few reports of GBV-B re-infection (Bukh et al, 2008; Woollard et al, 2008).…”