Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249
Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249
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DOI：
10.1073/pnas.0802666105
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发表时间：
2008-07-29
影响因子：
11.1
通讯作者：
Moore, John P.
中科院分区：
文献类型：
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作者：
Veazey, Ronald S.;Ketas, Thomas A.;Moore, John P.
我们已经评估了融合抑制肽T-1249作为一种阴道杀菌剂来预防HIV-1性传播的潜力。当以简单凝胶的形式配制时，T-1249为猕猴提供了剂量依赖的保护，以抵御使用CCR5或CXCR4感染的三种不同SHIV(115病毒Shiv-162P3、X4病毒Shiv-KU1和R5X4病毒Shiv-89.6P)的高剂量攻击，它还可以保护猕猴免受SIVmac251(115)的攻击。通过内插法估计，当T-1249的浓度接近40-130µM时，一半的实验动物得到了保护，而在0.1-2 mM的浓度下观察到了完全保护。在体外，T-1249对来自多个基因亚型的HIV-1毒株具有相当广泛的活性，并以辅助受体非依赖的方式发挥作用。因此，在基于外周血单核细胞的复制试验中，T-1249在1MU时抑制了测试组中的所有29种R5病毒、所有12种X4病毒和所有7种R5X4病毒，而不考虑它们的基因亚型。将较低浓度的T-1249与其他进入抑制剂(CMPD-167、BMS-C或AMD3465)相结合，可增加可被阻断的测试病毒的比例。在PhenoSense试验中，T-1249对来自临床样本的636种不同嗜性的HIV-1伪型病毒具有活性，IC50值通常在10倍范围内聚集，接近10 NM。总体而言，这些结果支持使用T-1249作为以进入抑制剂为基础的组合杀菌剂的一种成分的概念，以防止各种HIV-1变种的性传播。
We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the 115 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (115). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximate to 40-130 mu M, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 mu M in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC50 values typically clustered in a 10-fold range approximate to 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.