NOVEL MUTATION (K70E) IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE CONFERS DECREASED SUSCEPTIBILITY TO 9-[2-(PHOSPHONOMETHOXY)ETHYL]ADENINE IN-VITRO

9-[2-(Phosphonomethoxy)ethyl] adenine (PMEA), an acyclic nucleoside ph osphonate analog, is active against several retroviruses and herpesvir uses and has shown anti-human immunodeficiency virus (HIV) activity in clinical trials. Serial passage of HIV type 1 (strain IIIb) in MT2 ce lls in increasing concentrations of PMEA resulted in viruses with > 12 -fold increases in their 50% inhibitory concentrations of PMEA compare d with that for strain IIIb. Sequence analyses of these PMEA-selected viruses demonstrated the presence of a novel lysine-to-glutamic acid m utation at amino acid 70 (K70E) in HIV reverse transcriptase. A recomb inant virus carrying the K70E mutation was constructed and showed a 10 -fold increase in its 50% inhibitory concentrations of PMEA and 2',3'- dideoxy-3'-thiacytidine but showed wild-type susceptibility levels to 2',3'-dideoxycytosine, 2',3'-dideoxyinosine, 2',3'-didehydro-2',3'-did eoxythymidine, 3'-azido-3'-deolrythymidine, foscarnet, and two additio nal phosphonates, 9-[(R)-2-(phosphonomethoxy)propyl] adenine and 9-[2, 5-dihydro-5-(phosphonomethoxy) -2-furanyl]adenine. Additionally, the K 70E recombinant showed a minor reduction in growth kinetics compared w ith those of the wild-type virus in vitro.