The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against HIV-2 than against HIV-1.
The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against HIV-2 than against HIV-1.
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核苷类似物 BMS-986001 的体外抗 HIV-2 活性高于抗 HIV-1。
DOI：
10.1128/aac.01326-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
UniversityofWashington-DakarHIV-2StudyGroup
中科院分区：
文献类型：
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作者：
Smith,RobertA;Raugi,DanaN;Wu,VincentH;Leong,SallyS;Parker,KateM;Oakes,MariahK;Sow,PapaSalif;Ba,Selly;Seydi,Moussa;Gottlieb,GeoffreyS;UniversityofWashington-DakarHIV-2StudyGroup
人类免疫缺陷病毒2型（HIV-2）感染者的治疗选择受到病毒对非核苷类逆转录酶抑制剂（NNRTI）的内在耐药性以及HIV-2对抗逆转录病毒治疗（ART）中使用的几种蛋白酶抑制剂（PI）敏感性降低的限制。为了鉴定用于HIV-2治疗的新的抗逆转录病毒药物，我们评价了研究性核苷类似物BMS-986001（2′，3 ′-二氨基-3 ′-脱氧-4 ′-乙炔基胸苷;也称为censavudine、festinavir、OBP-601、4′-乙炔基司他夫定或4′-乙炔基-d4 T）的体外活性。在单周期试验中，BMS-986001可抑制来自未接受过治疗个体的HIV-2分离株，50%有效浓度（EC 50）范围为30 - 81 nM。相比之下，HIV-1的M组和O组分离株的EC 50范围为450至890 nM。在所有检测的分离株中，HIV-2的平均EC 50比HIV-1低9.5倍（分别为64 ± 18 nM和610 ± 200 nM;平均值±标准差）。BMS-986001对HIV-2变异体也表现出完全活性，这些变异体的基因组编码逆转录酶中的单个氨基酸变化K65 R和Q151 M，而M184 V突变体对药物的耐药性是亲本HIV-2 ROD 9株的15倍。综上所述，我们的研究结果表明BMS-986001是HIV-2复制的有效抑制剂。据我们所知，BMS-986001是第一个核苷类似物，当针对不同的HIV-1和HIV-2分离株进行检测时，其对HIV-2的活性比对培养物中的HIV-1的活性更强。
Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated thein vitroactivity of the investigational nucleoside analog BMS-986001 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4′-ethynyl stavudine, or 4′-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC50s) ranging from 30 to 81 nM. In contrast, EC50s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC50for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ± 18 nM versus 610 ± 200 nM, respectively; mean ± standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2ROD9strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture.