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 immunodefi ciency virus type 1 (HIV-1) replication in vitro and in animal AIDS mo dels. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is currently being ev aluated in clinical trials in patients with AIDS. In this study, we in vestigated the efficacy of PMEA and a related analog, 9-(2-phosphonylm ethoxypropyl)diaminopurine (PMPDAP), against HIV-1 isolates exhibiting various degrees of resistance to zidovudine (azidothymidine [AZT]). H IV isolates highly (similar to 50 to 200-fold) resistant to AZT were f ound to be about two- to eightfold less susceptible to PMEA. A compara ble degree of cross-resistance to PMPDAP, a structurally related analo g of PMEA, was also observed. However, the 50% effective doses values of PMEA or PMPDAP against a panel of HIV isolates showing intermediate levels (similar to 8 to 25-fold) of AZT resistance was indistinguisha ble from the 50% effective dose values of PMEA (0.7 to 1.7 versus 2 mu M) or PMPDAP (0.4 to 1.4 versus 0.8 to 1 mu M) against HIV isolates f rom patients who had not previously used AZT. In addition, we were una ble to generate PMEA- (or PMPDAP)-resistant HIV-1 variants by >30 seri al passages of the virus in the presence of increasing concentrations of PMEA. Careful analysis of HIV-1 isolates from patients previously t reated with AZT for cross-resistance to PMEA are needed to evaluate th e significance of these observations.