Dr L James
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
http://www2.mrc-lmb.cam.ac.uk/group-leaders/h-to-m/l-james
HIV-1 is a recently zoonosed pandemic virus that has killed and infected 10s of millions worldwide. There is no vaccine or cure and growing emergence of antiviral resistance. Despite intense research key questions remain. HIV uses its capsid to protect its genome and core components once inside the cell but how then does it recruit the cellular machines necessary for its transportation? And when, where and how does it uncoat?
Recent work in our lab and others has revealed that the HIV capsid is not the simple packaging structure it was once thought to be. It possesses conserved interfaces through which it recruits multiple diverse cellular proteins including the chaperone CypA, the TNPO3 cargo protein CPSF6 and nuclear pore proteins Nup153 and Nup358(1-4). The capsid is also dotted with hundreds of dynamic positively charged pores that recruit dNTPs and allow reverse transcription to be carried out inside the protein shell(5, 6). However, while this work has given us pieces of the puzzle we still do not know how they fit together. The precise role in infection of many of these cofactors is unclear as is the allostery between their binding sites. Unravelling these mysteries is key to understanding how HIV infects the cell. Furthermore, these sites are offering novel targets for new types of antiretroviral drugs.
We are looking for a talented PhD student to join our team and help provide an answer to these questions. You will have an interest in virology and host immunity and in employing diverse techniques to solve complex problems. Your project will involve structural and biophysical approaches but these will be combined with cellular infection experiments so that hypotheses can be tested. You will collaborate both with academic partners and the Drug Discovery Unit in Dundee in the design and testing of new capsid drugs.
Funding Notes
Please see the LMB PhD website for further details:
http://www2.mrc-lmb.cam.ac.uk/students/international-phd-programme/funding/
References
1. K. Bichel et al., HIV-1 capsid undergoes coupled binding and isomerization by the nuclear pore protein NUP358. Retrovirology 10, 81 (2013).
2. A. J. Price et al., CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog 8, e1002896 (2012).
3. A. J. Price et al., Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly. PLoS Pathog 10, e1004459 (2014).
4. T. Schaller et al., HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency. PLoS Pathog 7, e1002439 (2011).
5. D. A. Jacques et al., HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature 536, 349-353 (2016).
6. J. Rasaiyaah et al., HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402-405 (2013).
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