BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

用卡拉胶基化合物阻断 DCS 传播的病毒

• 批准号: 7958592
• 负责人: Melissa J Robbiani
• 金额: $ 5.81万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958592
• 关键词: Carrageenan; Cell Maturation; Cells; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Dose; Drug Formulations; Funding; Gel; Generations; Grant; HIV; HIV Infections; In Vitro; Infection; Institution; Macaca; Pharmaceutical Preparations; Placebos; Primates; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Source; Testing; Topical application; United States National Institutes of Health; Vagina; Viral; Virus; Work; anti-HIV microbicide; base; in vitro activity; in vivo; microbicide; non-nucleoside reverse transcriptase inhibitors; prevent; transmission process; vaginal transmission

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，同时证明体内功效，是推进新一代杀微生物剂的核心。我们评估了Carraguard和含有非核苷逆转录酶抑制剂（NNRTI）MIV-150（PC-817）的新一代Carraguard制剂。由于树突状细胞（DC）被认为在HIV传播中是重要的，因此测试了制剂在体外相对于用RT-SHIV（携带HIV逆转录酶的SIVmac 239）对猕猴的阴道感染限制DC驱动的感染的能力。Carraguard对无细胞和成熟DC驱动的RT-SHIV感染显示出有限的活性，并且令人惊讶的是，低剂量的Carraguard增强了感染。然而，纳摩尔量的MIV-150克服了增强并阻断了DC传播的感染。相比之下，Carraguard阻止与DC成熟一致的未成熟DC的感染。尽管这种体外活性可变，但在攻击前30分钟应用Carraguard和PC-817可防止RT-SHIV的阴道传播。由于单剂量MIV-150的有限活性和Carraguard的主要屏障效应，PC-817在体内的有效性似乎并不比Carraguard高。然而，在攻毒时和攻毒前后，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，当比较基于Carraguard的杀微生物剂的体外和体内功效时，观察结果不一致，突出了在体外测试推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Carraguard的制剂用于提供抗病毒药物以预防阴道HIV感染的潜力。