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Journal of Virology, April 2003, p. 4836-4847, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4836-4847.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Thomas D. Wu,1,{dagger} Celia A. Schiffer,2 Matthew J. Gonzales,3 Jonathan Taylor,4 Rami Kantor,3 Sunwen Chou,5 Dennis Israelski,3 Andrew R. Zolopa,3 W. Jeffrey Fessel,6 and Robert W. Shafer3*

Department of Biochemistry,1 Division of Infectious Diseases, Department of Medicine,3 Department of Statistics, Stanford University, Stanford,4 AIDS Research, Kaiser-Permanente, Northern California, San Francisco, California,6 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts,2 Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon5

Received 13 September 2002/ Accepted 14 January 2003

Although many human immunodeficiency virus type 1 (HIV-1)-infected persons are treated with multiple protease inhibitors in combination or in succession, mutation patterns of protease isolates from these persons have not been characterized. We collected and analyzed 2,244 subtype B HIV-1 isolates from 1,919 persons with different protease inhibitor experiences: 1,004 isolates from untreated persons, 637 isolates from persons who received one protease inhibitor, and 603 isolates from persons receiving two or more protease inhibitors. The median number of protease mutations per isolate increased from 4 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 and clusters of correlated (covarying) mutations were significantly more likely to occur in treated than in untreated persons: 115 versus 23 pairs and 30 versus 2 clusters, respectively. Of the 115 statistically significant pairs of covarying residues in the treated isolates, 59 were within 8 Å of each other—many more than would be expected by chance. 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 frequency of covariation among many of the protease residues. The presence of mutational clusters provides insight into the complex mutational patterns required for HIV-1 protease inhibitor resistance.

* Corresponding author. Mailing address: Division of Infectious Diseases, Room S-156, Stanford University, Stanford, CA 94305. Phone: (650) 725-2946. Fax: (650) 723-8596. E-mail: rshafer{at}stanford.edu.

{dagger} Present address: Genentech, Inc., South San Francisco, Calif.

Journal of Virology, April 2003, p. 4836-4847, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4836-4847.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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