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

Maya, S.; Hershkovich, L.; Cardozo-Ojeda, E. F.; Shirvani-Dastgerdi, E.; Srinivas, J.; Shektman, L.; Uprichard, S. L.; Berneshawi, A. R.; Cafiero, T. R.; Dahari, H.; Ploss, A.

doi:10.1101/2023.02.17.528964

bioRxiv · 10.1101/2023.02.17.528964

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

Maya, S.·Hershkovich, L.·Cardozo-Ojeda, E. F.·Shirvani-Dastgerdi, E.·Srinivas, J.·Shektman, L.·Uprichard, S. L.·Berneshawi, A. R.·Cafiero, T. R.·Dahari, H.·Ploss, A.

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Abstract

Background and AimsChronic infection with hepatitis B and hepatitis delta viruses (HDV) is considered the most serious form of viral hepatitis due to more severe manifestations of and accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. There is no FDA-approved treatment for HDV and current interferon-alpha treatment is suboptimal. We characterized early HDV kinetics post inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. MethodsWe 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 peptide (hNTCP). ResultsKinetic 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 18 minutes (standard error, SE: 2.4), binds to non-specific cells with a rate of 0.06 hour-1 (SE: 0.03), and returns as free virus with a rate of 0.23 hour-1 (SE: 0.03). ConclusionsUnderstanding early HDV-host kinetics will inform pre-clinical therapeutic kinetic studies on how the efficacy of anti-HDV therapeutics can be affected by early kinetics of viral decline. LAY SUMMARYThe 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. Understanding the kinetics of viral clearance in the blood can aid pre-clinical development and testing models for anti-HDV therapeutics.

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Maya, S., Hershkovich, L., Cardozo-Ojeda, E. F., Shirvani-Dastgerdi, E., Srinivas, J., Shektman, L., Uprichard, S. L., Berneshawi, A. R., Cafiero, T. R., Dahari, H., Ploss, A.. 2023-02-17. Hepatitis delta virus RNA decline post inoculation in human NTCP transgenic mice is biphasic. https://doi.org/10.1101/2023.02.17.528964

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