G. Tachedjian et al., ZIDOVUDINE RESISTANCE IS SUPPRESSED BY MUTATIONS CONFERRING RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TO FOSCARNET, Journal of virology, 70(10), 1996, pp. 7171-7181
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.