Katja Giersch1, Martina Helbig1, Tassilo Volz1, Lena Allweiss1, Lida V Mancke1, Ansgar W Lohse2, Susanne Polywka3, Jörg M Pollok4, Jörg Petersen5, John Taylor6, Maura Dandri7, Marc Lütgehetmann8. 1. I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. 3. Institute of Microbiology, Virology and Hygiene, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany. 4. Department for General, Visceral, Thoracic, and Vascular Surgery University Hospital Bonn, Germany. 5. IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany. 6. Fox Chase Cancer Center, Philadelphia, PA, United States. 7. I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. Electronic address: m.dandri@uke.de. 8. I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Microbiology, Virology and Hygiene, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND & AIMS: Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV in vivo and whether infectious HDV could subsequently be released following HBV super-infection. METHODS: Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry. RESULTS: The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 10(8) HDV RNA and 10(7) HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice. CONCLUSIONS: HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation.
BACKGROUND & AIMS: Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV in vivo and whether infectious HDV could subsequently be released following HBV super-infection. METHODS: Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry. RESULTS: The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 10(8) HDV RNA and 10(7) HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice. CONCLUSIONS:HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation.
Authors: Benjamin Y Winer; Tiffany Huang; Benjamin E Low; Cindy Avery; Mihai-Alexandru Pais; Gabriela Hrebikova; Evelyn Siu; Luis Chiriboga; Michael V Wiles; Alexander Ploss Journal: Virology Date: 2016-12-19 Impact factor: 3.616