Hepatitis delta virus RNA decline post-inoculation in human NTCP transgenic mice is biphasic

ABSTRACT Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor—human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics. The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics.

[1]  J. Niu,et al.  HDV Seroprevalence in HBsAg-Positive Patients in China Occurs in Hotspots and Is Not Associated with HCV Mono-Infection , 2021, Viruses.

[2]  T. Volz,et al.  Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice , 2021, Frontiers in Microbiology.

[3]  E. Sagnelli,et al.  HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges , 2021, Life.

[4]  C. Sureau,et al.  No Evidence of HCV-Assisted HDV Propagation in a Large Cohort of Hepatitis C Positive Blood Donors. , 2020, The Journal of infectious diseases.

[5]  A. Ploss,et al.  Master of Disguise: Hepatitis Delta Virus Packaging and Spread Facilitated by Diverse Viral Envelope Proteins , 2020, Hepatology.

[6]  G. Luo,et al.  Human apolipoprotein E promotes hepatitis B virus infection and production , 2019, PLoS pathogens.

[7]  Y. Ni,et al.  Recapitulation of HDV infection in a fully permissive hepatoma cell line allows efficient drug evaluation , 2019, Nature Communications.

[8]  F. Cosset,et al.  Enveloped viruses distinct from HBV induce dissemination of hepatitis D virus in vivo , 2019, Nature Communications.

[9]  J. Hepojoki,et al.  Identification of a Novel Deltavirus in Boa Constrictors , 2019, mBio.

[10]  F. Negro,et al.  A review on hepatitis D: From virology to new therapies , 2019, Journal of advanced research.

[11]  J. Hepojoki,et al.  Identification of a novel deltavirus in Boa constrictor , 2018, bioRxiv.

[12]  M. Shi,et al.  A Divergent Hepatitis D-Like Agent in Birds , 2018, bioRxiv.

[13]  H. Goyal,et al.  Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis , 2018, Gut.

[14]  Jared E. Toettcher,et al.  Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection , 2018, Science Translational Medicine.

[15]  A. Perelson,et al.  Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics , 2018, Hepatology.

[16]  Wenhui Li,et al.  Modification of Three Amino Acids in Sodium Taurocholate Cotransporting Polypeptide Renders Mice Susceptible to Infection with Hepatitis D Virus In Vivo , 2016, Journal of Virology.

[17]  Michael A. Smith,et al.  Hepatitis Delta Virus Detected in Salivary Glands of Sjögren's Syndrome Patients and Recapitulates a Sjögren's Syndrome-Like Phenotype in Vivo , 2016, Pathogens & immunity.

[18]  S. Urban,et al.  Hepatitis B Virus Infection of a Mouse Hepatic Cell Line Reconstituted with Human Sodium Taurocholate Cotransporting Polypeptide , 2016, Journal of Virology.

[19]  Wenhui Li,et al.  Hepatitis D Virus Infection of Mice Expressing Human Sodium Taurocholate Co-transporting Polypeptide , 2015, PLoS pathogens.

[20]  F. Negro.  Hepatitis D virus coinfection and superinfection. , 2014, Cold Spring Harbor perspectives in medicine.

[21]  M. Fälth,et al.  Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. , 2014, Gastroenterology.

[22]  S. Polywka,et al.  Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. , 2014, Journal of hepatology.

[23]  Jiahuai Han,et al.  HBV life cycle is restricted in mouse hepatocytes expressing human NTCP , 2014, Cellular and Molecular Immunology.

[24]  Wenhui Li,et al.  Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus , 2012, eLife.

[25]  A. Lohse,et al.  Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation , 2012, Hepatology.

[26]  Y. Ni,et al.  Fine Mapping of Pre-S Sequence Requirements for Hepatitis B Virus Large Envelope Protein-Mediated Receptor Interaction , 2009, Journal of Virology.

[27]  D. Greiner,et al.  Non‐obese diabetic–recombination activating gene‐1 (NOD–Rag 1 null) interleukin (IL)‐2 receptor common gamma chain (IL 2 rγnull) null mice: a radioresistant model for human lymphohaematopoietic engraftment , 2008, Clinical and experimental immunology.

[28]  C. Sureau,et al.  Entry of Hepatitis Delta Virus Requires the Conserved Cysteine Residues of the Hepatitis B Virus Envelope Protein Antigenic Loop and Is Blocked by Inhibitors of Thiol-Disulfide Exchange , 2007, Journal of Virology.

[29]  Harel Dahari,et al.  Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation. , 2005, Journal of hepatology.

[30]  S. Urban,et al.  Efficient Inhibition of Hepatitis B Virus Infection by Acylated Peptides Derived from the Large Viral Surface Protein , 2005 .

[31]  R. Locksley,et al.  Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. , 2002, Immunity.

[32]  M. Kay,et al.  Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses , 2000, Nature Medicine.

[33]  E. Christensen,et al.  Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B , 2000, Gut.

[34]  J. Taylor,et al.  Experimental transmission of human hepatitis delta virus to the laboratory mouse , 1993, Journal of virology.

[35]  M. Rizzetto,et al.  Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. , 1977, Gut.