Delineating Viral Determinants of HAD using SCID Mice

使用 SCID 小鼠描绘 HAD 的病毒决定因素

• 批准号: 7006314
• 负责人: Vinayaka R. Prasad
• 金额: $ 30.14万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006314
• 关键词: AIDS; AIDS /HIV neuropathy; AIDS dementia complex; HIV infections; RNase protection assay; SCID mouse; chemokine; chemokine receptor; gliosis; green fluorescent proteins; histopathology; human tissue; immunocytochemistry; magnetic resonance imaging; neural degeneration; pathologic process; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): This project aims to test whether differences between HIV-1 subtypes B and C are responsible for differential incidence of HIV-associated dementia (HAD) between US & Indian populations, where HAD occurs reportedly at rates of 15-30% or 0.5% respectively. We previously showed that this differential incidence correlates with a specific defect in the chemokine motif of the subtype C HIV Tat protein. While subtype B Tat contains a dicysteine motif and displays monocyte chemotactic function, the subtype C Tat lacks both. Specific aims of this project are: (1) To examine the differential ability of subtype B and C HIV-1 to induce HIV-1 encephalitis in SCID mice in collaboration with Dr. William Tyor (Medical University of South Carolina), Dr. U. Ranga (JNCASR, Bangalore, India) and Dr. Hoby Hetherington (AECOM). In this mouse model, intracranial injection of HIV-1 infected human monocytes induces a spectrum of neuropathological and cognitive changes that mimic HAD. We will attempt to: (i) test if subtype C HIV is unable to induce HAD/HIVE and (ii) confirm a role for Tat and set the stage to identify other viral genes that play a role in HAD. Dr. Ranga will generate molecular clones of subtype C HIV from the same population where the low incidence of HAD was reported. In collaboration with Drs. Tyor and Hetherington, we will test the ability of the two subtypes of HIV to induce HIVE/HAD symptoms in mice. Following intracranial injection of HIV-infected human MDM, we will: (i) assess cognitive function using a Morris water maze; (ii) evaluate the extent and severity of neuronal injury using MR spectroscopic imaging; (iii) evaluate neuronal apoptosis and gliosis (migration of activated murine monocytes/microglia to the site of injection). We will correlate results from imaging, pathology and cognitive studies. In Aim 2, we will examine the hypothesis that absence of a functional chemokine motif in Tat protein is responsible for the low incidence of HAD in subtype C HIV-infected individuals by comparing the ability of human MDM expressing clade B or clade C Tat proteins to induce HAD in SCID HIVE model, such as cognitive defect, neuronal loss or gliosis. The neuronal loss will be determined by both MR imaging, while neuronal apoptosis and gliosis will be evaluated by histopathology using the Einstein Pathology core. The implications of this work to human health lie in the possibility that viral determinants of HAD can be identified hopefully leading to studies aimed at direct interventions for HAD.

描述（由申请人提供）：该项目旨在测试HIV-1亚型B和C之间的差异是否负责美国和印度人口之间与HIV相关的痴呆症（HAT）的差异发生率，据报道，据报道以15-30％或0.5％的速度发生。我们先前表明，这种差异的发生率与亚型C HIV TAT蛋白的趋化因子基序中的特定缺陷相关。虽然亚型b tat包含双重状态基序并显示单核细胞趋化功能，但亚型c tat缺乏两者。该项目的具体目的是：（1）检查亚型B和C HIV-1的差异能力与SCID小鼠中诱导HIV-1脑炎的差异能力与William Tyor博士（南卡罗来纳州医科大学），U.Ranga博士（JNCASR，Bangalore，India）和Hoby Hoby Hetherington（Aecom）。在这种小鼠模型中，颅内注射HIV-1感染的人单核细胞会诱导模仿的神经病理和认知变化。我们将尝试：（i）测试亚型艾滋病毒是否无法诱导/hive和（ii）确认tat的作用，并为识别其他在HAT中起作用的病毒基因奠定了基础。 Ranga博士将从据报道HAD的同一人群中产生亚型C HIV的分子克隆。与Drs合作。 Tyor和Hetherington，我们将测试HIV两种亚型诱导蜂巢/具有小鼠症状的能力。颅内注入HIV感染的人MDM后，我们将：（i）使用Morris Water Maze评估认知功能； （ii）使用MR光谱成像评估神经元损伤的程度和严重程度； （iii）评估神经元凋亡和神经胶质病（活化的鼠单核细胞/小胶质细胞迁移到注射部位）。我们将从成像，病理和认知研究中的结果相关联。在AIM 2中，我们将研究以下假设：TAT蛋白中缺乏功能性趋化因子基序是导致亚型C HIV感染个体的HAD的低发生率，通过比较表达对进化枝B或进化枝c TAT蛋白诱导的人类MDM的能力，具有较低的Hive模型，例如认知性缺陷损失或诸如Nevect，Neuronalal或Gliiisis。神经元丧失将通过MR成像确定，而神经元细胞凋亡和神经胶质病将使用爱因斯坦病理学核心通过组织病理学评估。这项工作对人类健康的含义在于，可以确定有可能导致针对直接干预措施的研究的病毒决定因素的可能性。