INFECTIVITY OF HSIV-VIF CHIMERA IN NEWBORN PIGTAILED MACAQUES

HSIV-VIF 嵌合体在新生短尾猴中的感染性

• 批准号: 8172792
• 负责人: Shiu-Lok Hu
• 金额: $ 46.53万
• 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/8172792
• 关键词: Adolescent; Animal Model; Animals; Blood Cells; Chimera organism; Computer Retrieval of Information on Scientific Projects Database; Disease; Engineering; Evolution; Family suidae; Funding; Grant; HIV-1; Human; Infection; Institution; Integration Host Factors; Macaca; Macaca mulatta; Mediating; Medicine; Monitor; Newborn Animals; Newborn Infant; Pilot Projects; Plasma; Protein Isoforms; Research; Research Personnel; Resistance; Resources; SIV; Source; Tail; Testing; United States National Institutes of Health; Viral; Viral Load result; Viremia; Virus; college; vif Genes

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. Currently, there is no animal model for HIV-1 infection and disease because the virus is highly specific for humans. Macaques are generally resistant to HIV-1, with the exception being pig-tailed macaques. Our lab showed that pig-tailed macaques are unable to express functional isoforms of TRIM5-alpha, which has been identified as a host factor that restricts the replication of HIV-1 in rhesus monkeys. Therefore, it is possible that HIV-1 will only need to overcome restriction by another host factor, APOBEC3G/F, to replicate successfully in pig-tailed macaques. To test this hypothesis, we collaborated with Dr. J. Kimata of Baylor College of Medicine, who engineered an HIV-1 clone that includes the vif gene of SIVmne, allowing it to counteract APOBEC3G/F-mediated restriction. This chimeric virus, HSIV-vif, is 96% HIV-1 and 4% SIV. It replicates in stimulated pig-tailed macaque blood cells as efficiently as SIVmne. In another pilot study, we inoculated 2 juvenile pig-tailed macaques intravenously with HSIV-vif. Although both animals became infected, plasma viremia did not sustain beyond 10 months after infection. Since newborn animals are more susceptible to lentiviral infection and disease, we inoculated two newborn pig-tail macaques with HSIV-vif. Preliminary results indicate that both animals were infected, with a peak plasma viral load of 0.5-1x105 copies/ml. It is too early to tell if plasma viremia will sustain, but we will continue to monitor these animals to determine their setpoint viral load and the evolution of viral species.

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。子项目及 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。 目前，还没有 HIV-1 感染和疾病的动物模型，因为该病毒对人类具有高度特异性。猕猴普遍对 HIV-1 具有抵抗力，但猪尾猕猴除外。我们的实验室表明，猪尾猕猴无法表达 TRIM5-alpha 的功能亚型，TRIM5-alpha 已被确定为限制 HIV-1 在恒河猴中复制的宿主因子。因此，HIV-1可能只需要克服另一个宿主因子APOBEC3G/F的限制，就能在猪尾猕猴中成功复制。为了检验这一假设，我们与贝勒医学院的 J. Kimata 博士合作，他设计了一个 HIV-1 克隆，其中包含 SIVmne 的 vif 基因，使其能够抵消 APOBEC3G/F 介导的限制。这种嵌合病毒 HSIV-vif 的成分为 96% HIV-1 和 4% SIV。它在受刺激的猪尾猕猴血细胞中复制的效率与 SIVmne 一样。在另一项试点研究中，我们给 2 只幼年猪尾猕猴静脉注射了 HSIV-vif。尽管两只动物均被感染，但血浆病毒血症在感染后并未持续超过 10 个月。由于新生动物更容易受到慢病毒感染和疾病，我们给两只新生猪尾猕猴接种了 HSIV-vif。初步结果表明，两只动物均被感染，血浆病毒载量峰值为0.5-1x105拷贝/ml。现在判断血浆病毒血症是否会持续还为时过早，但我们将继续监测这些动物，以确定它们的病毒载量设定值和病毒种类的进化。