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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 SIV和HIV感染的一个关键特征是粘膜CD 4 + T淋巴细胞的快速和几乎完全耗竭，然而，这种耗竭也发生在自然宿主的非致病性感染中，这表明这是灵长类慢病毒感染的共同特征。在这里，我们评估病理相关性产生的高致病性SIVmac 239，<$nef和<$戈伊，在恒河猴的两个变种。与SIVmac 239相比，中缺失了Gly-Tyr。<$戈伊的急性病毒血症峰值出现在1周后，但与SIVmac 239相当（1.1 x 10^7 vs. 1.3 x 10^7），高于<$nef（3.2 x 10^5）。与致病性SIV相比，尽管血浆病毒载量高，但<$戈伊和<$nef的急性感染使肠道CD 4 + T淋巴细胞幸免。与SIVmac 239相比，戈伊感染肠道免疫效应位点，但是，感染的扩散性较低，并迅速转移到免疫诱导位点。共聚焦显微镜鉴定？戈伊感染的细胞为CD 3 + T淋巴细胞;在巨噬细胞或脑中未观察到戈伊，表明靶细胞群和组织分布的多样性低于SIVmac 239。随着时间的推移，具有最高病毒载量的GY感染的动物表现出肠道和血液CD 4 + T淋巴细胞的缓慢下降，并且在这些动物中，测序确定了包膜胞质尾中的两个重复突变，S727 P（先前确定的补偿突变）或新Yxx图案的产生。在所有包膜克隆中，尽管突变率高，但Gly-Tyr缺失保持完整。有趣的是，S727 P突变也发生在病毒载量最高的感染动物中。我们的结果显示，戈伊和nef具有降低的消耗粘膜CD 4 + T淋巴细胞的能力，这表明在该部位进入和/或复制的常见缺陷。