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.