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VIRULENCE

Population age structure and age structure modification via Wolbachia in Anopheles gambiae


HIV/AIDS

HIV-1 Reverse Transcriptase Inhibitor Resistance and Its Consequences for Viral Virulence
Framework programme:
5
Project number:
QLK2-CT-2002-01311
EC contribution:
€ 1 300 000
Duration:
36 months
Type:
RS
Starting date:
1 September 2002

Keywords: HIV-1; drug-resistance; reverse transcriptase; fitness; replication capacity; virulence; pathogenicity

Summary:

VIRULENCE will provide a strategy against a major health threat: occurrence of resistance against therapeutic HIV/AIDS-measures. Reverse transcriptase inhibitors play an essential role in HIV treatment. RT variants with reduced susceptibility to these inhibitors emerge even under potent combination therapies and may become less virulent. Thus, the emergence of RTI resistance negatively affects the inhibitor efficacy but may also result in virus variants with reduced pathogenicity. VIRULENCE aims at elucidating clinical consequences of changes in viral fitness for optimal use of antiviral drugs. VIRULENCE is the first to address this through development and validation of improved fitness assays, and by their application on one or more existing well-defined longitudinal clinical cohorts. The molecular mechanisms for viral fitness and resistance will be elucidated and new compounds active against drug resistant HIV defined. This integrated approach will improve care of patients with limited therapeutic option.

Problem:

The emergence of anti-viral drug resistance in HIV-infected individuals undergoing the commonly administered treatment with Highly Active Antiretroviral Therapy (HAART) is a significant drawback of the therapy efficacy that aims for a complete and sustained inhibition of viral replication. Failure to suppress viral replication is demonstrated by increasing concentration of the virus detected in the plasma of these individuals. In drug-naive individuals starting HAART, a combination of three drugs targeting the viral reverse transcriptase and protease enzymes usually achieves a complete inhibition of viral replication. Escape from this initial HAART regimen, as observed by a rise in viral load, generally occurs in approximately 10% of the patients under treatment per year. Subsequent therapy changes usually result in a viral suppression for a significantly shorter period, due to the rapid emergence of resistance to the administered drugs. Viruses expressing resistance to several, if not all, of the available drugs are frequently observed in patients that received and failed several different HAART regimens. It is estimated that, resistance to two or more reverse transcriptase inhibitors (RTIs) and/or protease inhibitors (PIs) can be observed in approximately 50% of the patients under HAART therapy, with hardly any effective therapeutic options left. Hence, in order to be able to find new drugs and improved corresponding therapies that can fight HAART resistant HIV effectively, it is essential to obtain a thorough understanding of the resistance effects and involved mechanisms regarding HIV virulence.

The VIRULENCE project will focus on investigating the reverse transcriptase. As described above, reverse transcriptase variants expressing resistance emerge even under potent combination therapy. In some cases, these variants express a reduced replication capacity (viral fitness) as a consequence of the resistance mutations selected, and as such become less virulent. Thus, the emergence of resistance to RTIs negatively affects the efficacy of the drug to inhibit viral replication, but on the other hand creates virus variants that are less virulent than the wild type. The clinical consequences of changes in viral fitness are, as yet, unknown. Therefore, it is of utmost importance to get a better understanding of the consequences of high-level resistance on the pathogenesis and virulence of these viruses in vivo. Moreover, it will provide a sound basis for the screening (within this project) and future development of new drugs that effectively inhibit the replication of these highly RTI-resistant HIV variants.

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