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Antimicrobial Agents and Chemotherapy, October 1998, p. 2637-2644, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from Patients Treated with the Protease Inhibitor Nelfinavir

A. K. Patick,1,* M. Duran,2 Y. Cao,2 D. Shugarts,3 M. R. Keller,1 E. Mazabel,1 M. Knowles,1 S. Chapman,1 D. R. Kuritzkes,3 and M. Markowitz2

Agouron Pharmaceuticals, Inc., San Diego, California 921211; Aaron Diamond AIDS Research Center, New York, New York 100162; and University of Colorado Health Sciences Center, Denver, Colorado 802623

Received 27 January 1998/Returned for modification 6 April 1998/Accepted 1 July 1998

Nelfinavir mesylate (formerly AG1343) is a potent and selective inhibitor of human immunodeficiency virus (HIV) protease approved for the treatment of individuals infected with HIV. Nucleotide sequence analysis of protease genes from plasma HIV type 1 (HIV-1) RNA revealed a unique aspartic acid (D)-to-asparagine (N) substitution at residue 30 (D30N) in 25 of 55 patients treated with nelfinavir for a median of 13 weeks. Although the appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes (e.g., at residues 35, 36, 46, 71, 77, and 88), genotypic changes associated with phenotypic resistance to other protease inhibitors were not observed (e.g., at residues 48, 50, 82, and 84) or were only rarely observed (e.g., at residue 90). In phenotypic assays, viral isolates with high-level resistance to nelfinavir remained susceptible to indinavir, saquinavir, ritonavir, and amprenavir (formerly VX-478/141W94). Similar results were observed in phenotypic assays utilizing HIV-1 NL4-3, which contained the D30N substitution alone or in combination with substitutions at other residues (e.g., residues 46, 71, and 88). These data indicate that the initial pathway of resistance to nelfinavir is unique and suggest that individuals failing short courses of nelfinavir-containing regimens may respond to regimens containing other protease inhibitors.

* Corresponding author. Mailing address: Department of Virology, Agouron Pharmaceuticals, Inc., 4245 Sorrento Valley Blvd., San Diego, CA 92121. Phone: (619) 622-3117. Fax: (619) 622-5999. E-mail: patick{at}agouron.com.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2637-2644, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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