In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'-beta-Fluoro-2',3'-dideoxyadenosine.
2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA) is an acid-stable purine dideoxynucleoside analog active against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains in vitro. F-ddA is presently undergoing a phase I clinical trial at the National Cancer Institute. We induced HIV-1 variants resistant to F-ddA by exposing wild-type HIV-1 (HIV-1LAI) to increasing concentrations of F-ddA in vitro. After 18 passages, the virus was fourfold less sensitive to F-ddA than HIV-1LAI. Sequence analyses of the passage 18 virus revealed changes in three amino acids in the reverse transcriptase (RT)-encoding region of the pol gene: P to S at codon 119 (P119S; present in 3 of 13 and 28 of 28 molecular clones before and after F-ddA exposure, respectively), V179D (0 of 13 and 9 of 28, respectively), and L214F (9 of 13 and 28 of 28, respectively). Drug sensitivity assays using recombinant infectious clones confirmed that P119S was directly responsible for the reduced sensitivity of HIV-1 to F-ddA. Various infectious clones with single or multiple amino acid substitutions conferring viral resistance against nucleoside RT inhibitors, including HIV-1 variants with multi-dideoxynucleoside resistance, were generally sensitive to F-ddA. The moderate level of resistance of HIV-1 to F-ddA, together with the lack of conferment of significant cross-resistance by the F-ddA-associated amino acid substitutions, warrants further investigation of F-ddA as a potential antiviral agent for use in treatment of HIV-1 infection.
Tanaka
M
M
Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Srinivas
R V
RV
Ueno
T
T
Kavlick
M F
MF
Hui
F K
FK
Fridland
A
A
Driscoll
J S
JS
Mitsuya
H
H
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019556:COS Cells; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D054306:Dideoxynucleotides; D004352:Drug Resistance, Microbial; D015751:Genes, pol; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology
D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C037773:2',3'-dideoxyadenosine triphosphate; C073072:lodenosine; D015215:Zidovudine; D016048:Dideoxyadenosine; C052873:zidovudine triphosphate; D054303:HIV Reverse Transcriptase