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J Virol, June 1998, p. 5093-5098, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Novel Polymorphism at Codon 333 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Can Facilitate Dual Resistance to Zidovudine and L-2',3'-Dideoxy-3'-Thiacytidine

Sharon D. Kemp,1,dagger Chaofu Shi,2 Stuart Bloor,1,dagger P. Richard Harrigan,1,Dagger John W. Mellors,2,3,4 and Brendan A. Larder1,*

Clinical Virology Research Unit, Medicines Research Centre, Glaxo Wellcome Research and Development, Stevenage, United Kingdom,1 and Department of Infectious Diseases and Microbiology, Graduate School of Public Health,2 and Department of Medicine, School of Medicine,3 University of Pittsburgh, and Veterans Affairs Medical Center,4 Pittsburgh, Pennsylvania

Received 8 September 1997/Accepted 3 March 1998

Recent clinical trials examining 3'-azido-3'-deoxythymidine (AZT, zidovudine, or Retrovir) combined with L-2',3'-dideoxy-3'-thiacytidine (3TC or lamivudine) have shown that combination therapy with these nucleoside analogs affords significant virological and clinical benefits. The addition of 3TC to AZT delays AZT resistance in therapy-naive patients and can restore viral AZT susceptibility in patients who previously received AZT alone. In some AZT-experienced patients, the virological response to AZT-3TC therapy is not sustained and virus resistant to both drugs can be identified. To gain insight into the possible mechanism of dual resistance, we studied a recently described variant resistant to both AZT and 3TC and obtained by simultaneous passage of an AZT-resistant clinical isolate in cell culture with AZT and 3TC. Genetic mapping and site-directed mutagenesis experiments demonstrated that a polymorphism at codon 333 (Gly to Glu) of human immunodeficiency virus type 1 reverse transcriptase (RT) was critical in facilitating dual resistance in a complex background of AZT and 3TC resistance mutations. To assess the potential clinical relevance of RT codon 333 changes, we studied dually resistant viruses from patients taking AZT and 3TC. Genetic mapping of RT molecular clones derived from patients' plasma samples demonstrated that in some cases polymorphism at codon 333 was responsible for facilitating dual resistance.

* Corresponding author. Present address: Virco UK, 162A Cambridge Science Park, Milton Rd., Cambridge CB4 4GH, United Kingdom. Phone: 44 1 223 425 450. Fax: 44 1 223 423 456. E-mail: brendan.larder{at}viro.co.uk.

dagger Present address: Virco UK, 162A Cambridge Science Park, Cambridge CB4 4GH, United Kingdom.

Dagger Present address: BC Center for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.

J Virol, June 1998, p. 5093-5098, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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