M.A.A. van de Klundert
- X: On the molecular biology of the hepatitis B virus X protein
- Award date
- 16 February 2016
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Expression of the hepatitis B virus (HBV) accessory protein HBx is a requirement for viral replication. In this thesis, we investigated how HBx supports HBV replication, and we performed studies to identify its function. In chapter 2 we show that the overlap of reading frames in the HBV genome restricts viral evolution and affects the mutation rate. The mutation rate varied and correlated negatively with viral load. Because no crystallography-based tertiary structure of HBx is available, we have predicted the tertiary structure by ab initio computer modelling in chapter 3. Our model shows that HBx seems to have significant structural homology with the human thymine DNA glycosylase (TDG). In chapter 4 we show that HBx inhibits TDG-initiated DNA repair. Amongst the HBx interacting proteins described in the literature are various epigenetic modulators. The data we present in chapter 5 show that an important class of these proteins, the histone deacetylases, indeed suppress HBV replication, but that their activity is not affected by HBx. Therefore we applied subtractive mass spectrometry to systematically identify relevant HBx interacting proteins. As described in chapter 6, we identified one HBx interacting protein, talin-1, which was targeted for proteasomal degradation by HBx. Subsequent analysis revealed that talin-1 is a viral restriction factor, and that HBV replication critically depends on HBx-mediated talin-1 degradation. In chapter 7, we explored the possibility to target HBV transcription in HBx dependent- and independent ways. By screening 640 FDA approved drugs, we identified compounds that suppressed HBV replication by targeting HBV RNA transcription.
- Research conducted at: Universiteit van Amsterdam
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