Iron Regulator Hepcidin Exhibits Antiviral Activity against Hepatitis C Virus

Liu, Hongyan; Trinh, Thu Le; Dong, Hui-Jia; Robertson, Keith D.; Nelson, David R.; Liu, Chen

doi:10.1371/journal.pone.0046631

Cited by 45 publications

(42 citation statements)

References 48 publications

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“…This interval coincides with the substantial decrease in ferritin following infection and could signify a viral need for iron. Although past research showed that hepcidin suppressed HCV replication, acting as an antiviral agent, 26 our data remain in agreement with researchers who suggested a positive regulatory role for hepcidin on HCV replication. 3,11 Macrophages induce hepcidin transcription in Huh7 cells, 22 while macrophagic hepcidin may regulate iron uptake and release in an autocrine manner.…”

Section: Discussionsupporting

confidence: 92%

“…Conversely, upon established infection, hepcidin expression dropped in our in vitro model and in patient sera, 12,13 in step with studies from chronic HCV patients with low intrahepatic HAMP mRNA 24 and decreased serum hepcidin, 12,13 and earlier in vitro RNA data. 25,26 Secreted protein expression was also increased throughout infection, albeit not as dramatically as mRNA. The latter may be due to post-transcriptional regulation of HAMP gene expression, including mRNA destabilisation 27 and secretion modulation.…”

Section: Discussionmentioning

confidence: 97%

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Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to na€ ıve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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“…21,22 On the contrary a direct antiviral activity of hepcidin against HCV replication in cell culture was also proved. 23 Foka et al attempt to clarify these mutual interactions between HCV, hepcidin and iron. Their results bring new light on the impact of hepcidin and iron on the promotion of HCV infection in its early phase.…”

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confidence: 99%

The iron homeostasis network and hepatitis C virus – a new challenge in the era of directly acting antivirals

Sikorska

2016

Virulence

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“…The inhibitory effect appears to occur at the viral replication level. Taken together, these results suggest that both exogenous addition of hepcidin peptide and over-expression of hepcidin could attenuate HCV replication in cell models (29) . It is possible to develop a therapy using hepcidin.…”

Section: Discussionmentioning

confidence: 60%

“…Recently, Liu et al (29) further examined the anti-HCV activity of hepcidin by gene over-expression and knockdown. The data clearly show that over-expression of hepcidin reduced HCV expression, while knockdown of hepcidin induced viral RNA expression.…”

Section: Discussionmentioning

confidence: 99%

Serum and Ascitic Fluid Hepcidin in HCV Positive Liver Cirrhosis with and without HCC

Atti¹,

Dawood²,

Essa³

et al. 2013

EJPM

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Background & Aim: Chronic HCV infection suppresses hepatic hepcidin expression which may enhance iron toxicity and lead to disease progression and HCC development. The aim of the study is to investigate the role of hepcidin in HCV+ve liver cirrhosis patients in relation to disease progression and HCC development. Patients and methods: The study population consists of: 20 HCV+ve patients without HCC (HCV patients), 20 HCV+ve patients with HCC (HCV-HCC patients) and 10 controls. In addition to comprehensive clinical examination, they were subjected to laboratory check-up for albumin, bilirubin, PT %, ferritin, AFP and hepcidin. Ascitic fluid hepcidin was done for all patients. Results: There was a significant difference among HCV and HCV-HCC patients and controls with regard serum ferritin and hepcidin (P = 0.001 & 0.0001 respectively). Serum hepcidin of HCV and HCV-HCC patients were significantly lower than controls (P = 0.0001). Serum and ascitic fluid hepcidin of HCV-HCC patients was significantly lower than HCV patients (P = 0.01 & 0.02 respectively). Serum ferritin was significantly higher in HCV and HCV-HCC patients than controls (P = 0.001). Serum ferritin of HCV-HCC patients was significantly higher than HCV patients (P = 0.02). . Conclusion: Low levels of hepcidin may be involved in the pathophysiologic mechanism of iron overload in patients with chronic HCV with and without HCC. Moreover, there is a positive relationship between hepcidin levels and synthetic liver function suggesting that uniform suppression of hepcidin may be linked to disease progression and HCC development. Further analysis is still required to evaluate its usefulness as a marker for early detection of HCC by serial measurement of hepcidin in blood and ascitic fluid.

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Iron Regulator Hepcidin Exhibits Antiviral Activity against Hepatitis C Virus

Cited by 45 publications

References 48 publications

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

The iron homeostasis network and hepatitis C virus – a new challenge in the era of directly acting antivirals

Serum and Ascitic Fluid Hepcidin in HCV Positive Liver Cirrhosis with and without HCC

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