Turville Stuart G, Aravantinou Meropi, Miller Todd, Kenney Jessica, Teitelbaum Aaron, Hu Lieyu, Chudolij Anne, Zydowsky Tom M, Piatak Michael, Bess Julian W, Lifson Jeffrey D, Blanchard James, Gettie Agegnehu, Robbiani Melissa
Center for Biomedical Research, HIV and AIDS Program, Population Council, New York, New York, United States of America.
PLoS One. 2008 Sep 8;3(9):e3162. doi: 10.1371/journal.pone.0003162.
Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard and a new generation Carraguard-based formulation containing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (PC-817). Since dendritic cells (DCs) are believed to be important in HIV transmission, the formulations were tested for the ability to limit DC-driven infection in vitro versus vaginal infection of macaques with RT-SHIV (SIVmac239 bearing HIV reverse transcriptase). Carraguard showed limited activity against cell-free and mature DC-driven RT-SHIV infections and, surprisingly, low doses of Carraguard enhanced infection. However, nanomolar amounts of MIV-150 overcame enhancement and blocked DC-transmitted infection. In contrast, Carraguard impeded infection of immature DCs coincident with DC maturation. Despite this variable activity in vitro, Carraguard and PC-817 prevented vaginal transmission of RT-SHIV when applied 30 min prior to challenge. PC-817 appeared no more effective than Carraguard in vivo, due to the limited activity of a single dose of MIV-150 and the dominant barrier effect of Carraguard. However, 3 doses of MIV-150 in placebo gel at and around challenge limited vaginal infection, demonstrating the potential activity of a topically applied NNRTI. These data demonstrate discordant observations when comparing in vitro and in vivo efficacy of Carraguard-based microbicides, highlighting the difficulties in testing putative anti-viral strategies in vitro to predict in vivo activity. This work also underscores the potential of Carraguard-based formulations for the delivery of anti-viral drugs to prevent vaginal HIV infection.
抗HIV杀微生物剂正在进行临床试验，了解有前景的策略如何发挥作用，并同时在体内证明其疗效，对于新一代杀微生物剂的研发至关重要。我们评估了角叉菜胶以及一种基于角叉菜胶的新一代制剂，该制剂含有非核苷逆转录酶抑制剂（NNRTI）MIV-150（PC-817）。由于树突状细胞（DCs）被认为在HIV传播中起重要作用，因此测试了这些制剂在体外限制DC驱动感染的能力，以及与猕猴经阴道感染RT-SHIV（携带HIV逆转录酶的SIVmac239）的对比情况。角叉菜胶对无细胞和成熟DC驱动的RT-SHIV感染显示出有限的活性，令人惊讶的是，低剂量的角叉菜胶会增强感染。然而，纳摩尔量的MIV-150克服了这种增强作用并阻断了DC传播的感染。相比之下，角叉菜胶在DC成熟的同时阻碍了未成熟DC的感染。尽管在体外有这种可变的活性，但角叉菜胶和PC-817在攻击前30分钟应用时可预防RT-SHIV的阴道传播。由于单剂量MIV-150的活性有限以及角叉菜胶的主要屏障作用，PC-817在体内似乎并不比角叉菜胶更有效。然而，在攻击时及攻击前后在安慰剂凝胶中使用3剂MIV-150可限制阴道感染，证明了局部应用NNRTI的潜在活性。这些数据表明，在比较基于角叉菜胶的杀微生物剂的体外和体内疗效时存在不一致的观察结果，突出了在体外测试假定的抗病毒策略以预测体内活性的困难。这项工作还强调了基于角叉菜胶的制剂在递送抗病毒药物以预防阴道HIV感染方面的潜力。
