Influence of reverse transcriptase variants, drugs, and Vpr on human immunodeficiency virus type 1 mutant frequencies.
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 lacZalpha 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.
Mansky
Louis M
LM
Department of Molecular Virology, Immunology, and Medical Genetics, Center for Retrovirus Research, Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210, USA. mansky.3@osu.edu
Le Rouzic
Erwann
E
Benichou
Serge
S
Gajary
Lisa C
LC
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D016336:Gene Products, vpr / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D009154:Mutation; D013866:Thioguanine / Q000494:pharmacology; D054325:vpr Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D054303:HIV Reverse Transcriptase; D013866:Thioguanine