Virological and clinical implications of resistance to HIV-I protease inhibitors

Resistance to HIV-1 protease inhibitors is associated with 25 or more amino acid substitutions in the protease and its cleavage sites. These appear in variable combinations and in different orders, and their effects depend on the combinations in which they occur. Substitutions within and away from the enzyme active site may engender resistance by drug-specific or drug-independent mechanisms. The correlates of resistance to the different protease inhibitors overlap substantially, and each can select for viral variants that are cross-resistant to others. An understanding of protease inhibitor resistance is critical for the appropriate use of these potent inhibitors of viral replication.