PRIMATE MODELS FOR HIV PREVENTION AND THERAPEUTIC STRATEGIES

HIV 预防和治疗策略的灵长类动物模型

• 批准号: 8172793
• 负责人: Che-Chung Tsai
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172793
• 关键词: Acute; Antibody Formation; CD4 Positive T Lymphocytes; Categories; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Evaluation; Exhibits; Exposure to; Funding; Grant; HIV-1; In Vitro; Incidence; Infection; Institution; Left; Macaca; Macaca nemestrina; Medroxyprogesterone 17-Acetate; Modeling; Pharmaceutical Preparations; Plasma; Prevention; Prevention strategy; Primates; Protease Inhibitor; Research; Research Personnel; Resources; SIV; Source; Staging; Systemic infection; T-Cell Depletion; Therapeutic; United States National Institutes of Health; Viral Antibodies; Viral Load result; Viremia; Virus; base; chemotherapy; in vivo; microbicide; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; transmission process; vaginal transmission; virus envelope

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 非核苷逆转录酶抑制剂（NNRTIS）是化学疗法和预防HIV-1感染的重要类别。 然而，由于对NNRTI的不敏感性，使用旧约免疫缺陷病毒（SIV）或常用的嵌合SHIV（SIV表达HIV-1信封的SIV）的当前非人类灵长类动物（NHP）模型由于对NNRTIS不敏感而不足。为了开发用于评估NNRTI化合物的NHP模型，我们表征了一种RT-SHIV病毒，该病毒表现出高感染性，CCR5使用和对HIV-1特异性NNRTIS的敏感性的体外特征，该病毒被认为适用于粘膜传播，然后用于粘液麦克阿（MacA）进行粘膜传播（Maca n Nnrtis）。 RT-SHIV表现出感染性CCR5嵌合病毒的体外特征。该病毒不仅对HIV-1 RT特异性nnrtis高度敏感；它的复制也受到多种NRTI和蛋白酶抑制剂的抑制。对于体内阴道传播研究，猕猴要么用单剂量的DMPA（乙酸二硫代二甲状腺酸酯）预处理，要么在使用500或1,000 TCID50的RT-SHIV之前未经处理。 所有猕猴在持续的高病毒血症，明显的CD4+T细胞耗竭和抗病毒抗体反应后全系统地感染了2或3周。 与没有DMPA预处理的猕猴相比，DMPA预处理的猕猴显示出更高的平均血浆病毒载量，高度可变的抗病毒抗体反应以及较高的艾滋病样疾病发生率。这项研究表明，在阴道内暴露于RT-SHIV之后，猕猴的全身感染迅速。这种RT-SHIV/猕猴模型可被认为可用于评估基于NNRTI的疗法，菌心或其他预防策略。