Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1.
Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1.
复制标题
多含轮廓微生物化合物的施用和去除可增强HIV-1的随后感染。
DOI：
10.1186/1743-422x-9-33
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发表时间：
2012-01-26
期刊：
影响因子：
4.8
通讯作者：
Krebs FC
中科院分区：
文献类型：
--
作者：
Pirrone V;Passic S;Wigdahl B;Krebs FC
目前正在继续努力开发杀微生物剂，用于减少或消除HIV-1性传播的风险。不幸的是，涉及含聚阴离子的杀微生物剂制剂的临床试验，包括Carraguard（λ-角叉菜胶[LC]）和Ushercell（硫酸纤维素[CS]），表明这些产品无效，并且在某些情况下可能增加HIV-1感染的风险。这些发现促使重新评估这些药物的体外活性，以确定在临床前试验期间是否忽略了可能影响药物安全性和有效性的变量。一个这样的变量是局部施用后的产品保留和损失。在目前涉及HIV-1易感细胞系和原代人免疫细胞的研究中，通过在HIV-1感染前引入然后去除聚阴离子化合物来模拟产物损失。在这些体外“洗脱”实验中，LC和CS显着增强HIV-1感染，尽管与病毒同时引入时具有有效的抗病毒活性。这种效应的存在和程度取决于化合物的特性和浓度;靶细胞;化合物去除和病毒攻击之间的间隔;和辅助受体的使用。增强水平（相对于对照）相当可观，在P4-R5 MAGI细胞中超过200%的增加（CS），在人外周血单核细胞中超过300%的增加（LC）。这些研究表明，在应用和去除LC和CS后，HIV-1感染显著增加，支持对由这些化合物配制的杀微生物剂失效的合理解释。目前正在进行详细的研究，以确定这种增强效应的机制，并评估这种效应对这些药物临床失败的潜在贡献。
Continued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission. Unfortunately, clinical trials involving polyanion-containing microbicide formulations, including Carraguard (λ-carrageenan [LC]) and Ushercell (cellulose sulfate [CS]) demonstrated that these products were ineffective and may have, in some circumstances, increased the risk of HIV-1 infection. These findings prompted reassessments of the in vitro activities of these agents to determine whether variables that can affect agent safety and efficacy had been overlooked during preclinical testing. One such variable is product retention and loss following topical application. In the present studies involving an HIV-1-susceptible cell line and primary human immune cells, product loss was mimicked by introducing and then removing polyanionic compounds prior to HIV-1 infection. In these in vitro "washout" experiments, LC and CS significantly enhanced HIV-1 infection, despite potent antiviral activity when introduced simultaneously with the virus. The presence and magnitude of this effect were dependent on compound identity and concentration; target cell; interval between compound removal and virus challenge; and coreceptor usage. Levels of enhancement (relative to controls) were considerable, exceeding a 200% increase (CS) in P4-R5 MAGI cells and a 300% increase (LC) in human peripheral blood mononuclear cells. These studies, which demonstrate significant increases in HIV-1 infection subsequent to application and removal of LC and CS, support plausible explanations for the failures of microbicides formulated from these compounds. Detailed studies are now underway to determine the mechanism responsible for this enhancement effect and to assess the potential contribution of this effect to the clinical failures of these agents.