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

Aim:

The main scientific and technological objectives of the VIRULENCE project are:

  • to determine the clinical consequences of high-level resistance against HIV rerverse transcriptase inhibitors (RTIs) on viral virulence in treated individuals
  • to develop, standardise and validate diagnostic tests for the in vivo management and in vitro determination of viral fitness
  • to clarify the underlying molecular mechanisms relating to changes in drug susceptibility with viral virulence
  • to identify and test novel RT inhibitors against highly drug resistant HIV variants
  • to create highly characterised reference materials available to the scientific community
  • to create a public accessible database on the consequences of drug resistance for viral fitness and in vivo virulence

Expected results:

A determined clinical impact of drug resistance on viral fitness and underlying molecular causes.
Standardised and validated diagnostic tests for patient management.
Public sample-bank of resistant variants suitable for the identification of novel inhibitors.
A database summarising all aspects of HIV RT-inhibitor resistance and consequences for viral virulence.
New lead compounds active against resistant viruses.

Potential applications:

Availability and implementation of new and clinically validated diagnostic tests to determine viral fitness. Rationale understanding of the role of viral fitness in the management of patients expressing treatment failure. Further exploration of identified lead compounds active against RTI resistant viruses.

Coordinator:

Rob Schuurman
Department of Virology (G04.614)
University Medical Center
Heidelberglaan 100
3584 CX Utrecht
The Netherlands
Tel: +31 30 2506526
Fax: +31 30 2505426
E-mail: rob.schuurman@lab.azu.nl

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Barbara SchmidtNational Reference Centre for Retroviruses
Institute for Clinical and Molecular Virology
Schlossgarten 4
DE-91054 Erlangen
Germany
Tel: +49 91 318522762
Fax: +49 91 318526485
E-mail: baschmid@viro.med.uni-erlangen.de
3Lidia Ruiz TabuencaRetrovirology Laboratory IRSICAIXA Foundation
Fundació irsiCaixa
Ctra. de Canyet s/n, 2nd Floor-Maternal Building
ES-08916 Barcelona
Spain
Tel: +34 93 4656374
Fax: +34 93 4653968
E-mail: ruiz@ns.hugtip.scs.es
4Bonaventura ClotetDepartment of Retrovirology
Hospital Universitari Germans Trias i Pujol
Ctra. de Canyet, s/n, 2nd Floor-Maternal Building
ES-08916 Badalona (Barcelona)
Spain
Tel : +34 93 4656374
Fax : +34 93 4653968
E-mail: bclotet@ns.hugtip.scs.es
5Claudia BalottaInstitute of Infectious and Tropical Diseases
Luigi Sacco Hospital
University of Milan
Via G.B. Grassi 74
IT-20157 Milano
Italy
Tel : +39 02 3820 0319
Fax: +39 02 3566644
E-mail: balotta@mailserver.unimi.it
6Francois ClavelInserm U552, IMEA, Hopital Bichat
Institut National de la Santé et de la Recherche Médicale
46, rue Henri Huchard
FR-75018 Paris
France
Tel: +33 1 40 25 63 63
Fax: +33 1 40 25 36 51
E-mail: clavel@bichat.inserm.fr
7Ben BerkhoutDepartment of Human Retrovirology
University of Amsterdam
Meibergdreef 15
NL-1105 AZ Amsterdam
The Netherlands
Tel: +31 20 566 4822
Fax: +31 20 691 6531
E-mail: b.berkhout@amc.uva.nl
8Dave StammersThe Wellcome Trust Centre for Human Genetics
Division of Structural Biology
Chancellor, Masters and Scholars of the University of Oxford
Roosevelt Drive
UK-OX3 7BN Oxford
United Kingdom
Tel: +44 1865 270043
Fax: +44 1865 280467
E-mail: daves@biop.ox.ac.uk
9Jan BalzariniRega Institute for Medical Research,
Laboratory of Virology and Chemotherapy
Katholieke Universiteit Leuven
Minderbroedersstraat 10
BE-3000 Leuven
Belgium
Tel: +32 16 324063
Fax: +32 16 324198
E-mail: jan.balzarini@rega.kuleuven.ac.be
10Charles A.B. Boucher and Monique NijhuisDepartment of Virology (G04.614)
University Medical Center
Heidelberglaan 100
NL-3584 CX Utrecht
The Netherlands
Tel: +31 30 250 6526
Fax: +31 30 250 5426
E-mail: c.boucher@lab.azu.nl
m.nijhuis@azu.nl

 
 
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