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Employing molecular virology to investigate hepatitis E virus replication (fully-funded PhD)


Faculty of Biological Sciences

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Dr M.R. Herod , Prof M Harris No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Hepatitis E virus (HEV), is a major causative agent of acute, severe hepatitis. The infection can also be chronic, particular in immunocompromised people, and fatal in pregnant women or those with existing liver diseases. The virus is zoonotic (i.e. it can spread from animals to humans) and can infect a wide range of organisms, most notable pigs where it can be passed onto humans through consumption of contaminated pork products. There are no licenced therapies to treat HEV infection and therefore there is a requirement to develop new therapeutic strategies. Until recently, probing details of HEV replication has been challenging, partly due to the lack of suitable reagents. This project aims to exploit recent developments of subgenomic replicon systems and infectious molecular clones to identify and characterise regions of the genome required for viral genome replication.

Subgenomic replicons are viral mini-genomes that facilitate the study of fundamental mechanisms of viral genome replication in the absence of infectious virus and have been established for many RNA viruses. Using random mutagenesis with HEV subgenomic replicons we will dissect regions of the viral genome that are essential for replication as well as locations that are malleable for introduction of genetic tags (eg FLAG, GFP). This approach will pave the way for studies on viral molecular interaction and identify novel roles of the essential non-structural proteins and their precursors (together with biochemistry, labelling techniques and state-of-the-art imaging facilities).

The long-term aim of the work is to use a greater knowledge of the molecular details of viral replication to develop new approaches for disease control and diagnosis.

Funding Notes

Studentship provides fees at UK/EU level plus a stipend at research council level (£15,009 for 2019-20) for 3.5 years.

Please apply online https://studentservices.leeds.ac.uk/pls/banprod/bwskalog_uol.P_DispLoginNon and include a CV and transcripts with your application.

Candidates should have a 2.1 or above (or equivalent) in a relevant area. If English is not your first language, you will need a recognised English Language qualification https://www.leeds.ac.uk/info/123100/admissions/143/entry_requirements

References

Selected References:

Herod MR, Adeyemi OO, Ward J, Bentley K, Harris M, Stonehouse NJ, Polyak SJ. The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication. J. Gen. Virol. doi: 10.1099/jgv.0.001283.

Shawli GT, Adeyemi OO, Stonehouse NJ, Herod MR. The Oxysterol 25-Hydroxycholesterol Inhibits Replication of Murine Norovirus. Viruses. 11(2)ːE97. doi: 10.3390/v11020097.

Herod MR, Gold S, Lasecka-Dykes L, Wright C, Ward JC, McLean TC, Forrest S, Jackson T, Tuthill TJ, Rowlands DJ, Stonehouse NJ. Genetic economy in picornaviruses: Foot-and-mouth disease virus replication exploits alternative precursor cleavage pathways. PLoS Pathog. 3(10):e1006666. doi: 10.1371/journal.ppat.1006666.

Herod MR, Loundras EA, Ward JC, Tulloch F, Rowlands DJ and Stonehouse NJ. (2015) Employing Transposon Mutagenesis to Investigate Foot-and-Mouth Disease Virus Replication. J. Gen. Virol. 96:3507-3518. doi: 10.1099/jgv.0.000306

Herod MR, Jones DM, McLauchlan J, and McCormick CJ. Increasing the rate of Cleavage at the Boundary Between Non-Structural Protein 4B and 5A Inhibits Replication of Hepatitis C Virus. J. Biol. Chem. 287:568-580. doi: 10.1074/jbc.M111.311407.

Goonawardane N, Gebhardt A, Bartlett C, Pichlmair A and Harris M. Phosphorylation of serine 225 in hepatitis C virus NS5A regulates protein-protein interactions. J. Virol 91:e00805-17 2017 doi:10.1128/JVI.00805-17.

Ross-Thriepland D, Harris M. Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation. J. Virol. 88 1421-1432 2014 doi:10.1128/JVI.03017-13.


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