Susceptibilities of zidovudine-resistant variants of human immunodeficiency virus type 1 to inhibition by acyclic nucleoside phosphonates.
The acyclic purine nucleoside phosphonates, a newly described class of broad-spectrum antiviral agents, effectively inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro and in animal AIDS models. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is currently being evaluated in clinical trials in patients with AIDS. In this study, we investigated the efficacy of PMEA and a related analog, 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP), against HIV-1 isolates exhibiting various degrees of resistance to zidovudine (azidothymidine [AZT]). HIV isolates highly (approximately 50 to 200-fold) resistant to AZT were found to be about two- to eightfold less susceptible to PMEA. A comparable degree of cross-resistance to PMPDAP, a structurally related analog of PMEA, was also observed. However, the 50% effective dose values of PMEA or PMPDAP against a panel of HIV isolates showing intermediate levels (approximately 8 to 25-fold) of AZT resistance was indistinguishable from the 50% effective dose values of PMEA (0.7 to 1.7 versus 2 microM) or PMPDAP (0.4 to 1.4 versus 0.8 to 1 microM) against HIV isolates from patients who had not previously used AZT. In addition, we were unable to generate PMEA- (or PMPDAP)-resistant HIV-1 variants by > 30 serial passages of the virus in the presence of increasing concentrations of PMEA. Careful analysis of HIV-1 isolates from patients previously treated with AZT for cross-resistance to PMEA are needed to evaluate the significance of these observations.
Gong
Y F
YF
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
Marshall
D R
DR
Srinivas
R V
RV
Fridland
A
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000382:microbiology; D015215:Zidovudine / Q000494:pharmacology
C090125:9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine; D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D015215:Zidovudine; C053001:adefovir; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine