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HIV RESISTANCE


HIV/AIDS

New Tools to Investigate and Suppress HIV Drug Resistance
Framework programme:
5
Project number:
QLK2-CT-2000-00291
EC contribution:
€ 1 826 279
Duration:
48 months
Type:
RS
Starting date:
1 September 2000

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.

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