Characterization of entry inhibitors in human cervical & rectal tissue models & d

人宫颈进入抑制剂的表征

• 批准号: 8075530
• 负责人: ROBIN J SHATTOCK
• 金额: $ 4.15万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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/8075530
• 关键词: Animal Model; Biological Markers; Biological Models; Cell Culture Techniques; Cells; Cervical; Clinical Trials; Collaborations; Dendritic Cells; Development; Drug Formulations; Epithelial; Epithelium; Evaluation; Event; Future; Genomics; Goals; HIV-1; Histocompatibility; Human; Individual; Infection; Infection prevention; Investigation; Knowledge; Langerhans cell; Learning; Length; Location; Macaca; Macaca mulatta; Measurement; Mediating; Modeling; Monitor; Mononuclear; Mucous Membrane; Mucous body substance; Outcome; Pathway interactions; Pattern; Penetration; Performance; Phase; Phase III Clinical Trials; Physiological; Population; Process; Property; Research; Research Project Grants; Role; Safety; Savings; Science; Scientist; Seminal fluid; Series; Sexual Transmission; Solid; Solvents; System; T-Lymphocyte; Technology; Time; Tissue Model; Tissues; Vagina; Vaginal Ring; Validation; Viral; Virus; Virus Diseases; Work; base; cell type; cellulose sulfate; chemokine; comparative; cost; cytokine; design; efficacy testing; efficacy trial; immune function; in vitro Model; in vivo; inhibitor/antagonist; innate immune function; macrophage; microbial; microbicide; particle; pathogen; pre-clinical; prevent; programs; receptor; rectal; research clinical testing; research study; response; transmission process; uptake

The potential role of microbicides in preventing the mucosal transmission of HIV-i has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given the expense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletely optimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL- 1492, SAVVY and Cellulose Sulphate); these trials have suggested that development and formulation of effective microbicides may not be as easy as first thought. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. Therefore a comprehensive program for pre-clinical development of microbicide candidates requires that information be accrued from several different model systems. Hence Dr. Shattock's and Robbiani's groups have developed in vitro models of the earliest events in HIV-i infection of human mucosal tissue and dendritic cell driven HIV-i spread. These models are ideally suited to test the efficacy of agents designed to block HIV-i sexual transmission and have been widely used to evaluate potential microbicide candidates. Furthermore, experiments described here and cross validation with experiments described in project III, may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials. In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-i entry inhibitors (alone and in combination) and their formulations. This research will be influenced and guided by work carried out within Core A, and will involve extensive interactions and collaborations with the scientists leading Research Projects II and III. The interactions between the different groups will result in the fasttracking of the most promising inhibitor combinations and formulations for evaluation in the macaque model (Research Project III).

杀微生物剂在预防HIV-i粘膜传播中的潜在作用已经明确