Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Pfaller, Christian K
Vondran, Florian W R
Brown, Richard J P
MetadataShow full item record
AbstractTranscriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Longitudinal sampling identified minimal gene dysregulation at six hours post infection (hpi). In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. We further find that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection, which can additionally reduce HCV RNA translation and replication. We also detected infection-induced downregulation of ∼90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits in PHHs, consistent with a signature of translational shutoff. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is likely pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity.IMPORTANCEAcute HCV infections are often asymptomatic and therefore frequently undiagnosed. We endeavored to recreate this understudied phase of HCV infection using explanted PHHs and monitored host responses to initial infection. We detected temporally distinct virus-induced perturbations in the transcriptional landscape, which were initially narrow but massively amplified in breadth and magnitude over time. At 72 hpi, we detected dysregulation of diverse gene programs, concurrently promoting both virus clearance and virus persistence. On the one hand, baseline expression of IRF1 combined with infection-induced upregulation of IFN-mediated effector genes suppresses virus propagation. On the other, we detect transcriptional signatures of host translational inhibition, which likely reduces processing of IFN-regulated gene transcripts and facilitates virus survival. Together, our data provide important insights into constitutive and virus-induced transcriptional programs in PHHs, and identifies simultaneous antagonistic dysregulation of pro-and anti-viral programs which may facilitate host tolerance and promote viral persistence.
CitationJ Virol. 2021 Mar 3:JVI.00245-21. doi: 10.1128/JVI.00245-21. Epub ahead of print.
AffiliationTWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover.; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Schneider-Straße 2, 97080 Würzburg, Germany.
JournalJournal of virology
The following license files are associated with this item:
- Creative Commons
- DDX60L Is an Interferon-Stimulated Gene Product Restricting Hepatitis C Virus Replication in Cell Culture.
- Authors: Grünvogel O, Esser-Nobis K, Reustle A, Schult P, Müller B, Metz P, Trippler M, Windisch MP, Frese M, Binder M, Fackler O, Bartenschlager R, Ruggieri A, Lohmann V
- Issue date: 2015 Oct
- HBV Bypasses the Innate Immune Response and Does Not Protect HCV From Antiviral Activity of Interferon.
- Authors: Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schöneweis K, Seitz S, Tu T, Restuccia A, Frankish J, Dächert C, Schusser B, Koschny R, Polychronidis G, Schemmer P, Hoffmann K, Baumert TF, Binder M, Urban S, Bartenschlager R
- Issue date: 2018 May
- GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
- Authors: Zhang X, Zhu C, Wang T, Jiang H, Ren Y, Zhang Q, Wu K, Liu F, Liu Y, Wu J
- Issue date: 2017 Apr
- Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.
- Authors: Nandakumar R, Finsterbusch K, Lipps C, Neumann B, Grashoff M, Nair S, Hochnadel I, Lienenklaus S, Wappler I, Steinmann E, Hauser H, Pietschmann T, Kröger A
- Issue date: 2013 Dec
- Transcriptional profiling of the effects of 25-hydroxycholesterol on human hepatocyte metabolism and the antiviral state it conveys against the hepatitis C virus.
- Authors: Pezacki JP, Sagan SM, Tonary AM, Rouleau Y, Bélanger S, Supekova L, Su AI
- Issue date: 2009 Jan 16