Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments

↵ a Positions that were associated with PIs are in boldface.

↵ b aa, amino acid.

↵ c PIs, protease inhibitors.

↵ d Chi-square test of independence between presence of mutation and having received a PI.

↵ e Logistic regression of the occurrence of mutation on the number of PIs. P values are shown for the 62 variable positions. Coefficient, logistic regression coefficient.

↵ f Mutations occurring in five or more isolates listed in the order of frequency.

↵ g P values in bold were significant at an FDR of 0.01 following correction for multiple comparisons.

↵ h Newly described treatment-associated mutations.

↵ i A22V and N83D were significant at an FDR of 0.05.

↵ a The 43 positive correlations with phi of ≥0.20 and the 7 negative correlations with phi of ≤−0.20. Correlations between specific amino acids at these positions are shown for those cases where phi ≥ 0.15 or phi ≤ −0.15. Pos, position.

↵ b Substrate cleft residues are directly in contact with one or more inhibitors. Residues in the flap and at position L90M often directly confer or contribute to protease inhibitor resistance even though they are not in direct inhibitor contact. Accessory mutations contribute to resistance only when present with a mutation in the substrate cleft or flap or at position 90. Of the polymorphisms in this table, those at positions 35, 55, and 62 are significantly associated with drug therapy, whereas those at positions 12, 14, 19, 37, and 64 are not associated with drug therapy (Table 2). The nonpolymorphic residues at positions 75 and 79 are significantly associated with drug therapy (Table 2). The substrate cleft residues at positions 48 and 50 are also in the flap.

↵ c P values shown have not been corrected for multiple comparisons.

↵ d The distance between two residues was considered to be the shortest interatomic distance between each of the atoms in the two residues. Residues 82 and 54 are 8.3 Å apart in the 1hsg structure (3) but only 5.6 Å apart in the molecular-dynamics simulation, both described in Materials and Methods (23). The remaining distances are based on the 1hsg structure.