ZIDOVUDINE RESISTANCE IS SUPPRESSED BY MUTATIONS CONFERRING RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TO FOSCARNET

Both foscarnet (PFA) and zidovudine (AZT) select for drug-resistant va riants of human immunodeficiency virus type 1 (HIV-1), but the interac tions between the mutations causing such resistance are unknown. The i ntroduction of the previously identified PFA resistance mutation W to G at codon 88 (W88G), E89K, L92I, or Q161L into an HIV-1 strain having the four known AZT resistance mutations completely reversed high-leve l AZT resistance. Two additional PFA resistance mutations, W88S and S1 56A, partially suppressed AZT resistance. Phenotypic reversion of AZT resistance by W88S, W88G, E89K, L92I, and S156A was associated with a concomitant suppression of PFA resistance. The degree to which PFA res istance mutations reversed AZT resistance was directly correlated with each mutation's ability to confer high-level PFA resistance (greater than or equal to 5.0-fold) and AZT hypersusceptibility in a wild-type genetic background. Highly PFA-resistant HIV-1 strains were hypersusce ptible to AZT; conversely, AZT-resistant strains with M41L and T215Y; M41L, L210W, and T215Y; or M41L, D67N, K70R, and T215Y mutations were 2.2- to 2.5-fold hypersusceptible to PFA. Prolonged in vitro selection of wild-type or AZT-resistant HIV-1 strains with the combination AZT and PFA failed to generate coresistant virus, indicating that dual res istance was relatively difficult to achieve. Strains selected by passa ge in PFA plus AZT were phenotypically PFA resistant and AZT susceptib le despite multiple reverse transcriptase mutations known to confer AZ T resistance, These data show that PFA resistance mutations can phenot ypically reverse AZT resistance and that AZT and PFA resistance might be mutually exclusive. The reciprocal interactions between AZT and PFA resistance-conferring mutations have implications for structure-funct ion studies of the HIV-1 reverse transcriptase.