Z Gastroenterol 2019; 57(01): e79
DOI: 10.1055/s-0038-1677259
5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

Differential response of culture-derived HDV-1 and HDV-3 strains to peg-IFNα treatment in human liver chimeric mice despite strong ISG induction

L Hendricks
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
,
L Hermanussen
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
,
K Giersch
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
,
TK Volz
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
,
L Allweiss
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
,
AW Lohse
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
4   German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel Partner Sites
,
C Sureau
2   Institut National de Transufusion Sanguine (INTS), France
,
J Casey
3   Georgetown University Medical Center, USA
,
M Dandri
1   I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Germany
4   German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel Partner Sites
,
M Lütgehetmann
5   Department of Mycrobiology Virology and Hygiene, University Medical Center Hamburg Eppendorf, Germany
4   German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel Partner Sites
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Publikationsdatum:
04. Januar 2019 (online)

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HDV is classified into eight genotypes with high variable sequences. HDV-3 is known to cause severe hepatitis, while patients infected with HDV-1 can develop a wide range of severity. In research, a particular cell culture-derived (cd) strain of HDV-1 (AJ000558) is commonly used. Regarding IFN-responsiveness, Zhang (J.Hep.2018) reported that this HDV-1 strain is insensitive to IFNα in vitro. Contrarily, patient-derived HDV-1 was shown to respond to IFNα in vivo (Giersch, Sci.Rep.2017). Besides, Borzacov (Int.J.Infect.Dis.2016) claimed HDV-3 to be a potential easy to treat variant when compared with HDV-1.

Aim:

to assess the sensitivity of cdHDV-1 and cdHDV-3 to peg-IFNα comparatively in vivo using human liver chimeric mice (A); to investigate, if any possible strain-specific IFN-responses appear different in coinfection with both HDV strains (B).

Methods:

Humanized USB mice were coinfected with HBV (GT-D) and either cdHDV-1 or -3 (A) or infected with HBV and 9 weeks later simultaneously super-coinfected with both cdHDV-1 and -3 (B). Viral parameters of HBV and HDV, transcriptional levels ofh-ISGs and cytokines were determined by qRT-PCR. Strain-specific HDV RNAs were detected by in situ hybridization (ISH) and HDAg by immunofluorescence.

Results:

A) Peg-IFNα (25 ng/g injected s.c. twice/week) exerts potent serological and intrahepatic effects against HDV-3 (viremia -1.74-log in 4 weeks), but not against cdHDV-1 (-0.3-log), despite evidence of comparably strong ISG induction. B) In the setting of super-coinfection, we also observed strain-specific IFN-responsiveness compared with untreated control mice (Δ-log-change: HDV-1 – 0,29-log; HDV-3 – 1,15-log). RNA ISH revealed the coexistence of genomic RNAs of both HDV strains also at single cell level.

Conclusion:

CdHDV-1 is resistant to peg-IFNα, but does not prevent the suppression of the sensitive HDV-3 in coinfected livers. Our study highlights a behavior of this commonly used strain, which may differ from that of other strains, such as HDV-3 and patient-derived HDV-1. Thus, comparative use of different HDV strains should be encouraged.