ABSTRACT:
Treatment with HIV protease inhibitors (PIs) can lead to class cross-resistance, rendering all current PIs less effective. Since considerable numbers of patients failing HAART harbor PI-resistant virus, the development of new PIs active against these variants is an urgent priority. Unlike all available PIs, tipranavir is a new non-peptide PI that binds in a flexible manner to the protease active site, making it potentially active against HIV resistant to all approved peptide PIs. To investigate this hypothesis, we tested over 125 clinical isolates with varying degrees of cross-resistance to indinavir, ritonavir, nelfinavir and saquinavir in a recombinant phenotypic assay. These isolates ranged from having resistance to a single PI with a limited number of PI mutations to those highly co-resistant and containing six to eight protease mutations.
In total, 85 isolates had >10-fold resistance to all four PIs. Of these, 74 (87%) remained completely susceptible to tipranavir, or even showed 5-10-fold hypersensitivity. Only 3/85 (4%) had IC50 values >10-fold that of a wild-type control and 7/85 (8%) had intermediate resistance levels (4-10-fold). Isolates containing combinations of 48V/82A/90M, plus secondaryš PI mutations were all tipranavir-susceptible (hypersensitiveity was also associated with 48V/82A). Common genotypic patterns in HIV with >four-fold reduced susceptibility included the uncommon 82T/84V combination, or 84V/90M (plus four to six secondary PI mutations). Interestingly, many additional isolates harboring 84V/90M remained tipranavir-susceptible. It is anticipated that mutagenesis and cell passage studies should further help to elucidate the precise nature of tipranavir resistance. This remarkable lack of PI cross-resistance makes tipranavir and attractive candidate as a new generation PI.
