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).

这个子项目是许多利用 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来源获得了主要资金， 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。 背景 人类免疫缺陷病毒（HIV-1）的逆转录酶（RT） 是控制人类HIV感染和/或获得性免疫缺陷综合征（AIDS）的主要目标。合适的猕猴模型是迫切需要的艾滋病预防和治疗策略，特别是针对HIV-1 RT的评估。我们已经确定了CCR5-trpoic SIV/HIV-RT嵌合病毒（RT-SHIVtc），表现出高敏感性的非核苷类RT抑制剂在体外和高致病性的粘膜传播的猪尾猕猴。该病毒用于在食蟹猴（Macaca fascicularis）中通过阴道传播进行感染剂量确定研究，食蟹猴比其他猕猴相对便宜且更容易获得。 方法 将15只健康食蟹猴随机分为3组（n = 5），阴道内接种4，800、1，200或300 TCID50的RT-SHIVtc。通过测定攻毒后24周期间的病毒学结果和免疫学应答，监测RT-SHIVtc暴露猕猴的全身感染。 结果 接种后2周内（PI），通过分离感染性病毒和PBMC中存在前病毒DNA以及高水平的持续性血浆病毒血症确定，接种最高剂量的所有5只猕猴和接种中等或最低剂量的4/5只猕猴全身感染。所有感染猕猴均表现出抗病毒抗体应答，大多数病毒血症猕猴血液中CD4 + T细胞下降。结论 我们的研究结果证实了RT-SHIVtc在M.束状肌这种新的猕猴模型将是非常有用的候选HIV-1非核苷RT抑制剂（NNRTI）的临床前评价。