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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 扎尾猕猴（PTM）被广泛认为是高度容易受到SIV诱导的疾病的影响，SIVMAC239可重复且迅速引起艾滋病。 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）。在RHMS（n = 4）中，Gy急性感染之后是病毒式设定点（VSP）的2-3对数减少，而lamina lamina propira中CD4细胞的急性损失最小，但在1年内CD4细胞的成绩下降。但是，在PTMS（n = 4）中，宿主免疫反应的发作Gy被抑制至极低至不可检测的水平（感染后19周，15、15、15、15和210拷贝/ml）在RHM中低于SIVMAC239（P = 0.003）和GY（P = 0.007）。令人惊讶的是，在PTM中，GY不会发生持续的，严重的固有椎板CD4 T细胞，而SIVMAC239感染并未发生。从预发现水平（中值43.9％；范围25.4 54.3％）中，急性感染期间仅发生适度的降低（中位18.4％；范围8.4 20.7％），恢复22周的证据（中位27％；范围为18.3-46％）。此外，与SIVMAC239感染的RHM相比，通过致病性SIV感染显示，通过BRDU标记确定的单核细胞更新仅在致病性SIV感染中增加，而在GY感染的PTM中仅瞬时增加（P = 0.03），可能反映了较低的微生物转运和/或或或或或或或或或或或或摩尔或或或或粘液膜。鉴于PTM和RHM的高急性病毒峰值，GY控制显然不是复制能力不良的结果。 GY突变如何改变SIVMAC239的致病潜力，以及为什么PTMS（一种更易感的致病SIVMAC感染物种）比RHM更好地控制了对RHM的控制，这将在确定病毒和宿主相互作用方面具有与病毒控制和疾病相关的宿主相互作用。