PATHOGENIC DETERMINANTS OF THE SIV ENVELOPE TRANSMEMBRANE CYTOPLASMIC DOMAIN

SIV 包膜跨膜细胞质域的致病决定因素

• 批准号: 8173001
• 负责人: James A Hoxie
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173001
• 关键词: Acute; Animals; Attenuated; Autopsy; Biopsy; CD4 Positive T Lymphocytes; Cells; Chronic; Competence; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Cytoplasmic Tail; Defect; Diffuse; Employee Strikes; Funding; Grant; Gut associated lymphoid tissue; Immune; Immune response; Infection; Infection Control; Institution; Intestines; Lamina Propria; Lymph; Lymphoid; Lymphoid Tissue; Macaca; Macaca mulatta; Nodule; Peripheral; Phenotype; Plasma; RNA; Research; Research Personnel; Resources; Signal Transduction; Site; Source; Structure of germinal center of lymph node; T-Lymphocyte; Tissues; United States National Institutes of Health; Viral; Virus; attenuation; lymph nodes; macrophage; trafficking; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We previously showed that disrupting a highly conserved trafficking signal (GYxx¿) in the Env cytoplasmic tail of SIVmac239 (i.e. deleting Gly-721 and Tyr-721) produces a profoundly attenuated phenotype in rhesus and pigtailed macaques. Following iv inoculation, deltaGY replicates to a high acute viral peak comparable to SIVmac239, but is suppressed to 100 copies/ml with no loss of peripheral CD4 cells. To determine the pathological correlates of attenuation, 4 rhesus macaques were infected iv with deltaGY. Two animals were necropsied on day 28; 2 are being followed with serial biopsies of GALT and peripheral lymph nodes. Four animals were inoculated intravaginally to determine deltaGY's competence for mucosal transmission. For iv-infected animals, the acute viral peak was 1.8x10^6 (2.2x10^5-6.0x10^7) with levels for 2 chronically infected animals declining to 1.4x10^3 and 6.4x10^3 by week 16. For ivag-inoculated animals, 1 of 4 became infected (peak= 2.6x10^7) despite 8 weekly inoculations of 350 TCID50. For necropsied animals, abundant virus was detectable in germinal centers of organized lymphoid tissue in intestine and peripheral lymph nodes. However, in striking contrast to SIVmac239- or SIVmac251-infected controls, infection was limited to immune inductive sites (organized lymphoid nodules) and absent from immune effector sites (diffuse lamina propria). There was also little to no depletion of intestinal CD4+/CCR5+ cells in chronic, deltaGY-infected animals (average CD4+/CCR5+= 43.8% of T-cells pre-infection; 33.3% wk 22 post-infection). For necropsied animals there was also no detectable virus in CNS despite high acute levels of plasma RNA. Multilabel confocal microscopy of peripheral lymph tissue showed deltaGY in T-cells but not macrophages. Thus, deltaGY replication is driven by infected T-cells in immune inductive sites, but with sparing of macrophages and LPL in immune effector sites. How a defect in Env trafficking disrupts viral spread, and what host immune responses correlate with its control is being investigated.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 我们先前表明，在SIVMAC239的ENV细胞质尾部（即删除的Gly-721和Tyr-721）中扰乱高度组成的运输信号（Gyxx¿）会产生恒河和粘液斑块中的严重减弱的表型。 IV接种后，三角洲复制到与SIVMAC239相当的高急性病毒峰值，但被抑制至100份/ml，而不会损失外周CD4细胞。为了确定衰减的病理相关性，将4颗猕猴感染了iv。在第28天，两只动物被尸检； 2随后是Galt和外周淋巴结的系列活检。将四只动物接种静脉内，以确定Deltagy在粘膜传播方面的能力。 For iv-infected animals, the acute viral peak was 1.8x10^6 (2.2x10^5-6.0x10^7) with levels for 2 chronically infected animals declining to 1.4x10^3 and 6.4x10^3 by week 16. For ivag-inoculated animals, 1 of 4 became infected (peak= 2.6x10^7) Despite 8 weekly inoculations of 350 TCID50.对于死灵动物，在有组织的淋巴组织和周围淋巴结的有组织淋巴组织的生发中心中检测到了丰富的病毒。然而，与SIVMAC239-或SIVMAC251感染的对照形成鲜明对比的是，感染仅限于免疫电感部位（有组织的淋巴结结节），而免疫效应部位（diffuse lamina propria）不存在。在慢性增长感染的动物中，肠CD4+/CCR5+细胞也几乎没有耗尽（平均CD4+/CCR5+= 43.8％的T细胞感染前的43.8％； 33.3％的感染后22 WK 22感染）。对于死灵动物，尽管血浆RNA水平较高，但中枢神经系统中也没有可检测的病毒。周围淋巴组织的多标记共聚焦显微镜在T细胞但没有巨噬细胞中显示出三角洲。这是由免疫电感部位中感染的T细胞驱动的，但在免疫效应部位中的T细胞和LPL持续。 ENV运输中的缺陷如何破坏病毒的传播，以及正在研究哪些宿主免疫反应与其控制相关。