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HIV PI resistance


HIV/AIDS

HIV protease inhibitor resistance by enzyme- substrate coevolution
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

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.
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