TO EVALUATE THE EFFICACY OF SAMMA AND ITS LEADING DERIVATIVES AGAINST HIV-1

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本项目的总体目标是开发安全有效的阴道或直肠外用抗菌药物，以阻断人类免疫缺陷病毒（HIV）和其他性传播病原体（包括单纯疱疹病毒（HSV））的性传播。整个项目的重点是基于母体化合物双苯二甲酸醚钠（SAMMA）开发一类新的候选化合物。SAMMA具有良好的抗hiv和HSV活性，但在组织培养中无细胞毒性。该计划的项目3侧重于确定SAMMA及其衍生物在生物相关培养系统中的功效。虽然单核细胞培养可能为评估杀微生物剂提供重要信息，但解剖学、生理学和免疫学问题表明，它们可能无法充分模拟发生在人类生殖道液体和粘膜组织中的事件。在初步研究中，我们已经证明宫颈阴道灌洗液（CVL）对HSV具有内在的抗病毒活性，并且在较小程度上对HIV具有抗病毒活性。这项辅助研究的目的是进一步表征CVL的抗病毒活性。重要的是要控制年龄、月经周期和并发感染等因素。因此，我们建议从20名受试者的队列中获得CVL，这些受试者将进行两次评估（间隔2周）。CVL中的抗病毒（HSV和HIV）活性将被检测，并与年龄、月经周期阶段和并发感染的存在相关。此外，还将开展明确抗hsv活性机制的研究。SAMMA，主要衍生物和其他候选局部化合物在CVL存在下的稳定性也将被评估。确定生殖道液体中存在的抗病毒活性及其对杀微生物剂活性的影响对于开发候选杀微生物剂至关重要。

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. The overall goal of this program project is to develop safe and effective topical antimicrobial agents for vaginal or rectal use that will block sexual transmission of human immunodeficiency virus (HIV) and other sexually transmitted pathogens including herpes simplex virus (HSV). The overall program project focuses on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has excellent anti-HIV and HSV activity, while exhibiting no cytotoxicity in tissue culture. Project 3 of the Program focuses on determining the efficacy of SAMMA and its derivatives in biologically relevant culture systems. While mononuclear cell cultures may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately simulate events that occur in human genital tract fluids and mucosal tissues. In preliminary studies, we have demonstrated that cervicovaginal lavage fluid (CVL) has intrinsic antiviral activity against HSV, and to a lesser extent, HIV. The goal of this ancillary study is to further characterize the anti-viral activity of CVL. It is important to control for factors such as age, menstrual cycle and intercurrent infections. Therefore, we propose to obtain CVL from a cohort of 20 subjects who will be assessed twice (2-weeks apart). The anti-viral (HSV and HIV) activity in the CVL will be assayed and correlated with age, phase of menstrual cycle, and presence of intercurrent infections. In addition, studies to define the mechanism of anti-HSV activity will be conducted. The stability of SAMMA, leading derivatives and other candidate topical compounds in the presence of CVL will also be assessed. Defining the antiviral activity present in genital tract fluids and their impact on microbicide activity is critical in the development of candidate microbicides.