Cummins James E, Doncel Gustavo F
Southern Research Institute, Frederick, Maryland, USA.
Sex Transm Dis. 2009 Mar;36(3 Suppl):S84-91. doi: 10.1097/OLQ.0b013e3181994191.
The human cervicovaginal mucosa is the primary target of HIV-1 infection during male to female transmission. This tissue contains the the full spectrum of cell types and immune modulators that comprise both the innate and adaptive arms of the immune system. Mounting evidence indicates that mucosal epithelial cells are sentinels of the female reproductive tract, producing innate immune mediators that control the vaginal microflora under normal conditions. Recent studies, however, indicate that certain factors secreted in response to another pathogen or after exposure to a vaginal product may in fact enhance infection by HIV-1. Mucosal inflammation and CD4 cell activation as well as disruption of TLR function and epithelial integrity represent potential causes for such effect. It is therefore important to make sure that vaginal products, including microbicides, do not disrupt the structure or function of the cervicovaginal mucosa. Although a number of biomarkers have been linked to microbicide-induced cervicovaginal inflammation and many of these markers have been measured in preclinical and clinical assays, there are currently no data that demonstrate a correlation between any one marker and susceptibility to HIV-1 infection in humans. To date, the lack of a validated biomarker of cervicovaginal safety represents a gap in the knowledge base that hinders the rational and expeditious selection of microbicide candidates entering clinical trials. Current discovery efforts and preclinical assessment of microbicide safety use an integrated sequential evaluation system that includes cell-based models, explant-based models, and animal-based models. Relevant research in these areas is yielding new assays and biomarkers that, if validated, will be essential to the rational selection of microbicide candidates for efficacy trials.
在男传女的过程中，人类宫颈阴道黏膜是HIV-1感染的主要靶标。该组织包含构成免疫系统固有免疫和适应性免疫分支的所有细胞类型和免疫调节剂。越来越多的证据表明，黏膜上皮细胞是女性生殖道的哨兵，在正常情况下可产生控制阴道微生物群的固有免疫介质。然而，最近的研究表明，对另一种病原体作出反应或接触阴道产品后分泌的某些因子实际上可能会增强HIV-1的感染。黏膜炎症、CD4细胞活化以及TLR功能和上皮完整性的破坏是造成这种影响的潜在原因。因此，确保包括杀微生物剂在内的阴道产品不会破坏宫颈阴道黏膜的结构或功能非常重要。尽管许多生物标志物与杀微生物剂引起的宫颈阴道炎症有关，并且其中许多标志物已在临床前和临床试验中进行了测量，但目前尚无数据表明任何一种标志物与人类对HIV-1感染的易感性之间存在相关性。迄今为止，缺乏经过验证的宫颈阴道安全性生物标志物代表了知识库中的一个空白，这阻碍了进入临床试验的杀微生物剂候选物的合理和快速选择。目前对杀微生物剂安全性的发现努力和临床前评估使用了一个综合的顺序评估系统，该系统包括基于细胞的模型、基于外植体的模型和基于动物的模型。这些领域的相关研究正在产生新的检测方法和生物标志物，如果得到验证，对于合理选择用于疗效试验的杀微生物剂候选物至关重要。
