VAGINAL TRANSMISSION OF A PATHOGENIC RT-SHIVTC IN CYNOMOLGUS MACAQUES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目的是利用包含HIV-1逆转录酶的RT-SHV，建立经阴道(IVAG)和直肠(IR)途径传播HIV的恒河猴模型。本项目的理论基础和意义在“背景和意义”一节中进行了说明。考虑到预算限制，本项目将重点研究RT-SHV在食蟹猴(猕猴)中的静脉传播。我们将确定静脉注射后对全身传染性的病毒剂量反应。感染的主要参数包括外周血和宫颈、阴道、直肠和肠道粘膜中的病毒RNA、病毒DNA和感染细胞。我们将对外周血液和阴道、宫颈外、直肠(定期冲洗)、小肠(尸检)和周围淋巴结的外周血液和粘膜表面RT-SHV的全身性和局部感染的性质进行描述。这些次级感染参数用于识别不同粘膜部位的感染细胞和辅助因子(即促进病毒感染的细胞因子和趋化因子)：宫颈外、阴道、直肠和小肠(空肠和回肠)。感染的其他次要参数是比较黏膜和全身对RT-SHV的免疫反应；因此，我们将检测阴道和直肠分泌物以及从外周血中获得的血清中SIV抗体的滴度，并检测粘膜和/或血清中产生的针对病毒蛋白的特异性抗体。综上所述，本研究的最终目的是建立成功的食蟹猴经阴道传播RT-SHV感染模型。此外，建立的RT-SHIV猕猴模型不仅适用于基于NNRTI的杀微生物剂候选药物的疗效评估，也适用于NNRTI和NRTI用于全身化疗的疗效评估。

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 objective of this project is to develop a validated macaque model for sexual transmission of HIV by intravaginal (ivag) and intrarectal (ir) routes using a well-characterized RT-SHIV containing the RT of HIV-1. The rationale and significance of this project are described in the "Background and Significance" section. Considering the budget restriction, this project will focus on an ivag transmission of RT-SHIV in cynomolgus macaques (Macaca fascicularis). We will determine the virus-dose response to systemic infectivity after ivag exposure. The primary parameters of infection will include viral RNA, viral DNA and infectious cells in peripheral blood and the mucosa of the ectocervix, vagina, rectum and gut. We will characterize the nature of systemic and local infection of RT-SHIV in peripheral blood and mucosal surfaces of vagina, ectocervix, and rectum (by periodic lavage) and small intestines (at necropsy) and surrounding lymph nodes. These secondary parameters of infection are to identify the infected cell population and accessory factors (i.e. cytokines and chemokines which facilitate virus infection) at different mucosal sites: ectocervix, vagina, rectum and small intestine (jejunum and ileum). Additional secondary parameters of infection are to compare mucosal and systemic immune responses to RT- SHIV; so we will measure titers of SIV-antibodies in vaginal and rectal secretions and in serum obtained from peripheral blood, and detect specific antibodies to viral proteins produced in mucosa and/or serum. In summary, the objective of this study is ultimately to develop the successful RT-SHIV infection model in the cynomolgus macaque by vaginal transmission. Moreover, this established RT-SHIV macaque model will be useful for the efficacy evaluations of not only NNRTI-based microbicide candidates but also NNRTI and NRTI for systemic chemotherapy.