1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

HIV-1 VARIANTS CARRYING RESISTANCE MUTATIONS TO SAQUINAVIR ARE NOT PRE-DISPOSED TO RESISTANCE TO OTHER PROTEASE INHIBITORS IN VITRO

Antiviral Therapy 1997;2 (Suppl 5):15 (abstract no. 23)

SM Gilbert, E Race, AR Moffatt, JG Sheldon and N Cammack
Roche Research Centre, Welwyn Garden City, UK

Reduction of sensitivity to saquinavir in vitro and in vivo is associated with G48V and L90M amino acid changes. These mutations alone do not confer resistance to ritonavir or indinavir, which have been mainly associated with amino acid changes V82F, M46I and I84V. Sequential or combination therapy with protease inhibitors must maximize the clinical benefit from each drug. We have examined in vitro the potential for resistance to ritonavir or indinavir to arise from a genetic background conferring resistance to saquinavir.

G48V and L90M mutations were selected by passage 11 of HIV-1GB8 (GB8) in the presence of increasing concentrations of saquinavir. The passage 11 virus (GB8(SR)) showed a 60-fold increase in IC₅₀ to saquinavir with no significant change in sensitivity to ritonavir or indinavir. GB8(SR) was subsequently passaged in the presence of increasing concentrations of ritonavir or indinavir in parallel with wild-type GB8. By passage 8 of GB8 in the presence of ritonavir, amino acid changes V32I and V82A had been selected and an additional M46V mutation appeared in passage 10. In contrast, passage 8 of GB8(SR) in the presence of ritonavir showed V32I and M46I amino acid changes, a V82F amino acid change did not appear until passage 10.

These genotypic changes were accompanied by a 30-fold increase in ritonavir IC₅₀ for GB8, but only a five-fold increase in IC₅₀ for GB8(SR) when compared to the parent virus. There was no reduction in sensitivity for either passage 10 virus when tested against saquinavir.

Selection of indinavir resistance on a background of saquinavir resistance has proved difficult. By passage 14 only a single clone of GB8(SR) expressed V82A and M46I mutations, where the 90M and 48V had reverted to wild-type. These passages are continuing.

Ritonavir-associated mutations were selected on a background of saquinavir-selected mutations. The mutations occurred at the same positions in the protease gene for both GB8 and GB8(SR), but the order of appearance and the amino acid changes were different. The resulting reduction in sensitivity to ritonavir was less in GB8(SR) than in GB8.

Saquinavir-associated resistance mutations do not predispose the virus to an increased rate of appearance of ritonavir-associated mutations or to a greater decrease in sensitivity to ritonavir.

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1997-06-25
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