Effect of polymorphisms on the replicative capacity of protease inhibitor-resistant HIV-1 variants under drug pressure.

The role of drug pressure on the replicative capacity of protease inhibitor-resistant HIV-1 variants and the contribution of a common amino-acid polymorphism in the protease gene (L63P) to this process were investigated. Using HIV-1 variants resistant to the protease inhibitors saquinavir (G48V/L90M) or indinavir (A71V/V82T/I84V), viral replication was studied in the presence or absence of inhibitor and a mutation at position 63. The initial changes diminished enzyme function of the protease and reduced replicative capacity for both virus mutants. Addition of the respective inhibitor blocked the wild-type, but was also able to delay the replication kinetics of either mutant, revealing the limits of resistance. Importantly, the polymorphic change L63P, although not conferring inhibitor resistance by itself, provided a significant replication benefit to both mutant viruses, particularly under drug pressure, and may reveal a far-reaching compensating power of polymorphic changes. This may drive evolution and the directed selection of protease inhibitor-resistant HIV-1 variants, a finding with significant clinical and diagnostic implications.