3'-AZIDO-3'-DEOXYTHYMIDINE (AZT) MEDIATES CROSS-RESISTANCE TO NUCLEOSIDE ANALOGS IN THE CASE OF AZT-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VARIANTS

Difficulties in deciphering the mechanisms of 3'-azido-3'-deoxythymidi ne (AZT)-resistance by human immunodeficiency virus type 1 (HIV-1) var iants are due in part to an inability to reconstitute resistance in vi tro using AZT-resistant reverse transcriptases. We decided to characte rize mechanisms of AZT resistance in tissue culture infections by stud ying the ability of drug-resistant viruses to synthesize viral DNA in the presence or absence of drug. Through use of PCR amplifications, we discovered an AZT-mediated stimulation of reverse transcription by AZ T-resistant viruses carrying the M4IL and T215Y mutations that can app arently override the inhibitory effects of AZT-5'-triphosphate. In add ition, the presence of AZT also causes viruses containing the M41L and T215Y substitutions to have diminished sensitivity to other nucleosid e analogs (i.e., ddC, ddI, and d4T), This AZT-mediated cross-resistanc e may help to explain the virological failure of treatment regimens th at included ddI plus AZT or ddC plus AZT in situations in which the T2 15Y and/or M41L mutations were present (F. Brun-Vezinet, C. Boucher, C . Loveday, D. Descamps, V. Fauveau, J. Izopet, D. Jeffries, S. Kaye, C . Krzyanowski, A. Nunn, R. Schuurman, J. M. Seigneurin, C. Tamalet, R. Tedder, J. Weber, and G. J. Weverling, Lancet 350:983-990, 1997). Our results suggest that the use of AZT may be contraindicated in those p atients for whom resistance to this compound (M41L and/or T215Y) has b een demonstrated.