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之间的差异是否是美国和印度人群之间HIV相关痴呆（HAD）发生率差异的原因，据报道，HAD的发生率分别为15 - 30%或0.5%。我们以前表明，这种差异发病率与C亚型HIV达特蛋白的趋化因子基序中的特定缺陷相关。亚型B达特含有双半胱氨酸基序并显示单核细胞趋化功能，而亚型C达特两者都缺乏。本项目的具体目标是：（1）与美国南卡罗来纳医科大学的William Tyor博士合作，研究B亚型和C亚型HIV-1在SCID小鼠中诱导HIV-1脑炎的差异能力。Ranga（JNCASR，印度班加罗尔）和Hoby Hetherington博士（AECOM）。在该小鼠模型中，颅内注射HIV-1感染的人单核细胞诱导了一系列类似HAD的神经病理学和认知变化。我们将尝试：（i）测试C亚型HIV是否不能诱导HAD/HIVE，和（ii）确认达特的作用，并为鉴定在HAD中起作用的其他病毒基因奠定基础。Ranga博士将从报告HAD低发病率的同一人群中产生C亚型HIV的分子克隆。与Tyor和Hetherington博士合作，我们将测试两种HIV亚型在小鼠中诱导HIVE/HAD症状的能力。颅内注射HIV感染的人MDM后，我们将：（i）使用Morris水迷宫评估认知功能;（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增生（活化的鼠单核细胞/小胶质细胞向注射部位的迁移）。我们将把影像学、病理学和认知研究的结果联系起来。在目的2中，我们将通过比较表达进化枝B或进化枝C达特蛋白的人MDM在SCID HIVE模型中诱导HAD（如认知缺陷、神经元损失或神经胶质增生）的能力来检验以下假设：达特蛋白中功能性趋化因子基序的缺失是C亚型HIV感染个体中HAD发生率低的原因。神经元损失将通过MR成像确定，而神经元凋亡和神经胶质增生将通过使用Einstein病理学核心的组织病理学进行评价。这项工作对人类健康的影响在于可以确定HAD的病毒决定因素的可能性，希望能够导致针对HAD直接干预的研究。