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HIV RESISTANCE
HIV/AIDS
Framework programme: 5
Project number:
QLK2-CT-2000-00291
EC contribution: € 1 826 279
Duration: 48 months
Type: RS
Starting date: 1 September 2000
Graphic element New Tools to Investigate and Suppress HIV Drug Resistance
Keywords: AIDS; human immunodeficiency virus (HIV); feline immunodeficiency virus (FIV); reverse transcriptase; dimerisation; drug resistance; error catastrophe; nonnucleoside reverse transcriptase inhibitors (NNRTIs); nucleoside RT inhibitors (NRTIs); RT-FHIV; chemotherapy; antimetabolites

Summary:

New drugs will be developed by targeting new amino acids in the non-nucleoside binding pocket of HIV-1 reverse transcriptase (RT) that are less prone to be mutated (i.e. W229, Y318 and N136/137), including the dimerisation interphase of the heterodimeric enzyme (i.e. the 134SINNET139 stretch in the p51 subunit of HIV-1 RT). Antimetabolites (i.e. purine nucleoside phosphorylase inhibitors) will be used in an attempt to modify the resistance spectrum of NRTIs and NNRTIs and to select for attenuated mutant virus strains. Several HIV-1 and FIV RTs in which one or several amino acids or amino acid blocks have been exchanged, and a RT FHIV [hybrid between HIV and feline immunodeficiency virus (FIV) in which the RT gene of HIV-1 has been placed in the FIV genetic background] will be constructed and developed to allow investigation of NNRTI drug resistance in an in vivo (cat) model.

Problem:

Resistance to the currently available drugs is one of the major obstacles to achieve a long-term suppression of HIV in drug-treated HIV-infected individuals. There is a direct correlation between drug resistance and deterioration of the clinical status of the treated individuals. Therefore, drug resistance development deserves careful attention in future treatment strategies.

Aim:

New avenues will be explored to develop alternative approaches to address HIV drug resistance more efficiently by developing new types of drugs and novel treatment modalities.

Expected results:

The non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) may become the cornerstone of future HIV treatment modalities when resistance can be adequately suppressed or avoided. Therefore, this proposal is entirely focused on this resistance issue. New (or modified) NNRTIs will be targeted and fine-tuned to those interaction points in the HIV-1 RT that are unable to mutate without heavily compromising the integrity of the RT and the fitness of HIV-1. In addition, entirely new targets on HIV RT (i.e. the interphase at the binding between both p66 and p51 subunits of the enzyme) will be explored and characterised, and new drugs (either non-nucleoside small molecules, or short peptides) will be designed and synthesised in an attempt to disturb the action of HIV RT. The role of endogenous nucleotide pool ratios in the HIV-infected cells on drug resistance development will be investigated, with the aim to force the virus to use alternative (and less optimal) drug-resistant patterns upon drug combination with antimetabolites in order to weaken the fitness and resistance level of the virus mutants. Also carefully selected RNA mutagens will be investigated on their potential role to hypermutate the RNA genome of HIV in a selective manner, causing error catastrophe in HIV. Cells from different body compartments, including T-lymphocytes and macrophages will be included in this study. In contrast with nucleoside RT inhibitors (NRTIs), there is a gap between in vitro research and clinical investigation of the NNRTIs, due to the lack of an appropriate animal model that can address important issues, in particular drug resistance, in a preclinical setting. Therefore, NNRTI-sensitive feline immunodeficiency virus (FIV) RTs and FIVs (RT-FHIVs) will be designed, constructed and generated to allow the establishment of a useful and representative small animal (cat) model for studying the NNRTI resistance patterns in vivo.

Potential applications:

Pharmaceutical and biotechnological companies will be involved in a later stage of the research to develop the novel drugs and concepts to the clinic. HIV-infected individuals will benefit from the outcome of the research project.

Coordinator:

Jan Balzarini
Rega Institute for Medical Research
Minderbroedersstraat 10
3000 Leuven
Belgium
Tel: +3216 337352
Fax: +32 16 337340
E-mail: jan.balzarini@rega.kuleuven.ac.be

Partners:

Principal
Scientific
Participants
Official Address Other Information
2M.-J. CamarasaInstituto de Química Médica, Consejo Superior Investigaciones Científicas
Juan de la Cierva 3
ES-28006 Madrid
Spain
Tel: +34 91 562 2900
Fax: +34 91 5644853
E-mail: mj.camarasa@iqm.csic.es
3H. EgberinkDepartment of Infectious Diseases and Immunology
Institute of Virology, Veterinary Faculty
Yalelaan 1
NL-3584 CL Utrecht
The Netherlands
Tel: +31 30 2532485
Fax: +31 30 2536723
E-mail: h.egberink@vet.uu.nl
4E. GagoDepartment of Pharmacology, University of Alcada
ES-28871 Alcade de Henares, Madrid
Spain
Tel: +34 918 854514
Fax: +34 918 854591
E-mail: fgago@uah.es
5A. KarlssonKarolinska Institute
Division of Clinical Virology
F68 Huddinge University Hospital
SE-141 86 Huddinge/Stockholm
Sweden
Tel: +46 8 58587932
Fax: +46 8 58587933
E-mail: anna.karlsson@mbb.ki.se
6C-F. PernoDepartment of Experimental Medicine
University of Rome ‘Tor Vergata’
Via Montpellier 1
IT-00135 Rome
Italy
Tel: +39 06 7259 6553
Fax: +39 06 7259 6552
E-mail: cf.perno@uniroma2.it
7D. StammersStructural Biology Division
Wellcome Trust Centre for Human Genetics
University of Oxford
Roosevelt Drive
UK-OX3 7BN Oxford
United Kingdom
Tel: +44 1865 287565
Fax: +44 1865 287547
E-mail: daves@strubi.ox.ac.uk
8B. ÖbergMedivir AB
Lunastigen 7
SE-14144 Huddinge
Sweden
Tel: +46 8 6083 1116
Fax: +46 8 6083 3199/+46 8 331.399
E-mail: bo.oberg@medivir.se

 
 
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