AZT-resistant foamy virus.
Azidothymidine (AZT) is a reverse transcriptase (RT) inhibitor that efficiently blocks the replication of spumaretroviruses or foamy viruses (FVs). To more precisely elucidate the mechanism of action of the FV RT enzyme, we generated an AZT-resistant FV in cell culture. Biologically resistant virus was obtained for simian foamy virus from macaque (SFVmac), which was insensitive to AZT concentrations of 1 mM, but not for FVs derived from chimpanzees. Nucleotide sequencing revealed four non-silent mutations in the pol gene. Introduction of these mutations into an infectious molecular clone identified all changes to be required for the fully AZT-resistant phenotype of SFVmac. The alteration of individual sites showed that AZT resistance in SFVmac was likely acquired by consecutive acquisition of pol mutations in a defined order, because some alterations on their own did not result in an efficiently replicating virus, neither in the presence nor in the absence of AZT. The introduction of the mutations into the RT of the closely related prototypic FV (PFV) did not yield an AZT-resistant virus, instead they significantly impaired the viral fitness.
Kretzschmar
Benedikt
B
Universität Würzburg, Institut für Virologie und Immunbiologie, Versbacher Str. 7, 97078 Würzburg, Germany.
Nowrouzi
Ali
A
Hartl
Maximilian J
MJ
Gärtner
Kathleen
K
Wiktorowicz
Tatiana
T
Herchenröder
Ottmar
O
Kanzler
Sylvia
S
Rudolph
Wolfram
W
Mergia
Ayalew
A
Wöhrl
Birgitta
B
Rethwilm
Axel
A
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D015684:Gene Products, pol / Q000737:chemistry / Q000235:genetics; D015751:Genes, pol / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D053150:Simian foamy virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D014779:Virus Replication; D015215:Zidovudine / Q000494:pharmacology*
D015684:Gene Products, pol; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine