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The hepatitis delta virus and chronic hepatitis D

  • Maura Dandri
    Correspondence
    Corresponding author. Address: I. Dept. of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D - 20246 Hamburg, Germany; Tel.: +49 - 40 - 7410 52949, fax: +49 - 40 - 7410 57232.
    Affiliations
    Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Germany
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  • Annika Volmari
    Affiliations
    Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Germany
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  • Marc Lütgehetmann
    Affiliations
    German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Germany

    Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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      The hepatitis delta virus (HDV) is the causative agent of chronic hepatitis delta (CHD), the most severe form of viral hepatitis. Efficient antiviral treatments are urgently needed to prevent its progressive course leading to the development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Infection with HDV can occur either simultaneously with hepatitis B virus (HBV), or as superinfection in patients already chronically infected with HBV.
      • Urban S.
      • Neumann-Haefelin C.
      • Lampertico P.
      Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.
      The dependency of HDV on HBV is exclusively due to the evolutionary adaptation of HDV in using HBV-encoded envelope proteins (HBsAg) for its release and de novo infection.
      • Dandri M.
      • Bertoletti A.
      • Lutgehetmann M.
      Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition.
      Since HBV envelope proteins can derive both from HBV genomes present in cell nuclei (covalently closed circular DNA [cccDNA] minichromosomes), and from chromosomally integrated sequences, both sources may contribute to HDV release.
      • Dandri M.
      • Bertoletti A.
      • Lutgehetmann M.
      Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition.
      The HDV genome is a small circular, negative-sense, single-stranded RNA of around 1.7 kb, which forms an unbranched rod-like structure with paired nucleotides. Upon infecting the hepatocytes through the sodium taurocholate co-transporting polypeptide (NTCP), HDV replicates in the nucleus, using the host RNA polymerase II and a double rolling-circle amplification process, leading to the accumulation of 2 additional RNAs: the antigenomic (AG) HDV RNA, and a smaller mRNA coding for the 2 isoforms of the hepatitis delta antigen (Large: L-HDAg and Small: S-HDAg). During replication, genomes and AG-HDV RNAs associate with HDAg proteins, and AG-HDV RNA is edited by host adenosine deaminase acting on RNA (ADAR) to introduce a mutation in the stop codon of the S-HDAg, enabling production of the L-HDAg. Prenylation of L-HDAg by the cellular farnesyl transferase promotes the acquisition of HBV envelope proteins at the endoplasmic reticulum and subsequently viral release (see also
      • Lucifora J.
      • Delphin M.
      Current knowledge on hepatitis delta virus replication.
      ).
      At least 12 million individuals are HBV/HDV-coinfected worldwide, but the global number may be underestimated due to suboptimal testing, particularly in high prevalence areas. HDV is classified into 8 genotypes. Sequence divergence among the genotypes is as high as 40% with the greatest differences observed between HDV genotype 1 and genotype 3.
      • Stockdale A.J.
      • Kreuels B.
      • Henrion M.Y.R.
      • Giorgi E.
      • Kyomuhangi I.
      • de Martel C.
      • et al.
      The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.
      Due to its unique replication modalities, HDV offers very few therapeutic targets.
      • Urban S.
      • Neumann-Haefelin C.
      • Lampertico P.
      Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.
      Pegylated interferon alpha (pegIFNα) has been used as an off-label treatment against HDV for decades, despite associated side effects, low response rates and high relapse rates. Among the new anti-HDV strategies, bulevirtide efficiently blocks HBV and HDV entry by targeting NTCP and is the first HDV-specific drug that obtained conditional marketing authorization in Europe. Lonafarnib, currently tested in clinical trials, is an inhibitor of the farnesyl transferase and thus inhibits HDV release. Although their mode of action (MoA) remains unclear, nucleic acid polymers hinder the secretion of HDV and HBsAg and are currently being investigated. Clinical trials are also assessing pegIFNλ-based therapies. However, IFNs’ MoA in HDV infection remains elusive and studies performed using distinct isolates
