Use of a CB2 Ligand to prevent HIV-1 Infection and Transmission

描述：本R21拨款提案的目标是测试使用大麻素受体（CB）激动剂作为杀微生物剂预防HIV感染和传播的可行性。这些四氢大麻酚（THC）的非精神活性衍生物具有广泛的抗炎特性，并在动物模型中增加阴道组织的分层。要测试的化合物是CB2的激动剂，它存在于免疫系统中，也存在于其他外周组织，包括阴道组织。在R21项目中，将研究这些激动剂对以下方面的影响：1)阴道组织厚度、紧密连接、基因表达和屏障功能，2)先天免疫相关因子的表达，3)上皮组织和HIV宿主细胞中CB2的表达，4)HIV感染细胞在阴道组织内的迁移，5)HIV捕获和转移到CD4+ T细胞。R21工作的成功完成预计将导致其中一种CB激动剂进入临床前/临床试验，用于预防性HIV治疗或作为HIV杀微生物剂佐剂。

DESCRIPTION: The goal of this R21 grant proposal is to test the feasibility of using cannabinoid receptor (CB) agonists as microbicides to prevent HIV infection and transmission. These non-psychoactive derivatives of tetrahydrocannabinol (THC) have a broad range of anti-inflammatory properties and increase the stratification of vaginal tissue in animal models. The compounds to be tested are agonists of CB2, which are found in the immune system and also present in other peripheral tissues, including vaginal tissue. During the R21 project, the effect o these agonists on the: 1) vaginal tissue thickness, tight junctions, gene expression, and barrier function, 2) expression of factors involved in innate immunity, 3) expression of CB2 in epithelial tissues and HIV host cells, 4) migration of HIV infected cells within vaginal tissue, and 5) capture and transfer HIV to CD4+ T cells will be investigated. Successful completion of the R21 work is anticipated to lead to advancement of one of the CB agonists into preclinical/clinical trials for use as a prophylactic HIV treatment or as an HIV microbicide adjuvant.