In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'-beta-Fluoro-2',3'-dideoxyadenosine.

Abstract

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.

• Authors: M Tanaka, R V Srinivas, T Ueno, M F Kavlick, F K Hui, A Fridland, J S Driscoll, H Mitsuya
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 41 Issue 6 Pg. 1313-8 (Jun 1997) ISSN: 0066-4804 [Print] United States
• PMID: 9174190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• Deoxyadenine Nucleotides
• Dideoxynucleotides
• Reverse Transcriptase Inhibitors
• Thymine Nucleotides
• 2',3'-dideoxyadenosine triphosphate
• lodenosine
• Zidovudine
• Dideoxyadenosine
• zidovudine triphosphate
• HIV Reverse Transcriptase

Topics

• Animals
• Anti-HIV Agents (pharmacology)
• COS Cells
• Deoxyadenine Nucleotides (pharmacology)
• Dideoxyadenosine (analogs & derivatives, pharmacology)
• Dideoxynucleotides
• Drug Resistance, Microbial
• Genes, pol
• HIV Reverse Transcriptase (drug effects, metabolism)
• HIV-1 (drug effects, genetics)
• Humans
• Microbial Sensitivity Tests
• Mutation
• Reverse Transcriptase Inhibitors (pharmacology)
• Thymine Nucleotides (pharmacology)
• Zidovudine (analogs & derivatives, pharmacology)