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The role of CD81 in hepatoma biology and hepatitis C virus infection.

Brimacombe, Claire (2011)
Ph.D. thesis, University of Birmingham.

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Abstract

Hepatitis C Virus (HCV) is a global health problem, with over 170 million infected individuals worldwide. 70-80% of infected individuals develop progressive disease, and approximately 2% of these acquire hepatocellular carcinoma (HCC). HCV entry is dependent on tetraspanin CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Tetraspanins are involved in multiple biological functions including cell-ECM adhesion and motility. An actin polymerization-dependent cell spread was observed upon ligation of CD81 on hepatoma cells. Importantly, HCV infection perturbed CD81-dependent cell spread, suggesting HCV infection may modulate CD81 function in hepatoma cells. Functional assays demonstrated that CD81 expression and HCV infection promote hepatoma cell motility. These findings allude to a link between HCV infection and associated HCC development. Establishment of a chronic infection demonstrates that HCV can escape from the host adaptive immune responses. We developed an in vitro cell culture system to monitor viral transmission in the presence of neutralizing antibodies (nAb). Separation of producer and target cells ablated nAb resistant transmission, suggesting that cell-cell contact was essential. Furthermore nAb resistant transmission was dependent upon all four co-receptors. These observations confirm HCV immune evasion by cell-to-cell transfer and have major implications for anti-glycoprotein targeted therapies.

Type of Work:Ph.D. thesis.
Supervisor(s):McKeating, Jane A. and Balfe, Peter
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Additional Information:

Research based on this thesis is published as

Brimacombe, Claire L et al (2011)
Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission. Journal of Virology, 85 (1).
http://eprints.bham.ac.uk/510/

Brimacombe, Claire L et al (2008)
Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity. Journal of virology, 82 (17). pp. 8797-811. ISSN 1098-5514
http://eprints.bham.ac.uk/474/

Brimacombe, Claire L et al (2010)
Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology (Baltimore, Md.), 51 (6). pp. 1912-21. ISSN 1527-3350
http://eprints.bham.ac.uk/460/

Subjects:QM Human anatomy
QR Microbiology
RA0421 Public health. Hygiene. Preventive Medicine
RB Pathology
RZ Other systems of medicine
Institution:University of Birmingham
ID Code:3131
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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