A joint Crick-King’s College London funded PhD position for the 2019 programme between the labs of Ian Taylor and Chad Swanson.
This joint project is part of the Taylor Macromolecular Structure Laboratory (http://www.crick.ac.uk/ian-taylor
) and Swanson Molecular Virology Laboratory at King’s College London ((https://www.kcl.ac.uk/research/profile/swanson-lab
) research programs that are analysing the interaction of viruses with cellular antiviral proteins that block infection [1, 2]. Understanding how antiviral proteins inhibit viral replication is important to delineate poorly characterised events in viral life cycles as well as develop new treatments and vaccines.
ZAP is an antiviral protein and component of the innate immune response that inhibits the replication of a diverse range of pathogenic viruses including retroviruses, hepatitis B virus and Ebola virus. In the cell, ZAP targets viral RNAs that contain CpG dinucleotides  and interacts with other proteins, including TRIM25  and KHNYN , to prevent viral protein synthesis by promoting RNA degradation or inhibiting translation. It is thought that the antiviral activity of ZAP has resulted in the suppression of CpG dinucleotides observed in the genomes of many RNA viruses, including HIV [3, 5].
Although ZAP is the master regulator of this antiviral pathway, how it interacts with viral RNA and recruits its protein cofactors at a molecular level is not known. The aim of this project is to use a combination of structural biology, biochemistry and molecular virology to characterize ZAP-RNA and ZAP-cofactor interactions. Biochemical and biophysical assays will be used to characterise how ZAP interacts with a panel of viral RNAs and partner proteins. Structural studies (cEM, X-ray and NMR) will be employed to visualise ZAP-RNA and ZAP-cofactor complexes. Based on these in vitro studies, specific mutations in ZAP that modify or inhibit RNA/cofactor binding will be analysed in terms of their effects on retrovirus replication (HIV and murine leukaemia virus) and Ebola virus replication using transcription and replication-competent virion-like particle (trVLP) systems.
This project would suit candidates with a background in structural biology or biochemistry and with an interest in molecular virology.
Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at King’s College London.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
1. Ordonez, P., Mann, M.C., Rueschenbaum, S., Goldstone, D.C., Pennell, S., Howell, S. A., Stoye, J. P., Webb, M., Taylor, I. A., and Bishop, K. N. (2015)
Phospho-dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction.
PLoS pathogens 11: e1005194. PubMed abstract
2. Ficarelli, M., Wilson, H., Galão, R. P., Neil, S. J. D. and Swanson, C. M. (2019)
Preprint: KHNYN is essential for ZAP-mediated restriction of HIV-1 containing clustered CpG dinucleotides.
Available at: BioRxiv. https://www.biorxiv.org/content/biorxiv/early/2019/03/18/581785.full.pdf
3. Takata, M. A., Goncalves-Carneiro, D., Zang, T. M., Soll, S. J., York, A., Blanco-Melo, D. and Bieniasz, P. D. (2017)
CG dinucleotide suppression enables antiviral defence targeting non-self RNA.
Nature 550: 124-127. PubMed abstract
4. Li, M. M. H., Lau, Z., Cheung, P., Aguilar, E. G., Schneider, W. M., Bozzacco, L., . . . MacDonald, M. R. (2017)
TRIM25 enhances the antiviral action of zinc-finger antiviral protein (ZAP).
PLOS Pathogens 13: e1006145. PubMed abstract
5. Antzin-Anduetza, I., Mahiet, C., Granger, L. A., Odendall, C. and Swanson, C. M. (2017)
Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication.
Retrovirology 14: 49. PubMed abstract