Mutation Patterns and Structural Correlates in HIV-1 Protease Following Varying Degrees of Protease Inhibitor Treatment
Thomas D. Wu, Celia A. Schiffer, Matthew J. Gonzales, Jonathan Taylor, Rami Kantor, Sunwen Chou, Dennis Israelski, Andrew R. Zolopa, W. Jeffrey Fessel, and Robert W. Shafer
Although many HIV-1-infected persons are treated with multiple protease inhibitors in combination or in succession, the patterns of protease mutations in isolates from these persons have not been characterized. We collected and analyzed 2,244 subtype B HIV-1 isolates from 1,919 persons with varying degrees of protease inhibitor experience: 1,004 isolates from untreated persons; 637 from persons who received one protease inhibitor; and 603 from persons receiving two or more protease inhibitors. The median number of protease mutations per isolate increased from four in untreated persons to 12 in persons who had received four or more protease inhibitors. Mutations at 45 of the 99 amino acid positions in the protease - including 22 not previously associated with drug resistance - were significantly associated with protease inhibitor treatment. Mutations at 17 of the remaining 99 positions were polymorphic but not associated with drug treatment. Pairs of correlated (covarying) mutations and mutational clusters were significantly more likely to occur in treated than in untreated persons, 113 vs 23 and 30 vs 2, respectively. Of the 115 covarying positions in the treated isolates, 59 were close to one another in the folded enzyme and 51 of the remaining 56 demonstrated chained covariation. In summary, nearly one-half of HIV-1 protease positions are under selective drug pressure - including many residues not previously associated with drug resistance. Structural factors appear to be responsible for the high rate of covariation between many of the protease residues. The presence of mutational clusters provides insight into the complex mutational patterns required for HIV-1 protease inhibitor resistance.
To download all data from this study click here
To download statistically significant correlation data click here