In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat)
In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat)
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DOI：
10.1128/jvi.01369-06
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发表时间：
2006-11-01
影响因子：
5.4
通讯作者：
Freed, Eric O.
中科院分区：
文献类型：
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作者：
Adamson, Catherine S.;Ablan, Sherimay D.;Freed, Eric O.
3- o -（3',3'-二甲基琥珀酰）白桦酸（PA-457或bevirimat）通过阻断Gag加工途径的一个后期步骤，特别是从衣壳（CA） C端切割SP1，有效抑制人类免疫缺陷病毒1型（HIV-1）的成熟。为了深入了解HIV-1对PA-457产生耐药性的机制，并评估在PA-457治疗的患者中产生这种耐药性的可能性，我们试图识别和表征能够对该化合物产生耐药性的广泛的HIV-1变异。多次独立的选择反复确定了6个独立赋予PA-457抗性的单氨基酸取代：三个位于CA的C端或附近（CA- h226y， -L231F和-L231M），三个位于SP1的第一个和第三个残基（SP1- a1v， -A3T和-A3V）。我们确定CA-H226Y、CA-L231F、CA-L231M和SP1-A1V突变不会对培养中的HIV-1造成显著的复制缺陷。相反，突变SP1-A3V和-A3T严重破坏病毒复制，抑制病毒核凝聚。SP1-A3V造成的复制缺陷被CA （CA- g225s）的二位点代偿性突变逆转。有趣的是，高浓度的PA-457促进了SP1残基3突变体的成熟。与赋予PA-457抗性的突变相关的不同表型表明存在多种机制，通过这些机制HIV-1可以进化出对这种成熟抑制剂的抗性。这些发现对PA-457在体内治疗HIV-1感染的持续发展具有启示意义。
3-O-(3',3'-dimethylsuceinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.