Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Basic Medical Sciences

First Advisor

Ourania Andrisani

Second Advisor

Fabien Zoulim

Committee Member 1

Robert Geahlen

Committee Member 2

Andy W Tao

Committee Member 3

Xiaoqi Liu

Abstract

With 250 million reported chronic infections globally, Hepatitis B Virus (HBV) is a major human health issue, linked to increased risk for development of hepatocellular carcinoma (HCC). Current treatments to control chronic HBV infection remain ineffective. New and effective therapies that target the persisting viral molecules are needed in order to clear infection. My research aims to understand the role of hepatitis B virus (HBV) in inducing HCC and identify novel host molecules that are targeted by HBV. Understanding how HBV modifies and manipulates host cellular pathways is critical for the development of mechanism based therapeutics. Here, I provide a review for the HBV core protein (HBc), its function and the host molecules it usurps during infection and pathogenesis. I also identify Polo-like-kinase 1 (PLK1) as a proviral factor in HBV pathogenesis. I demonstrate by loss of function as well as gain of function approaches that PLK1 inhibition suppresses viral replication both in vitro and in vivo. I also show that HBc is a phosphorylation substrate for PLK1 in vitro and I mapped the PLK1 phosphorylation sites to HBc residues S168, S176 and S178. Finally, I used a global proteomics approach to study human HBc interactome identifying potential interacting partners with interesting links to viral pathogenesis. Collectively, my research expands our understanding of the role of HBc in HBV pathogenesis and the ensuing transformation of the liver.

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