MULTITARGETED MICROBICIDE COMBINATIONS TO BLOCK HIV

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。尽管感染人类免疫缺陷病毒(艾滋病毒)的妇女人数稳步增加，不安全的性行为增加，但仍然没有有效的局部杀微生物剂来预防艾滋病毒感染。该计划的总体目标是开发安全有效的局部抗菌剂，用于阴道或直肠，阻止艾滋病毒的性传播。很少有产品进入临床试验，只有含非氧诺醇-9(N-9)的产品进入疗效试验。从N-9试验中学到的一个宝贵的教训是，使用局部杀微生物剂可能会在粘膜水平上改变女性生殖道的先天免疫反应，并加强艾滋病毒的性传播。很明显，在开始大规模临床试验之前，需要进行早期的体内试验性研究。在合作研究中，我们已确定PRO 2000为主要候选局部杀微生物剂。它在体外有效地抑制艾滋病毒感染，并对单纯疱疹病毒(HSV)具有活性，HSV是艾滋病毒传播的重要辅助因素。I期试验表明，在健康、禁欲的志愿者中，反复阴道内应用PRO 2000是安全和耐受性良好的。虽然监测宫颈阴道病变一直是临床安全杀菌剂试验的常规部分，但对宫颈阴道粘膜屏障潜在的细微变化知之甚少，包括诱导粘膜炎症和干扰宿主防御机制。项目3的目标是描述PRO 2000在阴道内使用后对女性生殖道分泌物中的炎症和免疫介质以及对当地病毒种群的影响。这项工作将为项目1和2中评估的联合杀微生物剂的未来临床试验奠定基础。

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. Despite the steadily increasing number of women infected with human immunodeficiency virus (HIV) and the rise in unsafe sexual practices, there remains no effective topical microbicide against HIV infection. The overall goal of this program is to develop safe and effective topical antimicrobial agents for vaginal or rectal use that will block sexual transmission of HIV. Few products have entered clinical trials and only nonoxynol-9 (N-9)-containing products have advanced to efficacy trials. A valuable lesson learned from the N-9 trials is that the use of topical microbicides may alter innate immune responses of the female genital tract at a mucosal level and enhance sexual transmission of HIV. It is clear that early pilot in vivo studies are needed prior to the initiation of large-scale clinical trials. In collaborative studies, we have identified PRO 2000 as a lead candidate topical microbicide. It effectively inhibits HIV infection in vitro and is active against herpes simplex virus (HSV), an important co-factor in HIV transmission. Phase I trials showed that repeated intravaginal application of PRO 2000 was safe and well tolerated in healthy, sexually abstinent volunteers. While monitoring for cervicovaginal lesions has been a routine part of clinical safety microbicide trials, little is known about potential subtle changes in the cervicovaginal mucosal barrier, including induction of mucosal inflammation and interference with host defense mechanisms. The goal of Project 3 is to characterize the effect of PRO 2000 following intravaginal use on mediators of inflammation and immunity in female genital tract secretions and on the local virus population. This work will lay the groundwork for future clinical trials with combination microbicides evaluated in Projects 1 and 2.