CONTROL OF AN SIVMAC239 TRANSMEMBRANE MUTANT IN PIGTAIL MACAQUES

尾猴中 SIVMAC239 跨膜突变体的控制

• 批准号: 8358143
• 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/8358143
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Bromodeoxyuridine; CD4 Positive T Lymphocytes; Cytoplasmic Tail; Disease; Exhibits; Funding; Grant; Immune response; Infection; Label; Lamina Propria; Macaca mulatta; Macaca nemestrina; Mutation; National Center for Research Resources; Primates; Principal Investigator; RNA; Recovery; Research; Research Infrastructure; Resources; SIV; Signal Transduction; Source; United States National Institutes of Health; Viral; Virus; cost; disorder control; interest; macrophage; microbial; monocyte; mutant; 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. The pigtail macaque (PTM) is well recognized as being highly susceptible to SIV-induced disease, with SIVmac239 reproducibly and rapidly causing AIDS. We have shown that when SIVmac239 contains a mutation that ablates a GYxx¿ trafficking signal in the Env TM cytoplasmic tail, the resulting virus (GY) replicates to a high acute RNA peak (1.8-9.3x10^6 copies/ml) comparable to SIVmac239 in PTMs (p=0.90) and to GY in rhesus macaques (RhM) (p=0.93). In RhMs (n=4) GY acute infection is followed by a 2-3 log reduction in viral set point (VSP) with minimal acute loss of CD4 cells in the lamina propria, but with a gradual decline in CD4 cells over 1 year. However, in PTMs (n=4) with the onset of host immune responses GY is suppressed to extremely low to undetectable levels (15, 15, 15, and 210 copies/ml by 19 weeks post infection), much lower than SIVmac239 (p=0.003) and GY (p=0.007) in RhM. Strikingly, the sustained, severe depletion of lamina propria CD4 T-cells that occurs with SIVmac239 infection did not occur with GY in PTM; from preinfection levels (median 43.9 %; range 25.4  54.3%) only a modest reduction occurred during acute infection (median 18.4 %; range 8.4  20.7%) with evidence of recovery by 22 weeks (median 27 %; range 18.3 - 46%). Moreover, monocyte turnover, determined by BrdU labeling, which we have shown increases with pathogenic SIV infection, was only minimally and transiently increased in GY-infected PTMs compared to SIVmac239-infected RhMs (p=0.03), possibly reflecting a lower level of microbial translocation and/or macrophage infection. GY control is clearly not the result of poor replicative ability, given its high acute viral peak in both PTM and RhM. How the GY mutation alters the pathogenic potential of SIVmac239 and why PTMs, a more susceptible species for pathogenic SIVmac infection, exhibit 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。 猪尾猕猴（PTM）被公认为对SIV诱导的疾病高度易感，SIVmac 239可重复并迅速引起AIDS。我们已经证明，当SIVmac 239含有一个突变，消除了GYxx <$TM胞质尾区的运输信号时，产生的病毒（戈伊）复制到高急性RNA峰（1.8-9.3x10^6拷贝/ml），与PTM中的SIVmac 239相当（p=0.90）， 恒河猴（RhM）中的戈伊（p=0.93）。在RhM中（n=4） 戈伊急性感染后，病毒设定点（VSP）降低2-3个对数，固有层中CD 4细胞的急性损失最小，但CD 4细胞在1年内逐渐下降。然而，在PTM（n=4）中，随着宿主免疫应答的发生， 戈伊被抑制至极低至检测不到的水平（感染后19周为15、15、15和210拷贝/ml），远低于SIVmac 239（p=0.003）， RhM中的戈伊（p=0.007）。引人注目的是，SIVmac 239感染时固有层CD 4 T细胞的持续严重耗竭在SIVmac 239感染后没有发生。 PTM中的戈伊;与感染前水平相比（中位数43.9%;范围25.4  54.3%）仅在急性感染期间发生中度降低（中位数18.4%;范围8.4  20.7%），22周时有恢复证据（中位数27%;范围18.3 - 46%）。此外，通过BrdU标记确定的单核细胞更新，我们已经表明随着致病性SIV感染而增加，在感染SIV的小鼠中， 与SIVmac 239感染的RhM相比，GY感染的PTM（p=0.03），可能反映了较低水平的微生物易位和/或巨噬细胞感染。 戈伊对照显然不是复制能力差的结果，因为其在PTM和RhM中都具有高急性病毒峰。如何 戈伊突变改变了SIVmac 239的致病潜力，以及为什么PTM（一种对致病性SIVmac感染更敏感的物种）比RhM表现出更好的戈伊控制，这将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引起极大的兴趣。