Effect of the Q207D mutation in HIV type 1 reverse transcriptase on zidovudine susceptibility and replicative fitness.
Although present as polymorphisms in HIV-1 sequences from untreated patients, mutations at reverse transcriptase (RT) codon 207 are found at higher frequency in samples from zidovudine-treated patients. Introduction of the Q207D mutation into the RT of a zidovudine (ZDV)-resistant isolate by site-directed mutagenesis increased ZDV resistance 2.7-fold but had no effect on ZDV susceptibility when introduced into wild-type RT. Zidovudine-resistant recombinant HIV-1 with and without 207D showed comparable fitness in growth competition assays in the absence of ZDV, but this mutation enhanced the fitness of ZDV-resistant recombinants in the presence of drug. These results suggest that when present with other thymidine analogue resistance mutations, 207D serves as a resistance mutation that improves the fitness of ZDV-resistant HIV-1. Analyzing viral fitness can provide important insights into the role of polymorphisms in drug resistance.
Lu
Jing
J
Section of Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Whitcomb
Jeannette
J
Kuritzkes
Daniel R
DR
D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000235:genetics; D015215:Zidovudine / Q000494:pharmacology*
D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase