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 该子项目的主要支持。 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 来源的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致病性感染中，表明这是灵长类慢病毒感染的共同特征。由高致病性 SIVmac239 的两种变体产生的相关性，¿内夫和 ¿ GY，在恒河猴中，与 SIVmac239 相比，¿ nef 有一个删除的 nef 基因，对体内毒力至关重要； GY 从保守的贩运基序 Yxx¿ 中删除了 Gly-Tyr ，在包膜细胞质尾部 ¿ 的急性峰值病毒血症。 GY 是 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) 急性感染。 GY 和 ¿与致病性 SIV 相比，nef 保留了肠道 CD4+ T 淋巴细胞，尽管与 SIVmac239 相比血浆病毒载量较高，但肠道免疫效应位点被 ¿然而，GY 的感染扩散程度较低，并迅速转移到共聚焦显微镜识别的免疫诱导部位。 GY- 感染细胞为 CD3+ T 淋巴细胞；在巨噬细胞或大脑中没有观察到 GY，这表明靶细胞群和组织分布的多样性低于 SIVmac239。病毒载量最高的 GY 感染动物表现出肠道和血液 CD4+ T 淋巴细胞缓慢下降，在这些动物中，测序发现包膜胞质尾部存在两个反复出现的突变，要么是 S727P（先前发现的补偿性突变），要么是产生新Yxx??在所有包膜克隆中，尽管突变率很高，但 Gly-Tyr 缺失仍然完整，S727P 突变也在 ¿我们的结果显示，感染 nef 的动物的病毒载量最高。 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。