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HIV PR INHIBITORS


HIV/AIDS

Rational Approaches Towards Understanding and Overcoming HIV Protease Inhibitor Resistance
Framework programme:
5
Project number:
QLK2-CT-2001-02360
EC contribution:
€ 1 457 986
Duration:
36 months
Type:
RS
Starting date:
1 October 2001

Keywords: AIDS; drug resistance; protease inhibitor; human immunodeficiency virus; viral fitness; inhibitor design; combination therapy

Summary:

The objective of this project is to determine and monitor the development of resistance against human immunodeficiency virus (HIV) Protease (PR) inhibitors in five European countries, to develop, standardise and validate diagnostic tests, to analyse changes in viral fitness on resistance development and determine the underlying molecular mechanisms, and to design and test novel PR inhibitors against drug resistant HIV variants. Complex approaches involving genotypic and phenotypic characterisation of HIV variants, as well as biochemical and structural analysis of resistant enzymes, are required to monitor drug resistance and changes in virulence accurately, and to provide new inhibitors. The proposed integrated studies will lead to a complete database covering all aspects of HIV PR inhibitor resistance in Europe.

Problem:

Infection with human immunodeficiency virus (HIV) has recently become the leading infectious disease killer worldwide and antiretroviral drugs are currently the only way to combat AIDS. Potent antivirals have been developed against HIV reverse transcriptase (RT) and protease (PR), and combination therapy including protease inhibitors (PI) has dramatically reduced disease progression in most patients. However, an emergence of drug resistant variants has been observed even for the most potent combination therapies. Therefore, development of drug resistance and spread of resistant variants are serious impediments to the control of HIV infection.

Aim:

It is the aim of this collaborative project to analyse the development of drug resistance against HIV PR inhibitors in an European multi-centre study and to provide the rational basis for understanding resistance development and the corresponding changes in viral fitness on a molecular level. To this end, seven closely collaborating groups from five European countries, with long-standing experience concerning biochemical, structural and virological aspects of HIV PR and its inhibitors, will join forces in an interdisciplinary approach. They will also involve hospitals and policlinics treating AIDS patients.

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