P2 - Topical tactics to limit HIV/HSV spread by mucosal DCs

P2 - 限制粘膜 DC 传播 HIV/HSV 的局部策略

• 批准号: 7929654
• 负责人: Melissa J Robbiani
• 金额: $ 34.8万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7929654
• 关键词: Animals; Binding; Biological Assay; Carrageenan; Cells; Chemicals; Chlamydia; Clinical; Communities; Dendritic Cells; Development; Drug Formulations; Drug Kinetics; Effectiveness; Generations; Goals; HIV; HIV Infections; Hepatitis B Virus; Human; Human Herpesvirus 2; Immunologic Deficiency Syndromes; In Vitro; Infection; Infection prevention; Macaca; Methods; Monitor; Mononuclear; Natural Immunity; Nucleotides; Reverse Transcriptase Inhibitors; System; Testing; Tissues; Toxic effect; Trichomonas; Vagina; Virus; Work; base; improved; in vivo; microbicide; novel; pathogen; preclinical study; prevent; programs; research study

DESCRIPTION (provided by applicant): The aim of this integrated Program is to develop and assay a novel broad-spectrum combination microbicide, ZCM. ZCM comprises Zn bound to carrageenan and the non-nucleotide reverse transcriptase inhibitor MIV-150. We rationalize that preventing pathogen attachment to target cells via carrageenan, combined with the anti-HIV/STI effects of Zn and MIV150, will render this combined formulation highly effective at limiting HIV infection and STIs. Project 1 (Maguire, Project Leader {PL}) focuses on optimizing the development and testing of ZCM formulations, to identify the strongest, most stable and safe ZCM for the studies proposed in Projects 2 and 3. Experiments will involve assaying;formulations containing different concentrations of the 3 components. Stability will be assessed by standard physical and chemical methods. In vitro and FDA-required animal assays will be employed to assay toxicity and animal systems will be used for preliminary pharmacokinetic studies. The major goal of Project 2 (Pope, PL) is to test ZCM for its ability to prevent vaginal infection with immunodeficiency viruses in healthy and HSV-2-infected macaques. Since dendritic cells (DCs) likely drive the early amplification of virus in the tissues and this may be exacerbated by pathogens like HSV-2, DC-based in vitro studies will be performed in parallel to the in vivo work. We will monitor how effective ZCM is at preventing DC-driven infections, while uncovering information about the ability of ZCM to trigger innate immunity that together would contribute to the microbicide actions in vivo. Proposal 3 (Phillips, PL) involves assaying ZCM for effectiveness in preventing infection of primary isolates of HIV in primary human mononuclear cells. In addition, work will focus on developing systems for assaying microbicides against hepatitis B virus (HBV), HSV-2, Chlamydia, and Trichomonas, important STIs that have been relatively understudied by the microbicide community. ZCM will be tested in these new and improved systems for (in vitro and in vivo) efficacy in blocking these important STIs. The ultimate goal of this integrated multi-project pre-clinical study is to develop a new generation carrageenan-based microbicide, ZCM, which will be highly effective against all clinical isolates of HIV and have robust activity in preventing infection by a broad spectrum of STIs.

描述（由申请人提供）：该集成程序的目的是开发和测定一种新颖的广谱组合菌心ZCM。 ZCM包括与角叉菜胶和非核苷酸逆转录酶抑制剂MIV-150结合的Zn。我们合理地认为，通过角叉菜胶与Zn和MIV150的抗HIV/STI效应相结合，可以防止病原体附着于靶细胞上，这将使这种合并的配方在限制HIV感染和性传播感染方面非常有效。项目1（Maguire，项目负责人{PL}）着重于优化ZCM公式的开发和测试，以确定项目2和3中提出的研究最强，最稳定和最安全的ZCM。实验将涉及分析；包含三个组成部分的不同浓度。稳定性将通过标准的物理和化学方法评估。体外和FDA需要的动物测定将用于测定毒性，动物系统将用于初步的药代动力学研究。项目2（POPE，PL）的主要目标是测试ZCM在健康和HSV-2感染的猕猴中预防具有免疫缺陷病毒的阴道感染的能力。由于树突状细胞（DC）可能会驱动组织中病毒的早期扩增，因此，基于HSV-2（基于DC）的病原体可能会与体外工作同时进行。我们将监视ZCM在防止DC驱动的感染方面的有效性，同时发现有关ZCM触发先天免疫能力的信息，这些信息将共同促进体内杀生性杀菌剂的作用。提案3（Phillips，PL）涉及分析ZCM，以防止原代人单核细胞感染HIV的原发性分离株。此外，工作将集中于开发用于针对丙型肝炎病毒（HBV），HSV-2，衣原体和毛毛虫的系统，这些系统已被微生物群体相对研究。 ZCM将在这些新的和改进的系统中测试（体外和体内）阻断这些重要性传播感染的功效。这项集成的多项目临床前研究的最终目的是开发新一代的基于角叉菜胶的菌心ZCM，它将对所有HIV的所有临床分离株非常有效，并具有强大的活性，以防止广泛的ETIS感染。