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).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 背景 人类免疫缺陷病毒 (HIV-1) 的逆转录酶 (RT) 是控制人类艾滋病毒感染和/或获得性免疫缺陷综合症（艾滋病）的主要目标。迫切需要合适的猕猴模型来评估专门针对 HIV-1 RT 的 HIV 预防和治疗策略。我们鉴定了一种 CCR5-trpoic SIV/HIV-RT 嵌合病毒 (RT-SHIVtc)，该病毒在体外对非核苷 RT 抑制剂表现出高度敏感性，并且对猪尾猕猴的粘膜传播具有高致病性。该病毒用于通过食蟹猴（Macaca fasciculis）阴道传播进行感染剂量测定研究，与其他猕猴相比，食蟹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4800、1200或300TCID50的RT-SHIVtc。通过确定攻击后 24 周内的病毒学结果和免疫反应来监测暴露于 RT-SHIVtc 的猕猴的全身感染。 结果 接种后两周 (PI) 内，所有五只接种最高剂量的猕猴和五只接种中等或最低剂量的猕猴中的四只均被全身感染，根据传染性病毒的分离和 PBMC 中前病毒 DNA 的存在确定以及高水平的持续性血浆病毒血症。所有受感染的猕猴均表现出抗病毒抗体反应，并且大多数病毒血症猕猴的血液中 CD4+T 细胞数量减少。结论 我们的结果有助于验证 RT-SHIVtc 在束状分枝杆菌中粘膜传播的致病性。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。