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Adaptation to oxidative stress in hepatitis C virus persistence: the role of IRES-dependent translation.


Project Description

Hepatitis C virus (HCV) causes a clinically important disease affecting 3% of the world population (Chan 2014). About 75% of the infection will develop into chronic hepatitis, which can then progress into fibrosis, cirrhosis and hepatocellular carcinoma. Oxidative stress is a prominent clinical feature in hepatitis C patients and yet HCV manages to establish a chronic infection in the face of an active host oxidative defence. Thus adaptation to oxidative stress is key to virus survival.

HCV utilizes an internal ribosome entry site (IRES) element in translation, which is distinctive from that of cap-dependent translation of the vast majority of cellular genes, thus allowing selective translation of viral genes under conditions when host global protein synthesis is compromised. Indeed, we were the first to show that HCV translation was stimulated by an important pro-oxidant-hydrogen peroxide (H2O2), suggesting that HCV is able to adapt to and utilize host anti-viral response to facilitate its own translation thus allowing the virus to thrive under oxidative stress condition to establish chronicity (MacCallum et al. 2006, Chan 2016). Understanding how HCV translation is regulated under oxidative stress condition will advance our knowledge on how HCV establishes chronicity and pathogenicity, which is particularly relevant to the development of anti-virals and improved treatments of HCV patients using anti-oxidants and anti-IRES. The overall aim of this proposal is to study how HCV IRES translation adapts to oxidative stress. This project will involve:

1. mapping the H2O2-responsive domain in the IRES element;
2. dissecting the mechanisms of H2O2-stimulated IRES translation;
3. elucidating how sequence variation in the HCV IRES element affects its translational response to H2O2;
4. studying how the IRES element evolves under oxidative stress pressure; and
5. determining the role of anti-oxidants in shaping H2O2 translational response and evolution of the IRES element.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with an interest in virology are encouraged to apply. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Chan, S. W. (2016). Hydrogen peroxide induces La cytoplasmic shuttling and increases hepatitis C virus internal ribosome entry site-dependent translation. J Gen Virol 97(9): 2301-2315.

Chan, S. W. (2014). Establishment of chronic hepatitis C virus infection: translational evasion of oxidative defence. World J Gastroenterol 20(11): 2785-2800.

Samantha C. Jack & Shiu-Wan Chan* (2011). The role of PERK and GCN2 in basal and hydrogen peroxide-regulated translation from the hepatitis C virus internal ribosome entry site. Virus Genes, 43(2):208-214.

*CHAN S. W. & Egan PA (2009). Effects of hepatitis C virus envelope glycoprotein unfolded protein response activation on translation and transcription. Archives of Virology, 154:1631-1640.

MacCallum, P. R., S. C. Jack, P. A. Egan, B. T. McDermott, R. M. Elliott and S. W. Chan (2006). Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2 alpha under oxidative stress. Journal of General Virology 87: 3251-3262.

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