SIV, IDO, and the Host Response in neuroAIDS

SIV、IDO 和神经艾滋病中的宿主反应

基本信息

批准号：
7746470
负责人：
LARISA Y POLUEKTOVA
金额：
$ 30.82万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7746470
关键词：
AIDS Dementia Complex AIDS neuropathy Acquired Immunodeficiency Syndrome Adherence Brain Catabolism Cells Chemosensitization Cognitive Complex Data Dementia Dependence Development Dioxygenases Disease Dose Environment Enzymes Generations Giant Cells HIV HIV-1 Highly Active Antiretroviral Therapy Human Immune Immune response Immune system Incidence Individual Infection Lead Life Microglia Minor Molecular Monkeys Nervous system structure Neuraxis Neurobiology Neuropathogenesis Pathway interactions Prevalence Production Quinolinic Acid Reaction Regimen Role SIV SIV encephalitis Staging T cell response T-Lymphocyte Therapeutic Time Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan-tRNA Ligase Viral Viral Encephalitis Viral Load result Viral Proteins Virus Virus Diseases base cytokine immunoregulation indoleamine macrophage mortality motor disorder motor impairment novel research study viral resistance

项目摘要

DESCRIPTION (provided by applicant): Even in the current era of HAART, the central nervous system remains a target for viral infection and disease-induced damage in HIV-infected individuals. HIV is known to infect and persist in the brain in cells of the monocytic lineage. We have recently identified co-expression of the enzyme indoleamine 2,3- dioxygenase (IDO) with SIV in the brains of monkeys with SIV encephalitis, and have found IDO induction in microglia and macrophages in brains at both early and late stages of disease. IDO catalyzes the oxidative breakdown of tryptophan, and this reaction leads to a number of effects on both the immune and nervous system with important implications for HIV neuropathogenesis. We hypothesize that the expression of IDO in virus-infected macrophage creates a safe haven for the virus in the CNS, allowing persistence and spread of the infection. In the three proposed specific aims, we will examine the basis for the induction of IDO in infected cells, assess the factors that modulate IDO expression, and perform functional studies to uncover how this safe haven is created. In these studies, will investigate three hypotheses: 1) SIV infection of macrophages leads to IDO induction and sensitizes the cells to produce IDO at low levels of other stimulating agents; 2) SIV and the local environment influence the production and activity of IDO through specific transcriptional and post- transcriptional mechanisms; and 3) IDO alters the ability of host T cells to inhibit viral replication, with compensatory mechanisms protecting macrophage viability and viral production. These studies will uncover the molecular mechanisms by which IDO is regulated in microglia and macrophages, the means by which it contributes to neuropathogenesis in HIV infection, and lead to discoveries allowing such pathways to be manipulated therapeutically.

描述（由申请人提供）：即使在当前的HAART时代，中枢神经系统仍然是HIV感染者病毒感染和疾病引起的损害的目标。众所周知，HIV 会感染大脑中的单核细胞谱系细胞并持续存在。我们最近在患有 SIV 脑炎的猴子的大脑中发现了吲哚胺 2,3-双加氧酶 (IDO) 与 SIV 的共表达，并且发现在疾病的早期和晚期阶段，IDO 在大脑中的小胶质细胞和巨噬细胞中诱导。 IDO 催化色氨酸的氧化分解，这种反应会对免疫和神经系统产生多种影响，对 HIV 神经发病机制具有重要意义。我们假设病毒感染的巨噬细胞中 IDO 的表达为中枢神经系统中的病毒创造了一个安全港，从而允许感染持续存在和传播。在提出的三个具体目标中，我们将检查受感染细胞中诱导 IDO 的基础，评估调节 IDO 表达的因素，并进行功能研究以揭示这个安全港是如何创建的。在这些研究中，将研究三个假设：1）巨噬细胞的SIV感染导致IDO诱导，并使细胞在低水平的其他刺激剂下敏感地产生IDO； 2）SIV和当地环境通过特定的转录和转录后机制影响IDO的产生和活性； 3) IDO 改变宿主 T 细胞抑制病毒复制的能力，并通过补偿机制保护巨噬细胞活力和病毒产生。这些研究将揭示 IDO 在小胶质细胞和巨噬细胞中调节的分子机制，它促进 HIV 感染的神经发病机制的方式，并导致允许在治疗上操纵这些途径的发现。