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Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, FranceUniversité de Strasbourg, Strasbourg, FrancePôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
As a leading cause of chronic liver disease worldwide, in more than 70% of infected individuals HCV establishes a persistent infection characterised by continuous replication and high serum titres. The high propensity for persistence and the insidious course of disease is suggestive of powerful mechanisms allowing HCV to subvert host antiviral immunity, to modify the inflammatory response, and to utilise host cell infrastructure without affecting cell viability. This enables the virus to avert development of overt disease over decades, despite ongoing viral replication.
being a major etiological factor for the development of liver cirrhosis and hepatocellular carcinoma (HCC). Acute HCV infection often progresses to chronicity and is characterized by a non-resolving liver inflammation leading to a broad range of alterations in the tissue microenvironment. About ninety percent of HCC cases arise in the context of chronic liver inflammation, highlighting the central role of this persistent immune response in disease pathogenesis.
Therefore, even in the DAA era, the understanding of virus-host interactions during chronic HCV-associated inflammation is key to identify and treat patients at high risk of developing HCC.
In this context, a recent article in Journal of Hepatology by Johannes G. Bode’s laboratory at the Heinrich-Heine University in Germany provides a novel mechanism by which HCV infection contributes to this pathologic inflammatory response.
Aiming to identify chemokines regulated by HCV, the authors performed a functional screen using an HCV subgenomic replicon system and identified an HCV-induced upregulation of C-X-C motif chemokine receptor 2 (CXCR2) ligands (CXCLs) 1, 2, 3 and 8. Consistently, similar results were obtained upon HCV infection using the cell culture-derived strain Jc1. Having previously shown that HCV infection enhances epidermal growth factor (EGF) signaling, the authors next explored the possible involvement of this pathway on CXCR2 ligand expression. EGF receptor (EGFR) perturbation studies combining RNAi knockdown of EGF and the use of MAPK inhibitors, confirmed an HCV-induced upregulation of CXCL8 via EGFR and the MAP kinase kinase, MEK1 (MAP2K1). Additionally, knockdown of the p65 subunit of the NF-κB complex was sufficient to abrogate basal and EGF-induced CXCL8 expression in replicon-expressing cells, while in HCV-infected cells this mainly affected basal CXCL8 levels. This suggests that the observed enhancement of chemokine expression during HCV infection not only depends on the EGFR pathway but also on the activation of additional transcription factors such as NF-κB. The in vivo relevance of the data is emphasized by an association of HCV viral load with CXCL8 serum levels in chronically infected patients. Similarly, serum levels of EGF and CXCL8 tend to positively correlate, although this did not reach statistical significance in their study cohort.
In a previous study, the authors demonstrated that HCV enhances EGFR signaling via NS3/4A-mediated proteolytic cleavage of T-cell protein tyrosine phosphatase (TC-PTP [PTPN2]), one of the major negative regulators of EGFR tyrosine-kinase activity.
Indeed, here they demonstrate that NS3/4A expression alone enhances EGF-inducible CXCL8 expression, an effect that can be mimicked by knocking down TC-PTP. As the major role of chemokines is the recruitment of immune cells to the site of inflammation, the authors next evaluated if in the context of HCV replication EGF-induced release of chemokines influences leukocyte migration. Remarkably, the authors demonstrate that media from EGF-treated cell lines expressing the HCV subgenomic replicon enhances the migration of neutrophils, an effect that was not observed with EGF-conditioned media alone. This suggests that HCV infection modulates chemoattraction of immune cells to the liver via EGF-regulated chemokine secretion.
The findings of Christina Groepper and co-workers are not just relevant for our understanding of HCV-EGFR interaction but most importantly provide insight into the pathologic consequences of derailed EGF signaling for liver inflammation and HCC development (Fig. 1). EGFR is a host factor for HCV by facilitating the assembly of the host entry complex, viral glycoprotein-dependent membrane fusion and cell-to-cell transmission of the virus.
Their finding that HCV replication promotes EGF expression is highly relevant in the study of HCV-induced chronic liver disease, as the EGF pathway is a key driver associated with progression towards cirrhosis
Equally interesting is the observation that HCV-induced EGF expression is a regulator of CXCR2 ligands. For example, HCV infection has previously been described to promote CXCL8 expression, which inhibits interferon antiviral activity and facilitates viral infection.
Hepatic CXCL8 is detected at low maintenance levels during acute HCV infection, although marked increases in serum and hepatic levels have been observed in HCV-infected patients with progressive inflammation and cirrhosis.
EGF-mediated recruitment of neutrophils during HCV infection is potentially relevant for liver pathobiology, since it has detrimental effects on the host by contributing to the necro-inflammatory process.
Although further studies in larger patient cohorts are needed to consolidate the model proposed by Groepper and co-workers, the impact of their findings for liver disease and its association to EGF signaling is evident.
In future studies, it would be very interesting and potentially relevant to follow-up HCV-induced EGF expression pattern in liver tissue and blood samples before and after sustained viral response and to compare them to liver fibrosis scores. Furthermore, does HCV genotype influence EGF and chemokine expression profiles since genotype 3 is associated with more severe liver disease manifestations? Taken together, this paper represents a further corroboration for the clinical potential of HCC chemo-preventive strategies based on regulators of signal transduction. Indeed, EGFR which is phosphorylated in hepatic stellate cells has been successfully targeted by the clinical EGFR inhibitor erlotinib in animal models, demonstrating proof of concept that EGF-based therapies attenuates chemically induced liver fibrosis and HCC nodules.
Therefore, EGFR or MAPK modulators could be part of a personalized immuno-therapeutic strategy modulating chemokine profiles and inflammatory responses associated with liver disease progression.
TFB acknowledges support by the European Union Horizon 2020 research and innovation program (ERC AdG HEPCIR – No. 667273; H2020 HEP-CAR – No. 667273; ERC POC PRELICAN – No. 755460), the NCI of the National Institutes of Health (1R21CA209940–01A1), the French National Research Agency (LABEX ANR-10-LABX-0028 HEPSYS) and the Office of the Assistant Secretary of Defense for Health Affairs (No. W81XWH-16–1-0363). JL and AARS acknowledge the French Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) (ECTZ4236; ECTZ4446).
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.