Constrained evolution of human immunodeficiency virus type 1 protease during sequential therapy with two distinct protease inhibitors

Human immunodeficiency virus type I (HIV-1) variants that have developed pr otease (PR) inhibitor resistance most often display cross-resistance to sev eral molecules within this class of antiretroviral agents. The clinical ben efit of the switch to a second PR inhibitor in the presence of such resista nt viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (ID V), In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, w hile few additional mutations emerged. In viruses where no SQV resistance m utations were detected before the switch to IDV, typical SQV resistance pro files emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the t ime of the inhibitor switch. Viruses committed to resistance to the first i nhibitor appear to bear the "imprint" of this initial selection and ran fur ther adapt to the selective pressure exerted by the second inhibitor follow ing a pathway that preserves most of the initially selected mutations.