MACACA FASCICULARIS SUSCEPTIBILITY TO RT-SHIV FOLLOWING INTRAVAGINAL INOCULATION

阴道内接种后食管猴对 RT-SHIV 的敏感性

• 批准号: 7958878
• 负责人: Che-Chung Tsai
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958878
• 关键词: Acquired Immunodeficiency Syndrome; Antibody Formation; Blood; CD4 Positive T Lymphocytes; Computer Retrieval of Information on Scientific Projects Database; DNA; Dose; Evaluation; Exhibits; Funding; Grant; HIV; HIV Infections; HIV-1; HIV-1 Reverse Transcriptase; Human; Immunologics; In Vitro; Institution; Macaca; Macaca fascicularis; Macaca nemestrina; Methods; Modeling; Monitor; Pathogenicity; Peripheral Blood Mononuclear Cell; Plasma; Predisposition; Preventive; Primates; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Source; Systemic infection; Therapeutic; United States National Institutes of Health; Viral Antibodies; Viremia; Virus; non-nucleoside reverse transcriptase inhibitors; preclinical evaluation; response; transmission process; vaginal transmission

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. Background The reverse transcriptase (RT) of the human immunodeficiency virus (HIV-1) is a major target for controlling HIV infection and/or acquired immunodeficiency syndrome (AIDS) in humans. Suitable macaque model is urgently needed for the evaluation of HIV preventive and therapeutic strategies specifically targeting HIV-1 RT. We have characterized a CCR5-trpoic SIV/HIV-RT chimeric virus (RT-SHIVtc) which exhibited high in vitro sensitivity to nonnucleoside RT inhibitors and is highly pathogenic to mucosal transmission in pigtail macaques. This virus was used to carry out an infectious dose determining study by vaginal transmission in cynomolgus macaques (Macaca fascicularis) which are relatively less expensive and more readily available than other macaques. Methods Fifteen healthy cynomolgus macaques were randomly divided into three groups (n = 5) and intravaginally inoculated with 4,800, 1,200 or 300 TCID50 of RT-SHIVtc. Systemic infections of RT-SHIVtc exposed macaques were monitored by determining both virological findings and immunologic responses during 24 weeks post challenge. Results Within two weeks post inoculation (PI), all five macaques inoculated with the highest dose and four of five macaques inoculated with either medium or the lowest dose, were systemically infected as determined by the isolation of infectious virus and presence of proviral DNA in PBMC and the high level of persistent plasma viremia. All the infected macaques exhibited antiviral antibody response and most of the viremic macaques showed declined CD4+T cells in their blood. Conclusions Our results serve to validate the pathogenicity of RT-SHIVtc mucosal transmission in M. fascicularis. This new macaque model will be very useful for the preclinical evaluation of candidate HIV-1 nonnucleoside RT inhibitors (NNRTI).

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。 背景人类免疫缺陷病毒（HIV-1）的逆转录酶（RT） 是控制人类中HIV感染和/或获得的免疫缺陷综合征（AIDS）的主要目标。迫切需要适当的猕猴模型来评估专门针对HIV-1 RT的HIV预防和治疗策略。我们已经表征了CCR5-Trpoic SIV/HIV-RT嵌合病毒（RT-SHIVTC），该病毒表现出对非核苷RT RT抑制剂的体外敏感性，并且对Pigtail猕猴的粘膜传播高度致病。该病毒被用来进行传染剂量，通过阴道传播在cynomolgus猕猴（Macaca fascicularis）中进行确定的研究，比其他猕猴相对便宜，更容易获得。 方法将15个健康的cynomolgus猕猴随机分为三组（n = 5），并在RT-SHIVTC的4,800、1,200或300 TCID50上静脉内接种。在挑战后24周内，通过确定病毒学发现和免疫反应来监测RT-SHIVTC暴露猕猴的全身感染。 接种后两周内（PI）的结果，所有五把猕猴接种了最高剂量和培养基或最低剂量接种的五个猕猴中的四个猕猴，全身感染，是通过分离感染性病毒和PBMC中的门型DNA的存在确定的，并且PBMC中的前尿症DNA的存在以及持久性血浆病毒的高水平。所有感染的猕猴均表现出抗病毒抗体反应，大多数病毒猕猴显示血液中的CD4+T细胞下降。结论我们的结果旨在验证筋膜分枝杆菌中RT-SHIVTC粘膜传播的致病性。这种新的猕猴模型对于候选HIV-1非核苷RT抑制剂（NNRTI）的临床前评估非常有用。