PRIMATE MODELS FOR HIV PREVENTION AND THERAPEUTIC STRATEGIES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 非核苷类逆转录酶抑制剂（non-nucleotide reverse transcriptase inhibitors，NNRTI）是一类重要的抗HIV-1感染药物。 然而，目前的非人灵长类动物（NHP）模型利用猿猴免疫缺陷病毒（SIV）或常用的嵌合SHIV（SIV表达HIV-1包膜）是不够的，由于不敏感的NNRTI。为了开发用于评价NNRTI化合物的NHP模型，我们表征了RT-SHIV病毒，其表现出高感染性、CCR 5使用和对HIV-1特异性NNRTI敏感的体外特征，认为该病毒适合于粘膜传播，然后用于在猪尾猕猴（Macaca nemestrina）中进行阴道传播研究。 RT-SHIV在体外表现出感染性嗜CCR 5嵌合病毒的特征。该病毒不仅对HIV-1 RT特异性NNRTIs高度敏感，其复制也被多种NRTIs和蛋白酶抑制剂抑制。对于体内阴道传播研究，猕猴用单剂量的DMPA（贮库型醋酸甲羟孕酮）预处理或在阴道内接种500或1，000 TCID 50的RT-SHIV之前不处理。 所有猕猴在接种后2或3周发生全身感染，表现出持续的高病毒血症、显著的CD 4 +T细胞耗竭和抗病毒抗体应答。 DMPA预处理的猕猴表现出较高的平均血浆病毒载量后，急性感染阶段，高度可变的抗病毒抗体反应，和艾滋病样疾病的发病率较高的猕猴相比，没有DMPA预处理。本研究证明了猕猴阴道内暴露于RT-SHIV后的快速全身感染。该RT-SHIV/猕猴模型可用于评估基于NNRTI的治疗、杀微生物剂或其他预防策略。

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.