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HIV PI resistance
HIV/AIDS
Framework programme: 6
Call: 4
Project number: LSHP-CT-2006-037693
EC contribution: € 2,500,000
Duration: 36 months
Type: STREP
Starting date: 1st January 2007
Graphic element HIV protease inhibitor resistance by enzyme- substrate coevolution
Keywords: HIV, AIDS, drug resistance, protease inhibitors, Gag

Summary:

This project addresses substrate-enzyme coevolution in the development of clinical resistance against HIV protease inhibitors. The central aim is to identify novel and hitherto unappreciated mechanisms of resistance; to discover their underlying molecular and structural principles and to decipher their clinical significance. This will be important for future drug development as well as for strategic choice of drug combinations.

Background:

Despite the success of antiretroviral drugs, therapy of HIV infection and AIDS still suffers from severe drawbacks, mainly because of resistance which renders individual drugs and complete drug classes ineffective. 70-80% of HIV-infected patients undergoing resistance testing carry drug resistant virus, and 10% of new transmissions involve resistant or multi-resistant viruses. Protease inhibitors (PI) have been a key factor in the success of HIV therapy, but resistance against PI is mechanistically less well understood. It is believed to be a stepwise process involving resistance mutations in protease (PR) and compensatory mutations in PR and its cleavage sites. In a previous EU-network, several participants of this project have identified a novel substrate-based PI resistance mechanism.

Aim:

To determine the actual underlying molecular and structural mechanism and in pursuit of the central objective, the team will, focus research on the following three scientific and technological aims; which are addressed in the three scientific work packages of the project:

  • Determine the functional and structural role of individual cleavages of the HIV Gag polyprotein and their alterations towards viral maturation, fitness and resistance
  • Identify the molecular and structural principles of substrate-dependent resistance against clinically used PI as well as newly developed drugs
  • Identify novel substrate-based resistance variants and substrate-enzyme pairs and determine the influence of genetic subtype on substrate associated resistance.

Expected results:

Understanding the underlying functional and structural mechanisms causing the development of antiviral drug resistance is a prerequisite for the efficacy of HIV/AIDS treatments and for identifying new treatments in the future. The results of this collaborative research project are highly relevant in this respect as they will be important both for drug development as well as for therapeutic management.

Potential applications:

The results of this project are expected to have implications for the future development of drug resistance testing of patients under antiretroviral therapy and may be used to modify resistance algorithms. Furthermore, understanding substrate-dependent resistance will also be important for further improvement of PI-based antiretroviral therapy.

Coordinator:

Prof. Hans-Georg Kräusslich
Department of Virology
University of Heidelberg
Im Neuenheimer Feld 324, D69120 Heidelberg, Germany
Tel: + 49 6221 565001
Fax: + 49 6221 565003
E-mail: hans-georg.kraeusslich@med.uni-heidelberg.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2 Monique Nijhuis Department of Virology, University
Medical Centre Utrecht
Heidelberglaan 100
NL-3508 GA - Utrecht
The Netherlands
Tel: +31-302506526
Fax: +31-302505426
E-mail: m.nijhuis@lab.azu.nl
3 Jan Konvalinka Institute of Organic Chemistry and Biochemistry
Academy of Science of the Czech Republic
Prague
Flemingovo nám 2
CZ- 16610 Prague 6
Czech Republic
Tel: +420220183218
Fax: +420220183578
E-mail: konval@uochb.cas.cz
4 Francois Clavel

U552
Institut National de la Santé et de la Recherche Medicale, Paris
Inserm 552, Hopital Bichat
46, rue Huchard
FR-75018 Paris
France

Tel: +33 (0) 1 40256363
Fax: +33 (0) 1 40256370
E-mail: clavel@bichat.inserm.fr
5 Juraj Sedlacek Institute of Molecular Genetics
Academy of Sciences of the Prague Czech Republic
Flemingovo nám 2
CZ-16637 Prague 6
Czech Republic
Tel: +420 220 183 280
Fax: +420 224 310 234
E-mail: sedlacek@img.cas.cz
6 Stephen Fuller Division of Structural Biology
Oxford University
Roosevelt Drive
OX3 7BN Oxford
UK
Tel: +44 1865 287817
Fax: +44 186587547
E-mail: n.Fuller@strubi.ox.ac.uk
7Elisabeth Dam BioalliancePharma SA,
6, rue Henry Huchard
FR-75018 Paris
France
Tel : +33 (0) 1 40256369
Fax: +33 (0) 1 40256370
E-mail: dam@bichat.inserm.fr

 
 
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