A COMPARISON OF PATHOLOGICAL CORRELATES OF ATTENUATED VARIANTS OF SIVMAC239

SIVMAC239 减毒变体病理相关性的比较

• 批准号: 8358144
• 负责人: ANDREW A LACKNER
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358144
• 关键词: Acute; Animals; Attenuated; Blood; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; Confocal Microscopy; Cytoplasmic Tail; Defect; Diffuse; Drug or chemical Tissue Distribution; Exhibits; Funding; Generations; Grant; HIV Infections; Immune; Infection; Macaca mulatta; Mutation; National Center for Research Resources; Plasma; Population Distributions; Primates; Principal Investigator; Research; Research Infrastructure; Resources; SIV; Site; Source; T-Lymphocyte; Time; United States National Institutes of Health; Variant; Viral Load result; Viremia; Virulence; cost; in vivo; macrophage; nef Genes; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A key feature of SIV and HIV infection is the rapid and near complete depletion of mucosal CD4+ T lymphocytes, however, this depletion also occurs in nonpathogenic infections of natural hosts, suggesting that it is a common feature of primate lentiviral infections. Here we evaluate pathological correlates produced by two variants of highly pathogenic SIVmac239, ¿nef and ¿GY, in rhesus macaques. Compared to SIVmac239, ¿nef has a deleted nef gene, critical for virulence in vivo; ¿GY has Gly-Tyr deletion from a conserved trafficking motif, Yxx¿, in the envelope cytoplasmic tail. Acute peak viremia of ¿GY was 1 week later, but comparable to, SIVmac239 (1.1 x 10^7 vs. 1.3 x 10^7) and higher than ¿nef (3.2 x 10^5). Acute infection with ¿GY and ¿nef spared gut CD4+ T lymphocytes, compared to pathogenic SIV, despite high plasma viral loads. Compared to SIVmac239, the gut immune effector sites were infected by ¿GY, however, the infection was less diffuse and rapidly shifted to immune inductive sites. Confocal microscopy identified ¿GY- infected cells as CD3+ T lymphocytes; ¿GY was not observed in macrophages or in the brain, indicating a less diverse target cell population and tissue distribution than for SIVmac239. Over time, the ¿GY-infected animals with the highest viral loads exhibited a slow decline in gut and blood CD4+ T lymphocytes, and in these animals, sequencing identified two recurring mutations in the envelope cytoplasmic tail, either S727P (a previously identified compensatory mutation) or the generation of new Yxx¿ motifs. In all envelope clones the Gly-Tyr deletion remained intact despite a high mutation rate. Interestingly, the S727P mutation also developed in the ¿nef-infected animal with the highest viral load. Our results show ¿GY and ¿nef have a reduced ability to deplete mucosal CD4+ T lymphocytes, suggesting a common defect in entering and/or replicating at this site.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 SIV和HIV感染的一个关键特征是粘膜CD4+T淋巴细胞的快速且接近完全的耗竭，然而，这种耗竭也发生在自然宿主的非病原性感染中，表明这是灵长类慢病毒感染的共同特征。在这里，我们评估了恒河猴中高致病性 SIVmac239 的两种变体 ¿nef 和 ¿GY 产生的病理相关性。与 SIVmac239 相比，¿nef 缺失了一个 nef 基因，这对于体内毒力至关重要； “GY”从包膜细胞质尾部的保守运输基序 Yxx 中删除了 Gly-Tyr。 ¿GY 的急性病毒血症峰值出现在 1 周后，但与 SIVmac239 相当（1.1 x 10^7 与 1.3 x 10^7），并且高于 ¿nef (3.2 x 10^5)。与致病性 SIV 相比，尽管血浆病毒载量较高，但 ¿GY 和 ¿nef 的急性感染仍能保留肠道 CD4+ T 淋巴细胞。与 SIVmac239 相比，肠道免疫效应位点被 ¿GY 感染，但感染扩散程度较低，并迅速转移到免疫诱导位点。共聚焦显微镜将 ¿GY 感染的细胞鉴定为 CD3+ T 淋巴细胞；在巨噬细胞或大脑中没有观察到 GY，这表明与 SIVmac239 相比，靶细胞群和组织分布的多样性较低。随着时间的推移，病毒载量最高的“GY”感染动物的肠道和血液 CD4+ T 淋巴细胞表现出缓慢下降，在这些动物中，测序发现了包膜细胞质尾部的两个重复突变，要么是 S727P（之前发现的补偿性突变），要么是新的 Yxx 基序的产生。在所有包膜克隆中，尽管突变率很高，但 Gly-Tyr 缺失仍保持完整。有趣的是，S727P 突变也在病毒载量最高的感染 nef 的动物中出现。我们的结果显示 ¿GY 和 ¿nef 消耗粘膜 CD4+ T 淋巴细胞的能力降低，表明在该位点进入和/或复制存在常见缺陷。