Mutations that code for alterations of the conformational shape facilitate resistance of HIV to protease inhibitors. The locations of these mutations are primarily in the active site of the HIV protease enzyme as well as outside of the active site, including those at protease cleavage sites in the Gag-Pol polyprotein precursors. The cleavage sites have highly diverse sequences, so the protease recognizes its substrates not based on sequence but rather the conserved 3D shape the substrates share when bound at the active site. This conserved shape has been named the  substrate envelope. The active site mutations have been shown to directly change the interactions of the inhibitors, and mostly occur at positions where inhibitors contact protease residues beyond the substrate envelope. The non-active site mutations are considered to affect by other mechanisms, like influencing dimer stability and conformational flexibility.
Over 100 single gene point mutations have been described, of which at least 26 are specific to protease inhibitors. Of these, there are about 15 primary or major mutations that are significant enough to change drug activity.
Many mutated residues have been found in HIV-1 protease which cause drug resistance, for example Leu33 changes to Ile, Val, or Phe; Val82 to Ala, Phe, Leu, or Thr; Ile84 to Val; and Leu90 to Met. Different mutations affects different protease inhibitors. For instance, mutations at Leu90 evidently affect saquinavir and nelfinavir while indinavir activity is affected by mutations at Met46, Val82, and Ile84, and fosamprenavir is affected when Ile50 changes to Val and at Ile84. A combination of mutations can render high-level drug resistance but single mutations normally do not equate with drug resistance to protease inhibitors.
The mutations can be divided into primary mutations and secondary mutations. Primary mutations often have only a small effect on resistance. The chemical structures of most protease inhibitors are quite similar, so it is not surprising that some primary mutations lead simultaneously to resistance to multiple protease inhibitors. Cross-resistance is one of the major problems of protease inhibitor treatment. Additional mutations emerging in the protease during continuous protease inhibitor therapy are commonly referred to as secondary mutations. This can lead to high-level protease inhibitor resistance.
The Stanford HIV RT and Protease Sequence Database (also called the “HIV Drug Resistance Database”) was formed in 1998 with HIV reverse transcriptase and protease sequences from persons with well-characterized antiretroviral treatment histories, and is publicly available to query resistance mutations and genotype-treatment, genotype-phenotype, and genotype-outcome correlations
Although the substrate envelope provides the general strategy of designing inhibitors that mimic the substrate and stay within the envelope to avoid resistance conferred by most active site mutations, there is no general strategy to tackle the problem of drug resistance, especially due to those away from the active site. Researches directed towards development of new therapies to cure AIDS are focused on avoiding cross-resistance to drugs that are already on the market.