A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice.
A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice.
复制标题
CCR5拮抗剂maraviroc的局部菌心凝胶制剂可防止人源化rag-hu小鼠中的HIV-1阴道传播。
DOI：
10.1371/journal.pone.0020209
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Akkina R
中科院分区：
文献类型：
--
作者：
Neff CP;Kurisu T;Ndolo T;Fox K;Akkina R
为了预防艾滋病毒感染，许多目前获得许可的抗艾滋病毒药物和正在开发的新药物显示出作为局部应用的杀微生物剂的潜力。虽然猕猴模型一直是体内杀微生物剂测试的黄金标准，但它们价格昂贵，而且没有足够的数量。因此，在杀微生物剂领域迫切需要一种有助于快速评价潜在候选物的初步功效的小动物模型。我们先前证明RAG-hu人源化小鼠模型允许HIV-1通过阴道和直肠途径的粘膜传播，并且可以在该系统中测试口服暴露前化学预防策略。在这些概念验证研究中，我们将该系统扩展到使用HIV-1作为挑战病毒的局部杀微生物剂测试。Maraviroc是一种临床批准的用于HIV治疗的CCR 5抑制剂药物，在2.2%羟乙基纤维素中配制成5 mM浓度的杀微生物剂凝胶。在阴道内施用马拉韦罗凝胶后1小时，用HIV-1阴道攻击雌性RAG-hu小鼠。我们的结果表明，与安慰剂凝胶治疗的小鼠相比，马拉韦罗凝胶治疗的小鼠完全免受阴道HIV-1攻击，而安慰剂凝胶治疗的小鼠都被感染。这些发现突出了人源化小鼠模型用于杀微生物剂测试的实用性，并且与来自猕猴研究的最新数据一起，表明马拉韦罗是该领域未来杀微生物剂临床试验的有希望的候选者。
For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.
登录
查看更多内容
影响因子：
56.3
作者：
Cutler, Blayne;Justman, Jessica
通讯作者：
Justman, Jessica
直肠内传播，全身感染和感染HIV-1的人型小鼠的CD4+ T细胞耗竭。
影响因子：
15.3
作者：
Sun, Zhifeng;Denton, Paul W.;Estes, Jacob D.;Othieno, Florence A.;Wei, Bangdong L.;Wege, Anja K.;Melkus, Michael W.;Padgett-Thomas, Angela;Zupancic, Mary;Haase, Ashley T.;Garcia, J. Victor
通讯作者：
Garcia, J. Victor
影响因子：
3.8
作者：
Di Fabio, S;Giannini, G;Vella, S
通讯作者：
Vella, S
影响因子：
4.1
作者：
Veazey RS
通讯作者：
Veazey RS
影响因子：
--
作者：
An, Dong Sung;Poon, Betty;Uittenbogaart, Christel H.
通讯作者：
Uittenbogaart, Christel H.