INFANT IMMUNOPROPHYLAXIS AGAINST A PRIMATE LENTIVIRUS

婴儿针对灵长类慢病毒的免疫预防

• 批准号: 8172331
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 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/8172331
• 关键词: Acute; African; Animals; Blood Cells; Brain; Brain Diseases; CCR5 gene; CD8-Positive T-Lymphocytes; Cell Nucleus; Cells; Cerebrospinal Fluid; Chronic; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Funding; Genes; Genetic; Giant Cells; Grant; HIV; HIV-1; Human; Hybrids; Infant; Infection; Institution; Macaca mulatta; Macaca nemestrina; Microglia; Monkeys; Phase; Plasma; Primate Lentiviruses; Process; Research; Research Personnel; Resources; SIV; Source; Testing; United States National Institutes of Health; Viral Load result; Viremia; Virus; Virus Diseases; immunoprophylaxis; in vivo; novel; simian human immunodeficiency virus; viral RNA

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. We have constructed a novel simian-human immunodeficiency virus (SHIV), a hybrid virus that is part monkey AIDS virus (termed SIV), part human AIDS virus (termed HIV-1). This hybrid virus, SHIV-Bo159N4, encodes the envelope gene of a primary HIV-1 strain that was adapted in human brain-derived cells. Our new virus, SHIV-Bo159N4, replicated well in blood cells of all monkeys tested. Like the original HIV-1 strain from which we derived the envelope gene, our SHIV-Bo159N4 enters cells through a molecule called CCR5. Cells infected with our new virus form giant cells that contain many nuclei. To test whether SHIV-Bo159N4 can replicate in vivo, rhesus monkeys were inoculated intravenously and mucosally with this new virus; all had high viral RNA loads. To increase viremia in the acute phase, the CD8+ cells were depleted in some animals shortly after inoculation; high viral RNA levels were seen in plasma and cerebrospinal fluid (CSF). We have also inoculated pigtailed monkeys with SHIV-Bo159N4 under depletion of CD8+ cells; again, very high viral loads were observed in plasma and CSF. The animals with the highest CSF viral RNA loads were euthanized, microglia were isolated and transferred to new recipients. Brain sections are being tested for evidence of productive viral infection and brain disease. We are currently following 10 rhesus and 2 pigtailed monkeys with chronic infection for the development of disease. We have also constructed a second new SHIV that encodes the envelope gene of an African HIV-1 strain that is a genetic subtype (or Clade) A strain. This new Clade A SHIV is called SHIV-KNH1144. We are now in the process of adapting this new SHIV to replicate to high levels in rhesus monkeys. Two rhesus monkeys have already become systemically infected.

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 中心，不一定是研究者的机构。 我们构建了一种新型猿猴-人类免疫缺陷病毒（SHIV），这是一种混合病毒，其部分为猴艾滋病病毒（称为 SIV），部分为人类艾滋病病毒（称为 HIV-1）。 这种杂交病毒 SHIV-Bo159N4 编码一种主要 HIV-1 毒株的包膜基因，该毒株适应了人脑衍生细胞。 我们的新病毒 SHIV-Bo159N4 在所有测试的猴子的血细胞中复制良好。 与我们衍生出包膜基因的原始 HIV-1 毒株一样，我们的 SHIV-Bo159N4 通过一种名为 CCR5 的分子进入细胞。 感染我们的新病毒的细胞形成含有许多细胞核的巨细胞。为了测试SHIV-Bo159N4是否可以在体内复制，恒河猴通过静脉和粘膜接种了这种新病毒；所有病毒RNA载量都很高。 为了增加急性期的病毒血症，一些动物在接种后不久就耗尽了 CD8+ 细胞；血浆和脑脊液 (CSF) 中病毒 RNA 水平较高。 我们还在 CD8+ 细胞耗尽的情况下给猪尾猴接种了 SHIV-Bo159N4；再次在血浆和脑脊液中观察到非常高的病毒载量。 脑脊液病毒RNA载量最高的动物被安乐死，小胶质细胞被分离并转移给新的受体。正在测试大脑切片是否存在有效病毒感染和脑部疾病的证据。 我们目前正在追踪 10 只恒河猴和 2 只患有慢性感染的猪尾猴的疾病发展情况。 我们还构建了第二种新的 SHIV，它编码非洲 HIV-1 毒株的包膜基因，该毒株是遗传亚型（或分支）A 毒株。 这个新的 A 分支 SHIV 被称为 SHIV-KNH1144。我们现在正在改造这种新的 SHIV，以便在恒河猴中复制到高水平。 两只恒河猴已经全身感染。