Evidence for cellular uptake of recombinant hepatitis C virus non‐enveloped capsid‐like particles

Tsitoura, Panagiota; Georgopoulou, Urania; Pêtres, Stéphane; Varaklioti, Agoritsa; Karafoulidou, Anastasia; Vagena, Dimitra; Politis, C.; Mavromara, Penelope

doi:10.1016/j.febslet.2007.07.032

Cited by 20 publications

(39 citation statements)

References 56 publications

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“…The polyclonal HCV-1a core antibody used in this study has been described elsewhere. 57 Huh7.5 and Huh7-Lunet cells were supplied by Dr R. Bartenschlager (University of Heidelberg, Germany).…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…Τα ανασυνδυασμένα καψίδια απομονώθηκαν από τα κυτταρικά εκχυλίσματα σύμφωνα με το πρωτόκολλο που έχει ήδη περιγραφεί (200)(201)(202). Συνοπτικά, τα κυτταρικά εκχυλίσματα μετά από φυγοκέντρηση σε χαμηλές στροφές υπέστησαν αντίδραση με DNAse και RNAse για 30 λεπτά σε θερμοκρασία δωματίου.…”

Section: απο κυτταρα εντομωνunclassified

“…Προηγούμενη έρευνα του εργαστηρίου έδειξε πως τα core καψίδια έχουν την ιδιότητα να εισέρχονται στα κύτταρα χωρίς να αποικοδομούνται στις χρονικές περιόδους που δοκιμάστηκαν (200). Για να μελετηθεί αν η συγκεκριμένη ιδιότητα ισχύει και στα κατασκευασθέντα φθορίζοντα καψίδια, κύτταρα ηπατικής προέλευσης (Huh7) επωάστηκαν με τα καψίδια 1736, 1740 και 1741, για μια ώρα σε θερμοκρασία 37 ο C, μονιμοποιήθηκαν και …”

Section: εισοδος χωρις αποδιαταξη των καψιδιωνunclassified

“…Το ίδιο ισχύει και για τα core καψίδια, όπου έχει αποδειχτεί ότι επηρεάζουν το μονοπάτι σηματοδότησης ERK 1/2 (200). Για να μελετηθεί η λειτουργικότητα των φθοριζόντων core καψιδίων, πραγματοποιήθηκαν αντίστοιχα πειράματα.…”

Section: πρωτεϊνη καψιδιαunclassified

“…Το μονοπάτι σηματοδότησης ERK 1/2 εμπλέκεται εκτός από την ενδοκύτωση και σε πολλές άλλες κυτταρικές λειτουργίες και γι'αυτό αποτελεί στόχο για πολλούς ιούς που προσπαθούν να εκμεταλλευτούν κυτταρικές διεργασίες προς όφελος τους (162,234). Στη συγκεκριμένη περίπτωση υπήρχαν αρκετές ενδείξεις για την ενεργοποίηση του συγκεκριμένου μονοπατιού, αρχικά με την αποδεδειγμένη μετατόπιση της πρωτεΐνης ERF, δείκτη της ενεργοποίησης της πρωτεΐνης ERK 1/2 (200,201) και έπειτα με την χρήση των χημικών αναστολέων UO126 και PD98059 που φαίνεται να επηρεάζουν την μετακίνηση των καψιδίων από τα πρώιμα ενδοσώματα στα λυσοσώματα.…”

Section: μονοπατι ενεργοποιησης Erk 1/2unclassified

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Μελέτη της τροποποίησης της σηματοδότησης των MAPKs - ERKs παρουσία των HCV δομικών πρωτεϊνών

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The Hepatitis C virus NS5A and core proteins exert antagonistic effects on HAMP gene expression: the hidden interplay with the MTF‐1/MRE pathway

et al. 2020

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Hepcidin, a 25-amino acid peptide encoded by the HAMP gene and produced mainly by hepatocytes and macrophages, is a mediator of innate immunity and the central iron-regulatory hormone. Circulating hepcidin controls iron efflux by inducing degradation of the cellular iron exporter ferroportin. HCV infection is associated with hepatic iron overload and elevated serum iron, which correlate with poor antiviral responses. The HCV non-structural NS5A protein is known to function in multiple aspects of the HCV life cycle, probably exerting its activity in concert with cellular factor(s). In this study, we attempted to delineate the effect of HCV NS5A on HAMP gene expression. We observed that transient transfection of hepatoma cell lines with HCV NS5A resulted in downregulation of HAMP promoter activity. A similar effect was evident after transduction of Huh7 cells with a recombinant baculovirus vector expressing NS5A protein. We proceeded to construct an NS5A-expressing stable cell line, which also exhibited down-regulation of HAMP gene promoter activity and significant reduction of HAMP mRNA and hepcidin protein levels. Concurrent expression of HCV core protein, a well characterized hepcidin inducer, revealed antagonism between those two proteins for hepcidin regulation. In attempting to identify the pathways involved in NS5Adriven reduction of hepcidin levels, we ruled out any NS5A-induced alterations in the expression of the well-known hepcidin inducers SMAD4 and STAT3. Further analysis linked the abundance of intracellular zinc ions and the deregulation of the MTF-1/MRE/hepcidin axis with the observed phenomenon. This effect could be associated with distinct phases in HCV life cycle.

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Evidence for cellular uptake of recombinant hepatitis C virus non‐enveloped capsid‐like particles

Cited by 20 publications

References 56 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

Μελέτη της τροποποίησης της σηματοδότησης των MAPKs - ERKs παρουσία των HCV δομικών πρωτεϊνών

The Hepatitis C virus NS5A and core proteins exert antagonistic effects on HAMP gene expression: the hidden interplay with the MTF‐1/MRE pathway

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