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P0530
MYRCLUDEX-B INHIBITS ESTABLISHMENT OF HDV
SUPER-INFECTION IN HBV INFECTED MICE AND REDUCES
HDV VIREMIA IN STABLY HBV/HDV CO-INFECTED MICE
T. Volz1, K. Giersch1, L. Allweiss1, O.D. Bhadra1, J. Petersen2,
A.W. Lohse1,3, M. L¨utgehetmann1,4, S. Urban5,6, M. Dandri1,3. 1I.
Department of Internal Medicine, University Medical Center Hamburg
Eppendorf, 2IFI Institute for Interdisciplinary Medicine, Asklepios
Clinic St. Georg, 3Hamburg and Heidelberg Sites, German Center
for Infection Research, 4Institute of Microbiology, Virology and
Hygiene, University Medical Center Hamburg Eppendorf, Hamburg,
5Department of Infectious Diseases, Molecular Virology, University
Hospital Heidelberg, 6Hamburg and Heidelberg Sites, German Center
for Infection Research, Heidelberg, Germany
E-mail: [email protected]
Background and Aims: 15 million people are infected with the
hepatitis Delta virus (HDV) worldwide. Therapeutic strategies
specifically targeting HDV infection are not available but urgently
needed. We previously demonstrated prevention of de novo
HBV/HDV co-infection using the entry inhibitor Myrcludex-B
in naïve human liver-chimeric uPA/SCID mice (L ¨ utgehetmann,
Hepatology 2012). Aim of the study was to assess (I) whether
treatment with Myrcludex-B can hinder infection establishment
and spreading of HDV also in humanized mice already infected
with HBV, and (II) whether long-term entry inhibition can affect
viremia levels in stably HBV/HDV co-infected mice.
Methods: Humanized uPA/SCID mice were first stably infected
with HBV, then super-infected with HDV and treated with
Myrcludex-B (2 mg/kg; daily) 2 days before until 5 weeks after
HDV inoculation (I), while stably HBV/HDV co-infected mice
received Myrcludex-B daily for 9 weeks (II). Viral loads were
quantified in serum and liver by qRT-PCR and visualized by
immunohistochemistry.
Results: (I) In HBV-infected mice, which received Myrcludex-B
during the first 5 weeks of HDV super-infection, HDV viremia,
intrahepatic HDV RNA and HDAg remained below detection levels.
However, one mouse showed development of HDV viremia 3 weeks
after treatment cessation, demonstrating that Myrcludex-B strongly
hindered but did not completely abrogate establishment of HDV
infection in humanized mice. (II) In stably HBV/HDV co-infected
mice, 9 weeks of Myrcludex-B treatment induced 1-log reduction
of HDV, while HBV viremia was similar in untreated and treated
mice. However, no significant intrahepatic viral changes could be
determined by comparing treated and untreated animals. The ratio
of HDV RNA quasi-species encoding for the small and large HDAg
was also maintained after 9 weeks of Myrcludex-B administration.
Conclusions: Myrcludex-B significantly inhibited HDV infection
establishment also in the presence of a productive HBV infection.
However, continuous drug administration was necessary to prevent
HDV spreading from the very few initially infected human
hepatocytes. Long-term treatment of HBV/HDV co-infected mice
with the entry inhibitor was needed to detect HDV viremia
decrease. The high infection efficiency and great survival capacities
of HDV shown in this study highlight the difficulties encountered
in treating HBV/HDV co-infected patients.
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发表于 2015-4-23 15:00