PATHOGENESIS OF AN ATTENUATED SIVMAC239 IN RHESUS AND PIGTAIL MACAQUES

减毒 SIVMAC239 在恒河猴和尾猴中的发病机制

• 批准号: 8358095
• 负责人: James A Hoxie
• 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/8358095
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Animals; Attenuated; CD4 Positive T Lymphocytes; CD8B1 gene; Cytoplasmic Tail; Exhibits; Funding; Grant; Infection; Lamina Propria; Lymphoid Tissue; Macaca; Macaca mulatta; Macaca nemestrina; National Center for Research Resources; Pathogenesis; Peripheral; Plasma; Primates; Principal Investigator; RNA; Reporting; Research; Research Infrastructure; Resources; SIV; Source; United States National Institutes of Health; Viral; Viremia; attenuation; cost; disorder control; follow-up; interest; 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. Differences in SIV pathogenesis have been noted between rhesus (RhM) and pigtail (PTM) macaques with PTMs progressing more rapidly to AIDS. We previously reported that SIVmac239 containing a Gly-Tyr deletion (designated GY) in a conserved trafficking motif in the Env cytoplasmic tail was attenuated in RhM. In more recent studies to identify pathological correlates of attenuation we observed in 6 RhM that GY acute peak viremia was later (3 wks vs. 2 wks) and slightly lower than for SIVmac239 (0.5 log) with viral set points that were considerably reduced (~2 logs). Despite robust replication in organized lymphoid tissues, GY infection in lamina propria was transient with little if any infection or CD4 depletion seen from day 28 to 1 year. In PTMs GY showed a rapid (10-14 day) and high (1.8x10^6-1.6x10^7 copies/RNA) acute peak, but remarkably, in all 5 animals viral set points declined to undetectable levels with animals maintaining normal numbers of peripheral CD4 cells for e3 years. In two animals, GY reappeared after CD8 depletion, and both were protected from an i.v. SIVmac239 challenge. Notably, although all 5 were infectable by heterologous SIVmacE660, and in three E660 was controlled to d10^2 copies/ml for 3- 5 years. In follow-up studies at TNPRC, 4 PTMs have been infected with GY to determine pathological correlates of control. Preliminary results at 4 weeks indicate that peak viremia in PTM again appears earlier (2 wks) than for RhM with a more rapid decline in plasma viremia. Follow-up studies to determine the distribution of GY infection in gut and peripheral lymphoid tissues are in progress. Why PTM, a more susceptible species for pathogenic SIVmac infection exhibits better control of GY than RhM will be of great interest in determining viral and host interactions that are relevant to virologic control and disease.

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， 包括其他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。 恒河猴（RhM）和猪尾（PTM）猕猴之间SIV发病机制的差异已被注意到，PTM更快地进展为AIDS。我们先前报道了含有Gly-Tyr缺失的SIVmac 239（命名为 戈伊）在RhM中减弱。在最近的研究中，我们在6例RhM中观察到， 戈伊急性峰值病毒血症较晚（3周对2周），并且略低于SIVmac 239（0.5 log），病毒设定点显著降低（~2 log）。尽管在有组织的淋巴组织中有很强的复制， 固有层中的戈伊感染是短暂的，从第28天到第1年几乎没有感染或CD 4耗竭。在PTM中 戈伊显示出快速（10-14天）和高（1.8x10^6-1.6x10^7拷贝/RNA）的急性峰值，但值得注意的是，在所有5只动物中，病毒设定点下降至不可检测的水平，动物维持正常的外周CD 4细胞数量达e3年。在两种动物中， 戈伊在CD 8耗尽后再次出现，并且两者都受到保护免于静脉内SIVmac 239攻击。值得注意的是，尽管所有5个都可被异源SIVmacE 660感染，并且在3个中E660被控制在d10^2拷贝/ml持续3- 5年。在TNPRC的后续研究中，4名PTM感染了 戈伊以确定对照的病理相关性。4周时的初步结果表明，PTM中的峰值病毒血症再次比RhM更早出现（2周），血浆病毒血症下降更快。后续研究，以确定 肠道和外周淋巴组织中的戈伊感染正在进行中。为什么PTM，一种对致病性SIVmac感染更敏感的物种， 相比RhM，戈伊在确定与病毒学控制和疾病相关的病毒和宿主相互作用方面将具有极大的兴趣。