Stolte-Leeb Nicole, Loddo Roberta, Antimisiaris Sophia, Schultheiss Tina, Sauermann Ulrike, Franz Monika, Mourtas Spyridon, Parsy Christophe, Storer Richard, La Colla Paolo, Stahl-Hennig Christiane
Unit "Infection Models," Deutsches Primatenzentrum GmbH, Goettingen, Germany.
AIDS Res Hum Retroviruses. 2011 Sep;27(9):933-43. doi: 10.1089/AID.2010.0339. Epub 2011 Mar 23.
The availability of an effective vaginal microbicide would be a major step toward containment of HIV transmission as well as allowing women self-protection against HIV infection. Here we evaluated the efficacy of vaginal application of the potent nonnucleoside reverse transcriptase inhibitor (NNRTI) MC 1220 against vaginal challenge of macaques with RT-SHIV, a chimeric simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT) gene of HIV-1. Challenge infection of monkeys with RT-SHIV currently represents the only nonhuman primate model available to test the anti-HIV-1 effects of NNRTIs. Two different gel formulations containing different MC 1220 concentrations were evaluated for efficacy in female rhesus macaques exposed to RT-SHIV. Five groups of five animals each were treated with two different gel compositions containing no drug, 0.1% or 0.5% MC 1220, followed by vaginal RT-SHIV challenge 30 min later. One animal in each group treated with the low concentration of MC 1220 as well as one control animal remained uninfected after vaginal challenge. By contrast, three of the animals receiving 0.5% MC 1220 remained uninfected, suggesting a threshold of the drug. Despite being negative for plasma viral RNA and absence of seroconversion, almost all uninfected animals exhibited SIV-specific T cells, either in the periphery or in lymph nodes draining the portal of virus entry. Our results make MC 1220 a promising compound for further development as a topical microbicide and warrant additional testing with improved formulation, long-lasting vaginal delivery systems, or even combinations with other inhibitors.
一种有效的阴道杀微生物剂的出现将是朝着控制艾滋病毒传播以及让女性自我保护免受艾滋病毒感染迈出的重要一步。在此，我们评估了强效非核苷类逆转录酶抑制剂（NNRTI）MC 1220经阴道给药对猕猴进行RT-SHIV阴道攻击的疗效，RT-SHIV是一种嵌合猿猴免疫缺陷病毒（SIV），含有HIV-1的逆转录酶（RT）基因。用RT-SHIV对猴子进行攻击感染目前是可用于测试NNRTIs抗HIV-1作用的唯一非人灵长类动物模型。评估了含有不同MC 1220浓度的两种不同凝胶制剂对暴露于RT-SHIV的雌性恒河猴的疗效。将五组，每组五只动物分别用不含药物、含0.1%或0.5% MC 1220的两种不同凝胶组合物进行治疗，30分钟后进行阴道RT-SHIV攻击。用低浓度MC 1220治疗的每组中的一只动物以及一只对照动物在阴道攻击后仍未感染。相比之下，接受0.5% MC 1220的动物中有三只仍未感染，这表明存在药物阈值。尽管血浆病毒RNA呈阴性且未发生血清转化，但几乎所有未感染的动物在外周或引流病毒进入门户的淋巴结中都表现出SIV特异性T细胞。我们的结果使MC 1220成为一种有前景的化合物，可进一步开发为局部杀微生物剂，并需要用改进的制剂、长效阴道给药系统甚至与其他抑制剂联合进行额外测试。
