Tachedjian G, Mellors J, Bazmi H, Birch C, Mills J
National Centre in HIV Virology Research, Macfarlane Burnet Centre for Medical Research, Fairfield, Australia.
J Virol. 1996 Oct;70(10):7171-81. doi: 10.1128/JVI.70.10.7171-7181.1996.
Both foscarnet (PFA) and zidovudine (AZT) select for drug-resistant variants of human immunodeficiency virus type 1 (HIV-1), but the interactions between the mutations causing such resistance are unknown. The introduction 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-level AZT resistance. Two additional PFA resistance mutations, W88S and S156A, partially suppressed AZT resistance. Phenotypic reversion of AZT resistance by W88S, W88G, E89K, L921, and S156A was associated with a concomitant suppression of PFA resistance. The degree to which PFA resistance mutations reversed AZT resistance was directly correlated with each mutation's ability to confer high-level PFA resistance (> or = 5.0-fold) and AZT hypersusceptibility in a wild-type genetic background. Highly PFA-resistant HIV- 1 strains were hypersusceptible 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 resistance was relatively difficult to achieve. Strains selected by passage in PFA plus AZT were phenotypically PFA resistant and AZT susceptible despite multiple reverse transcriptase mutations known to confer AZT resistance. These data show that PFA resistance mutations can phenotypically 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-function studies of the HIV-1 reverse transcriptase.
膦甲酸钠（PFA）和齐多夫定（AZT）都会筛选出1型人类免疫缺陷病毒（HIV-1）的耐药变异株，但导致这种耐药性的突变之间的相互作用尚不清楚。将先前鉴定出的密码子88处的PFA耐药突变W88G、E89K、L92I或Q161L引入具有四个已知AZT耐药突变的HIV-1毒株中，可完全逆转高水平的AZT耐药性。另外两个PFA耐药突变W88S和S156A可部分抑制AZT耐药性。W88S、W88G、E89K、L92I和S156A导致的AZT耐药性表型逆转与同时出现的PFA耐药性抑制相关。PFA耐药突变逆转AZT耐药性的程度与每个突变在野生型基因背景下赋予高水平PFA耐药性（≥5.0倍）和AZT超敏感性的能力直接相关。高度耐PFA的HIV-1毒株对AZT超敏感；相反，具有M41L和T215Y、M41L、L210W和T215Y或M41L、D67N、K70R和T215Y突变的AZT耐药毒株对PFA的敏感性高2.2至2.5倍。用AZT和PFA联合对野生型或AZT耐药的HIV-1毒株进行长时间体外筛选，未能产生对两种药物均耐药的病毒，这表明双重耐药相对难以实现。尽管存在多个已知可赋予AZT耐药性的逆转录酶突变，但通过在PFA加AZT中传代筛选出的毒株在表型上对PFA耐药而对AZT敏感。这些数据表明，PFA耐药突变可在表型上逆转AZT耐药性，并且AZT耐药性和PFA耐药性可能是相互排斥的。AZT和PFA耐药性赋予突变之间的相互作用对HIV-1逆转录酶的结构-功能研究具有重要意义。
