SIV, IDO, and the Host Response in neuroAIDS

SIV、IDO 和神经艾滋病中的宿主反应

• 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
• 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

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(申请人提供)：即使在当前的HAART时代，中枢神经系统仍然是艾滋病毒感染者病毒感染和疾病诱导损害的目标。众所周知，艾滋病毒会感染并持续存在于单核细胞系的大脑细胞中。我们最近在SIV脑炎猴的脑中发现了吲哚胺2，3-双加氧酶(IDO)与SIV的共表达，并在疾病的早期和晚期发现IDO诱导了大脑中的小胶质细胞和巨噬细胞。IDO催化色氨酸的氧化分解，这一反应对免疫和神经系统都产生了一系列影响，对HIV的神经发病机制具有重要意义。我们推测，IDO在感染病毒的巨噬细胞中的表达为病毒在中枢神经系统创造了一个安全的避风港，使感染得以持续和传播。在提出的三个具体目标中，我们将研究在感染细胞中诱导IDO的基础，评估调节IDO表达的因素，并进行功能研究，以揭示这种安全港是如何创建的。在这些研究中，将探讨三个假说：1)SIV感染巨噬细胞导致IDO诱导，并使细胞敏感地在低水平的其他刺激剂的作用下产生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；以及3)IDO改变宿主T细胞抑制病毒复制的能力，补偿机制保护巨噬细胞的活性和病毒的产生。这些研究将揭示IDO在小胶质细胞和巨噬细胞中受到调控的分子机制，以及它在艾滋病毒感染中促进神经发病的方式，并导致发现这些途径可以在治疗上进行操纵。