      • Zhang Z.
      • Urban S.
      New insights into HDV persistence: the role of interferon response and implications for upcoming novel therapies.
      ,
      • Giersch K.
      • Homs M.
      • Volz T.
      • Helbig M.
      • Allweiss L.
      • Lohse A.W.
      • et al.
      Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice.
      indicated that IFN-responsiveness may differ substantially among strains.
      Mechanisms of HDV sensing are unclear, but studies showed that HDV provokes a strong induction of the antiviral state in human hepatocytes by enhancing the expression of IFN-stimulated genes and cytokines.
      • Dandri M.
      • Bertoletti A.
      • Lutgehetmann M.
      Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition.
      Notably, HDV was shown to enhance genes involved in antigen presentation and processing, thus boosting the presentation of HBV antigens in HBV/HDV-coinfected hepatocytes.
      • Tham C.Y.L.
      • Kah J.
      • Tan A.T.
      • Volz T.
      • Chia A.
      • Giersch K.
      • et al.
      Hepatitis delta virus acts as an immunogenic adjuvant in hepatitis B virus-infected hepatocytes.
      Such enhanced antigen presentation increased the efficiency of T-cell recognition; a feature that could be explored in HBV/HDV-directed T-cell therapies. Nevertheless, cytokines may also contribute to the recruitment and activation of various innate and adaptive immune cells, thus promoting the exhaustion of virus-specific immune responses and disease progression.
      • Dandri M.
      • Bertoletti A.
      • Lutgehetmann M.
      Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition.
      When HBV and HDV replication levels are high, as in acute HBV/HDV coinfection, in highly viremic CHD patients or in humanized mice, HBV envelope proteins mostly derive from HBV cccDNA, and HBV and HDV particles are released together with high amounts of HBsAg+ subviral particles. In this situation, the proportion of infected cells is high, with viral release and new infection events mostly occurring via the NTCP receptor. However, in the natural course of CHD, ongoing inflammation triggering cell death and compensatory cell turnover can substantially reduce intrahepatic HBV cccDNA loads, generating cells that have cleared the cccDNA, but still contain HBV DNA integrations, possibly producing HBV envelope proteins. In striking contrast to HBV, HDV can propagate efficiently through cell division both in vitro and in vivo.
      • Giersch K.
      • Bhadra O.D.
      • Volz T.
      • Allweiss L.
      • Riecken K.
      • Fehse B.
      • et al.
      Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo.
      It is therefore plausible that over the years, inflammatory events shall accelerate intrahepatic HDV propagation among daughter cells, while lowering intrahepatic cccDNA amounts. This heterogeneous infection landscape can evolve, particularly in a setting where de novo infection events are low, as often observed in HBeAg-negative CHD and in patients receiving nucleotide analogues to lower HBV viremia. Enhanced cytokine levels may also lower viremia and limit NTCP-mediated HBV and HDV infection events, while still promoting the expansion of cells containing HBV DNA integrations and/or HDV. Since HDV can persist within the hepatocytes in the absence of HBV, a latent HDV-monoinfection can be reverted to a productive coinfection through HBV infection (see also
      • Dandri M.
      • Bertoletti A.
      • Lutgehetmann M.
      Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition.
      ). Thus, control of new infection events may play a key role in therapeutic strategies aimed at curing CHD.

      Financial support

      The authors received funding from the German Research Foundation, Germany (DFG; SFB841: A5 and A8 ) and from the German Center for Infection Research, Germany (DZIF TTU-Hepatitis 05.822 and 05.820).

      Authors’ contributions

      AV: figure; MD and ML: figure and text; all authors approved the final version of text and figure.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors thank Dr Lena Allweiss for her comments on manuscript and figure.

      Supplementary data

      The following is the supplementary data to this article:

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