PRIMATE MODELS FOR HIV PREVENTION AND THERAPEUTIC STRATEGIES

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。 非核苷类逆转录酶抑制剂(NNRTI)是一类重要的化疗和预防HIV-1感染的药物。然而，目前使用猴免疫缺陷病毒(SIV)或常用的嵌合SIV(表达HIV-1包膜的SIV)建立的非人类灵长类动物模型由于对NNRTIs不敏感而存在不足。为了建立评价NNRTI化合物的NHP模型，我们在体外鉴定了一种RT-Shiv病毒，该病毒具有高感染性、CCR5使用和对HIV-1特异性NNRTI敏感的特征，该病毒被认为适合于粘膜传播，并被用来进行猪尾猕猴(Macaca Nomestrina)的阴道传播研究。RT-SHV具有传染性CCR5嗜性嵌合病毒的体外特征。该病毒不仅对HIV-1RT特异性NNRTI高度敏感，而且其复制也被多种NRTI和蛋白酶抑制剂抑制。在体内的阴道传播研究中，猕猴要么被单剂DMPA(醋酸甲羟孕酮)预处理，要么在经阴道接种500或1000 TCID50的RT-SHV之前不进行处理。所有的猕猴在接种后2或3周成为系统感染，表现出持续的高病毒血症，显著的CD4T细胞耗尽，以及抗病毒抗体反应。与未经DMPA处理的猕猴相比，经DMPA处理的猕猴在急性感染阶段后表现出更高的平均血浆病毒载量，高度可变的抗病毒抗体应答，以及更高的艾滋病样疾病的发生率。这项研究表明，经阴道感染RT-SHV后，猕猴会迅速发生全身感染。这种RT-SHIV/猕猴模型可以被认为对基于NNRTI的治疗、杀微生物剂或其他预防策略的评估有用。

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. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important category of drugs for both chemotherapy and prevention of HIV-1 infection. However, current non-human primate (NHP) models utilizing simian immunodeficiency virus (SIV) or commonly used chimeric SHIV (SIV expressing HIV-1 envelope) are inadequate due to the insensitivity to NNRTIs. To develop a NHP model for evaluation of NNRTI compounds, we characterized a RT-SHIV virus that exhibited in vitro characteristics of high infectivity, CCR5-usage, and sensitivity to HIV-1 specific NNRTIs, this virus was thought to be suitable for mucosal transmission and then was used to carry out a vaginal transmission study in pigtail macaques (Macaca nemestrina). RT-SHIV exhibited in vitro characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For in vivo vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate) or left untreated before intravaginal inoculation with 500 or 1,000 TCID50 of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4+T cell depletion, and antiviral antibody responses. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be considered useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.