Population age structure and age structure modification via Wolbachia in Anopheles gambiae
Keywords: HIV-1; drug-resistance; reverse transcriptase; fitness; replication capacity; virulence; pathogenicity
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.
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.
The main scientific and technological objectives of the VIRULENCE project are:
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.
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.
Department of Virology (G04.614)
University Medical Center
3584 CX Utrecht
Tel: +31 30 2506526
Fax: +31 30 2505426
|Official Address||Other Information|
|2||Barbara Schmidt||National Reference Centre for Retroviruses |
Institute for Clinical and Molecular Virology
|Tel: +49 91 318522762 |
Fax: +49 91 318526485
|3||Lidia Ruiz Tabuenca||Retrovirology Laboratory IRSICAIXA Foundation |
Ctra. de Canyet s/n, 2nd Floor-Maternal Building
|Tel: +34 93 4656374 |
Fax: +34 93 4653968
|4||Bonaventura Clotet||Department of Retrovirology |
Hospital Universitari Germans Trias i Pujol
Ctra. de Canyet, s/n, 2nd Floor-Maternal Building
ES-08916 Badalona (Barcelona)
|Tel : +34 93 4656374 |
Fax : +34 93 4653968
|5||Claudia Balotta||Institute of Infectious and Tropical Diseases |
Luigi Sacco Hospital
University of Milan
Via G.B. Grassi 74
|Tel : +39 02 3820 0319 |
Fax: +39 02 3566644
|6||Francois Clavel||Inserm U552, IMEA, Hopital Bichat |
Institut National de la Santé et de la Recherche Médicale
46, rue Henri Huchard
|Tel: +33 1 40 25 63 63 |
Fax: +33 1 40 25 36 51
|7||Ben Berkhout||Department of Human Retrovirology |
University of Amsterdam
NL-1105 AZ Amsterdam
|Tel: +31 20 566 4822 |
Fax: +31 20 691 6531
|8||Dave Stammers||The Wellcome Trust Centre for Human Genetics |
Division of Structural Biology
Chancellor, Masters and Scholars of the University of Oxford
UK-OX3 7BN Oxford
|Tel: +44 1865 270043 |
Fax: +44 1865 280467
|9||Jan Balzarini||Rega Institute for Medical Research, |
Laboratory of Virology and Chemotherapy
Katholieke Universiteit Leuven
|Tel: +32 16 324063 |
Fax: +32 16 324198
|10||Charles A.B. Boucher and Monique Nijhuis||Department of Virology (G04.614) |
University Medical Center
NL-3584 CX Utrecht
|Tel: +31 30 250 6526 |
Fax: +31 30 250 5426