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Journal of Virology, February 2003, p. 2071-2080, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.2071-2080.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Influence of Reverse Transcriptase Variants, Drugs, and Vpr on Human Immunodeficiency Virus Type 1 Mutant Frequencies

Louis M. Mansky,1* Erwann Le Rouzic,2 Serge Benichou,2 and Lisa C. Gajary1

Department of Molecular Virology, Immunology, and Medical Genetics, Center for Retrovirus Research, Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210,1 Department of Infectious Diseases, Institut Cochin, INSERM U567, CNRS UMR 8104, Paris, France2

Received 18 July 2002/ Accepted 23 October 2002

The evolution of drug resistance is a major complication of human immunodeficiency virus type 1 (HIV-1) chemotherapy. HIV-1 reverse transcriptase (RT) is a major target of antiretroviral therapy and ultimately the target of drug resistance mutations. Previous studies have indicated that drug-resistant HIV-1 RTs can alter HIV-1 mutant frequencies. In this study, we have tested a panel of HIV-1 RT variants for their ability to influence virus mutant frequencies. The RT variants tested included drug-resistant RT variants as well as other variants analyzed in enzyme fidelity studies with the lacZ{alpha} gene as a mutation target and/or implicated as being important for enzyme fidelity by structural studies. Combinations of mutations that alone had a statistically significant influence on virus mutant frequencies resulted in different mutant frequency phenotypes. Furthermore, when virus replication occurred in the presence of drugs [e.g., 3'-azido-3'-deoxythymidine, (-)2/,3'-dideoxy-3'-thiacytidine, hydroxyurea, thymidine, or thioguanine] with selected RT variants, virus mutant frequencies increased. Similarly, Vpr variants deficient for binding to the uracil DNA glycosylase repair enzyme were observed to influence HIV-1 virus mutant frequencies when tested alone or in combination with RT variants. In summary, these observations indicate that HIV-1 mutant frequencies can significantly change by single amino acid substitutions in RT and that these effects can be altered by additional mutations in RT, by drugs, and/or by expression of Vpr variants. Such altered virus mutant frequencies could impact HIV-1 dynamics and evolution in small population sizes.

* Corresponding author. Mailing address: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, 2078 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210. Phone: (614) 292-5525. Fax: (614) 292-9805. E-mail: mansky.3{at}osu.edu.

Journal of Virology, February 2003, p. 2071-2080, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.2071-2080.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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