title: 3'-Azido-3'-deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1.
abstract: How antiretroviral drug resistance influences human immunodeficiency virus type 1 (HIV-1) evolution is not clear. This study tested the hypothesis that antiretroviral drugs such as 3'-azido-3'-deoxythymidine (AZT) can influence the in vivo mutation rate of HIV-1. It was observed that AZT can increase the rate of HIV-1 mutation by a factor of 7 in a single round of replication. In addition, (-)2',3'-dideoxy-3'-thiacytidine (3TC) was also found to increase the mutation rate of HIV-1 by a factor of 3. It was also found that HIV-1 drug-resistant reverse transcriptase (RT) variants can influence the in vivo mutation rate. Replication of HIV-1 with AZT-resistant RTs increased the mutation rate by as much as a factor of 3, while replication of HIV-1 with a 3TC-resistant RT (M184V) had no significant effect on the mutation rate. It was observed that only high-level, AZT-resistant RT variants could influence the in vivo mutation rate (i.e., M41L/T215Y and M41L/D67N/K70R/T215Y). In total, these observations indicate that both antiretroviral drugs and drug resistance mutations can influence the in vivo mutation rate of HIV-1.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, Ohio 43210, USA. mansky.3@osu.edu
authors.forename: L M
authors.initials: LM
authors.lastname: Mansky
authors.forename: L C
authors.initials: LC
authors.lastname: Bernard
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019556:COS Cells; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005822:Genetic Vectors; D054303:HIV Reverse Transcriptase / Q000502:physiology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D009154:Mutation; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine; D054303:HIV Reverse Transcriptase