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J Virol, March 1998, p. 2335-2340, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Novel Point Mutation at Position 156 of Reverse Transcriptase from Feline Immunodeficiency Virus Confers Resistance to the Combination of (-)-beta -2',3'-Dideoxy-3'-Thiacytidine and 3'-Azido-3'-Deoxythymidine

Robert A. Smith,1,dagger Kathryn M. Remington,1,Dagger Bradley D. Preston,2 Raymond F. Schinazi,3 and Thomas W. North1,*

Division of Biological Sciences, the University of Montana, Missoula, Montana 598121; Departments of Biochemistry and Radiation Oncology, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 841122; and Georgia VA Research Center for AIDS and HIV Infections and Department of Pediatrics, Emory University School of Medicine, Decatur, Georgia 300333

Received 27 June 1997/Accepted 26 November 1997

Mutants of feline immunodeficiency virus (FIV) resistant to (-)-beta -2',3'-dideoxy-3'-thiacytidine (3TC) were selected by culturing virus in the presence of increasing stepwise concentrations of 3TC. Two plaque-purified variants were isolated from the original mutant population, and both of these mutants were resistant to 3TC. Surprisingly, these mutants were also phenotypically resistant to 3'-azido-3'-deoxythymidine (AZT) and to the combination of 3TC and AZT. Purified reverse transcriptase (RT) from one of these plaque-purified mutants was resistant to the 5'-triphosphates of 3TC and AZT. DNA sequence analysis of the RT-encoding region of the pol gene amplified from the plaque-purified mutants revealed a Pro-to-Ser mutation at position 156 of RT. A site-directed mutant of FIV engineered to contain this Pro-156-Ser mutation was resistant to 3TC, AZT, and the combination of 3TC and AZT, confirming the role of the Pro-156-Ser mutation in the resistance of FIV to these two nucleoside analogs. This represents the first report of a lentiviral mutant resistant to the combination of AZT and 3TC due to a single, unique point mutation.

* Corresponding author. Present address: Center for Comparative Medicine, University of California, Davis, CA 95616. Phone: (530) 752-3414. Fax: (530) 752-7914. E-mail: twnorth{at}ucdavis.edu.

dagger Present address: Departments of Biochemistry and Radiation Oncology, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112.

Dagger Present address: Bayer Corporation, Clayton, NC 27520.




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