Modeling HCV disease in animals: virology, immunology and pathogenesis of HCV and GBV-B infections

Manickam, Cordelia; Reeves, R. Keith

doi:10.3389/fmicb.2014.00690

Cited by 18 publications

(22 citation statements)

References 117 publications

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“…Empirical HCV studies suggest that enhanced NK cell function during acute infection can lead to viral containment (46)(47)(48), and in persons accidentally exposed to HCV, NK cells exert upregulated effector functions (36). Collectively, these data may suggest that the robust NK cell response we observed in acute GBV-B infection is related to the virus clearance normally observed (40,49). Further, CXCR3 expression on circulating NK cells was upregulated soon after GBV-B infection, which may indicate recruitment of immunocompetent cells into the liver.…”

Section: Discussionsupporting

confidence: 53%

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

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

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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...

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Section: Discussionsupporting

confidence: 53%

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

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

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“…The GBV-B virus has been shown to cause hepatitis in experimentally infected tamarins (genus Saguinus ) 161,162 . Specifically, infection of New World primates with GBV-B recapitulates the phenotypes of acute viral clearance and chronic pathological disease, and this model has been used for drug testing 163–165 . In this regard, GBV-B seems to be a viable surrogate model for the study of HCV infection with possible utility in the testing of novel vaccine strategies.…”

Section: Animal Modelsmentioning

confidence: 99%

Experimental models of hepatitis B and C — new insights and progress

Thomas

Liang

2016

Nat Rev Gastroenterol Hepatol

125

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Viral hepatitis is a major cause of morbidity and mortality, affecting hundreds of millions of people worldwide. Hepatitis-causing viruses initiate disease by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma. Consequently, intense research efforts have been focusing on increasing our understanding of hepatitis virus biology and on improving antiviral therapy and vaccination strategies. Although valuable information on viral hepatitis emerged from careful epidemiological studies on sporadic outbreaks in humans, experimental models using cell culture, rodent and non-human primates were essential in advancing the field. Through the use of these experimental models, improvement in both the treatment and prevention of viral hepatitis has progressed rapidly; however, agents of viral hepatitis are still among the most common pathogens infecting humans. In this Review, we describe the important part that these experimental models have played in the study of viral hepatitis and led to monumental advances in our understanding and treatment of these pathogens. Ongoing developments in experimental models are also described.

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Section: Discussionmentioning

confidence: 99%

“…The HCV/GBV-B chimera-infected marmoset model, with relatively low cost and ready availability, can be considered a potential tool for future development of novel antiviral drugs, immunotherapies, and vaccines against HCV infection (21). Besides the differences between GBV-B and HCV, GBV-B infection in marmosets mostly resulted in an acute and self-limited infection with rare cases of persistence (13,14,21,52). HCV/GBV-B chimeras carrying a short section of the HCV genome hardly mimicked the functions of HCV structural or nonstructural proteins (17,19,20), which limited the utility of these small-primate models for understanding the mechanisms of persistent HCV infection.…”

Section: Discussionmentioning

confidence: 99%

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus

Zhu

Liu

et al. 2016

J Virol

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A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection. H epatitis C virus (HCV) infection is a global health threat thatcauses chronic hepatitis and is associated with 78% of primary hepatocellular carcinoma (1). Currently, limitations of small-primate models hamper the development of HCV vaccines and affordable antiviral drugs. Chimpanzees have been used as a uniquely reliable animal for HCV infection in past decades (2), significantly contributing to defining the infection natural history, pathogenesis, immune response, and rechallenge of HCV (3-6). However, the utility of chimpanzees has been more and more restricted by ethical concerns, and though rare, the use of this primate model in medical studies is extremely costly (2). The nonprimate animal models simulating HCV infection might potentially be mimicked with rodent hepacivirus (RHV)-infected rats (7,8), canine hepacivirus (CHV)-infected dogs (9), and equine hepacivirus (EHCV) (nonprimate hepacivirus [NPHV])-infected horses (10). HCV infection in immunocompetent mice was reported in genetically humanized mouse CD81 and occludin (OCLN) (11,12). However, the differences in infection courses and immune responses fundamentally separate these mice from HCV-infected patients.Common marmosets (Callithrix jacchus), one of the New World small ...

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Modeling HCV disease in animals: virology, immunology and pathogenesis of HCV and GBV-B infections

Cited by 18 publications

References 117 publications

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

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

Experimental models of hepatitis B and C — new insights and progress

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus

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