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Journal of Virology, November 2000, p. 10707-10713, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Genotypic, Phenotypic, and Modeling Studies of a Deletion in the 3-4 Region of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene That Is Associated with Resistance to Nucleoside Reverse Transcriptase Inhibitors

Mark A. Winters,^1,* Kristi L. Coolley,¹ Peng Cheng,² Yvette A. Girard,¹ Hasnah Hamdan,³ Ladislau C. Kovari,² and Thomas C. Merigan¹

Stanford University, Stanford,¹ and Quest Diagnostics, San Juan Capistrano,³ California, and Wayne State University, Detroit, Michigan²

Received 2 December 1999/Accepted 19 August 2000

Point mutations and inserts in the 3-4 region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are associated with resistance to nucleoside analog inhibitors. This report describes HIV-1 strains from seven patients that were found to have a 3-bp deletion in the 3-4 region of the RT gene. These patient strains also had a mean of 6.2 drug resistance-associated mutations in their RT genes (range, 3 to 10 mutations). The deletion was most frequently found in strains with the Q151M mutation. Nonnucleoside RT inhibitor mutations were found in six of seven strains. Culture-based drug sensitivity assays showed that deletion-containing isolates had reduced susceptibility to four to eight RT inhibitors. Site-directed mutagenesis experiments showed that the deletion alone conferred reduced susceptibility to nucleoside analogs. Changes in the three-dimensional models of the RT deletion mutants were consistently observed at the 3-4 loop and at helices C and E in both the presence and the absence of dTTP. Loss of hydrogen bonds between the RT and dTTP were also observed in the RT deletion mutant. These results suggest that the deletion in the RT gene contributes to resistance to several nucleoside analogs through a complex interaction with other mutations in the RT gene.

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^* Corresponding author. Mailing address: Stanford Medical Center, Room S156, 300 Pasteur Dr., Stanford, CA 94305. Phone: (650) 723-5715. Fax: (650) 725-2395. E-mail: mark.winters{at}stanford.edu.

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Journal of Virology, November 2000, p. 10707-10713, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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