Structural and functional studies in lentivirus RNA encapsidation

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Despite remarkable recent advances in treatment of HIV/AIDS it is still one of the largest global health threats and the number of infected people is still rising. There are now a number of drugs which inhibit the virus but it can develop resistance to all of them. Combination therapy is the best and ideally drugs should block different stages of the virus life cycle. Finding new targets is vital. The virus packages its genetic material by allowing the genes which are in the form of RNA to fold into a special structure which distinguishes them from other RNAs in the cell. This structure is called a ‘packaging signal’. We have been studying this structure and that of related viruses for several years. We plan to analyse this RNA structure further and to work out where in the cell the recognition process is occurring. We can then design agents to bind to the RNA in the critical region and block packaging of the genes into the virus. This will be a new drug target. If we block the genes entering the virus then an infected cell will release only protein containing, non infectious, virus-like particles which will boost the immune response in the patient.

Technical Summary

Lentiviruses such as HIV, the causative agent of AIDS, are important pathogens in humans. They also have uniquely useful properties as gene delivery agents. Understanding the process by which the virus encapsidates its own RNA genome is critical to the development of safe lentiviral vectors and also provides a new therapeutic target for antiviral studies. We plan to extend our understanding of the sites and structures of lentiviral packaging signals in HIV-1, HIV-2 and SIV using structural techniques such as NMR crystallography and EM. We will pursue functional studies seeking the site in the cell at which RNA capture occurs using confocal methodologies and FRET. We will explore the interaction between packaging and translation and use our understanding of the critical structures involved and the site of the process within the cell to design antiviral therapeutics to inhibit encapsidation of RNA and hence viral replication.

Publications

10 25 50

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Groom HCT (2009) Rev regulates translation of human immunodeficiency virus type 1 RNAs. in The Journal of general virology

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Lever AM (2006) Replication of human immunodeficiency virus type 1 from entry to exit. in International journal of hematology

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Mok HP (2008) Waking up the sleepers: HIV latency and reactivation. in Journal of the Formosan Medical Association = Taiwan yi zhi

 
Description Milstein award
Amount £300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2009 
End 11/2012
 
Description Programme Grant
Amount £1,600,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2009 
End 06/2014
 
Description Licensing agreement 
Organisation Lentigen
Country United States 
Sector Private 
PI Contribution Lentigen have licensed our lentiviral vectors
Collaborator Contribution Lentigen have licensed our lentiviral vectorsFunding for patent costs
Impact Lentigen have licensed our lentiviral vectors
Start Year 2008
 
Description Licensing agreement 
Organisation Lentigen
Country United States 
Sector Private 
PI Contribution Lentigen have licensed our lentiviral vectors
Collaborator Contribution Lentigen have licensed our lentiviral vectorsFunding for patent costs
Impact Lentigen have licensed our lentiviral vectors
Start Year 2008
 
Title Novel lentiviral vectors 
Description Important cis acting sequences in HIV vectors and novel cross packaging in chimeric vectors 
IP Reference EP1262554 
Protection Patent granted
Year Protection Granted
Licensed Commercial In Confidence
Impact patent costs covered vectors licensed to Lentigen. Royalty payment in 2012 to University, Department of Medicine and Inventors as Lentigen completed Phase 1 clinical trial using lentiviral vectors based on the IPR
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Talk to 6th forms

Much interest
Year(s) Of Engagement Activity 2006,2008