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@ARTICLE{Riedl:168826,
      author       = {T. Riedl$^*$ and S. Faure-Dupuy$^*$ and M. Rolland and S.
                      Schuehle$^*$ and Z. Hizir and S. Calderazzo$^*$ and X.
                      Zhuang and J. Wettengel and M. A. Lopez and R. Barnault and
                      V. Mirakaj and S. Prokosch$^*$ and D. Heide$^*$ and C.
                      Leuchtenbergeg$^*$ and M. Schneider$^*$ and B. Heßling$^*$
                      and B. Stottmeier and I. M. Wessbecher and P. Schirmacher
                      and J. A. McKeating and U. Protzer and D. Durantel and J.
                      Lucifora and E. Dejardin and M. Heikenwälder$^*$},
      title        = {{HIF}1α-mediated {R}el{B}/{APOBEC}3{B} downregulation
                      allows {H}epatitis {B} {V}irus persistence.},
      journal      = {Hepatology},
      volume       = {74},
      number       = {4},
      issn         = {1527-3350},
      address      = {New York [u.a.]},
      publisher    = {Wiley Interscience},
      reportid     = {DKFZ-2021-01077},
      pages        = {1766-1781},
      year         = {2021},
      note         = {#EA:F180#LA:F180# / 2021 Oct;74(4):1766-1781},
      abstract     = {New therapeutic strategies against Hepatitis B virus (HBV)
                      focus, among others, on the activation of the immune system
                      to enable the infected host to eliminate HBV. Hypoxia
                      inducible factor 1 alpha (HIF1α) stabilisation has been
                      associated with impaired immune responses. HBV pathogenesis
                      triggers chronic hepatitis-related scaring, leading inter
                      alia to modulation of liver oxygenation and transient immune
                      activation, both factors playing a role in HIF1α
                      stabilisation. We addressed whether HIF1α interferes with
                      immune-mediated induction of the cytidine deaminase APOBEC3B
                      and subsequent covalently closed circular DNA (cccDNA)
                      decay. Liver biopsies of chronic HBV patients (CHB) were
                      analysed by IHC, and in situ hybridization. The effect of
                      HIF1α induction/stabilisation on differentiated HepaRG or
                      mice +/- HBV +/- LTβR-agonist (BS1) was assessed in vitro
                      and in vivo. Induction of A3B and subsequent effects were
                      analysed by RT-qPCR, immunoblotting, ChIP, ICC, and
                      mass-spectrometry. Analysing CHB highlighted that areas with
                      high HIF1α levels and low A3B expression correlated with
                      high HBcAg, potentially representing a reservoir for HBV
                      survival in immune-active patients. In vitro, HIF1α
                      stabilisation, strongly impaired A3B expression and anti-HBV
                      effect. Interestingly, HIF1α knock-down was sufficient to
                      rescue the inhibition of A3B-upregulation and -mediated
                      antiviral effects, whereas HIF2α knock-down had no effect.
                      HIF1α stabilisation decreased the level of RelB protein but
                      not its mRNA, which was confirmed in vivo. Noteworthy, this
                      function of HIF1α was independent of its partner ARNT. In
                      conclusion, inhibiting HIF1α expression or stabilisation
                      represents a novel anti-HBV strategy in the context of
                      immune-mediated A3B induction. High HIF1α, mediated by
                      hypoxia or inflammation, offers a reservoir for HBV survival
                      in vivo, and should be considered as a restricting factor in
                      the development of novel immune therapies.},
      keywords     = {HIF1α (Other) / Hepatitis B virus (Other) / NF-κB (Other)
                      / cccDNA (Other) / reservoir (Other)},
      cin          = {F180 / C060 / W120},
      ddc          = {610},
      cid          = {I:(DE-He78)F180-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)W120-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33991110},
      doi          = {10.1002/hep.31902},
      url          = {https://inrepo02.dkfz.de/record/168826},
}