BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 抗HIV杀微生物剂正在临床试验中进行研究，了解有希望的策略如何发挥作用，同时在体内展示有效性，是推进新一代杀微生物剂的核心。我们评估了CarraGuard和包含非核苷逆转录酶抑制剂(NNRTI)MIV-150(PC-817)的新一代基于CarraGuard的配方。由于树突状细胞(DC)被认为在HIV传播中起重要作用，因此通过RT-SHIV(携带HIV逆转录酶的SIVmac239)，测试了这些配方在体外限制DC驱动的感染与通过RT-Shiv(携带HIV逆转录酶)的猕猴经阴道感染的能力。CarraGuard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CarraGuard增强了感染。然而，纳摩尔量的MIV-150克服了增强作用，并阻止了DC传播的感染。相反，CarraGuard可抑制未成熟DC的感染，这与DC成熟相一致。尽管在体外有这种可变的活性，但CarraGuard和PC-817在挑战前30分钟应用时，可以防止RT-Shiv的阴道传播。在体内，PC-817似乎并不比CarraGuard有效，这是由于单剂量MIV-150的活性有限以及CarraGuard的主要屏障作用所致。然而，在挑战期间和周围，安慰剂凝胶中的3剂MIV-150限制了阴道感染，证明了局部应用NNRTI的潜在活性。这些数据表明，在比较以CarraGuard为基础的杀菌剂的体外和体内有效性时，观察到的结果不一致，突显了在体外测试假定的抗病毒策略以预测体内活性的困难。这项工作还强调了以CarraGuard为基础的配方在提供抗病毒药物以预防阴道艾滋病毒感染方面的潜力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.