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Host-virus interactions in chronic Hepatitis B

Suslov, Aleksei. Host-virus interactions in chronic Hepatitis B. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13237

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Abstract

Hepatitis B virus (HBV) is a blood-borne human pathogen of worldwide importance. It replicates in the hepatocytes in the liver and causes a disease known as Hepatitis B. Approximately 3% of the world population are chronically infected with HBV. Chronic Hepatitis B (CHB) is the number one cause of hepatocellular carcinoma in the world leading to close to 1 million deaths every year. Treatment options are limited and none of them are curative due to persistence of the viral covalently closed circular (ccc)DNA, a plasmid-like molecule which serves as the template for viral transcription and replication. New therapies are urgently needed that would decrease the global burden of HBV. A better understanding of the HBV immunobiology and host-virus interactions is critical in this regard. Due to the narrow species and tissue tropism, research in this area has been hindered by a lack of suitable experimental in vivo models of HBV infection leaving a lot of gaps in our understanding of the viral immunobiology. For example, HBV interaction with the host innate immune system has been a matter of debates for years. Although most viruses trigger various pathogen recognition receptors (PRRs) in the cells they infect leading to the induction of interferons and an antiviral state, HBV does not seem to do that. It remained controversial however, whether this is because HBV is invisible to PRRs (i.e. acting as a “stealth virus”) or because it efficiently suppresses innate immune responses very early after infection. Another example is HBV immune control. In the natural history of CHB most of the patients reach the so called HBeAg-negative chronic infections stage, when the virus is under control characterized by no or a very low viral load in the absence of noticeable immune activity that is otherwise known to control the HBV replication.
In this thesis we used human liver biopsy material from a large biobank of the University Hospital Basel in order to shed light on host-virus interactions in chronic hepatitis B. We established a novel short-term ex vivo liver biopsy culture system, allowing to study innate immune activation in situ in the human liver. We successfully used this system to demonstrate that HBV does not induce innate immune responses in the human liver in CHB. Importantly, HBV did also not interfere with the experimental induction of innate responses, suggesting that it behaves like a “stealth virus” staying under the radar of the cell’s defense systems. As a follow-up to this study, we discuss the implication of these findings on the potential use of modulators of innate immunity as novel therapeutics for the treatment of chronic hepatitis B.
In a separate study, we sought to get an insight on how the host controls the virus during the HBeAg-negative chronic infection (ENCI) stage. By carefully analyzing HBV replication intermediates in the liver biopsies of patients of different stages of CHB, we have discovered that HBV replication is specifically inhibited downstream of pregenomic (pg)RNA production during the ENCI stage of CHB. Our findings provide a starting point for further studies in this direction that eventually should identify the mechanism behind this inhibition and harness it for therapeutic use.
Advisors:Heim, Markus and Moradpour, Darius
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13237
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (V, 117 Seiten)
Language:English
Identification Number:
Last Modified:21 Aug 2019 08:36
Deposited On:21 Aug 2019 08:36

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