Ex Vivo Comparison of Microbicide Efficacies for Preventing HIV-1 Genomic Integration in Intraepithelial Vaginal Cells
Ex Vivo Comparison of Microbicide Efficacies for Preventing HIV-1 Genomic Integration in Intraepithelial Vaginal Cells
复制标题
DOI：
10.1128/aac.00891-09
复制
发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Hladik, Florian
中科院分区：
文献类型：
--
作者：
McElrath, M. Juliana;Ballweber, Lamar;Hladik, Florian
阴道使用杀菌剂有望成为预防艾滋病毒性传播的一种策略。几种非特异性杀菌剂，包括聚阴离子硫酸纤维素，已经在大规模临床试验中进行了评估，但未能显示出显著的疗效。这些发现促使人们重新寻找能够预测杀微生物剂试验的负面结果的临床前测试系统。此外，潜在的局部杀微生物剂已经扩展到包括抗逆转录病毒药物，如逆转录酶、融合酶和整合酶抑制剂。使用一种新的阴道HIV-1感染的体外模型，我们比较了两种形式的融合抑制剂T-20、CCR5拮抗剂TAK-778、整合酶抑制剂118-D-24和硫酸纤维素（Ushercell）的预防潜力。通过优化的实时PCR检测，具有游离N端和c端氨基酸的T-20肽是最有效的化合物，对阴道上皮内白细胞病毒基因组整合的抑制作用显著高于水溶性N-乙酰化T-20肽（Fuzeon）（50%抑制浓度[IC50]， 0.153 μ M对51.2 μ M [0.687 ng/ml对230 ng/ml]； P < 0.0001）。相比之下，外周血细胞IC(50)s无显著差异（IC50, 13.58 μ M vs 7.57 μ M [61 ng/ml vs 34 ng/ml]; P = 0.0614）。硫酸纤维素是所有化合物中最不有效的（IC50为1.8 μ g/ml）。这些结果突出了我们的模型在筛选新型杀微生物剂及其配方的粘膜功效方面的优点，并有可能对临床评估的候选药物进行排序。
Vaginally applied microbicides hold promise as a strategy to prevent sexual HIV transmission. Several nonspecific microbicides, including the polyanion cellulose sulfate, have been evaluated in large-scale clinical trials but have failed to show significant efficacy. These findings have prompted a renewed search for preclinical testing systems that can predict negative outcomes of microbicide trials. Moreover, the pipeline of potential topical microbicides has been expanded to include antiretroviral agents, such as reverse transcriptase, fusion, and integrase inhibitors. Using a novel ex vivo model of vaginal HIV-1 infection, we compared the prophylactic potentials of two forms of the fusion inhibitor T-20, the CCR5 antagonist TAK-778, the integrase inhibitor 118-D-24, and cellulose sulfate (Ushercell). The T-20 peptide with free N- and C-terminal amino acids was the most efficacious compound, causing significantly greater inhibition of viral genomic integration in intraepithelial vaginal leukocytes, measured by an optimized real-time PCR assay, than the more water-soluble N- acetylated T-20 peptide (Fuzeon) (50% inhibitory concentration [IC50], 0.153 mu M versus 51.2 mu M [0.687 ng/ml versus 230 ng/ml]; P < 0.0001). In contrast, no significant difference in IC(50)s was noted in peripheral blood cells (IC50, 13.58 mu M versus 7.57 mu M [61 ng/ml versus 34 ng/ml]; P = 0.0614). Cellulose sulfate was the least effective of all the compounds tested (IC50, 1.8 mu g/ml). These results highlight the merit of our model for screening the mucosal efficacies of novel microbicides and their formulations and potentially rank ordering candidates for clinical evaluation.