SIV, IDO, and the Host Response in neuroAIDS

描述（由申请人提供）：即使在HAART的当前时代，在hiv感染者中，中枢神经系统仍然是病毒感染和疾病引起的损伤的目标。已知HIV在单核细胞谱系中感染并持续存在于大脑中。我们最近在SIV脑炎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，并在疾病早期和晚期的大脑小胶质细胞和巨噬细胞中发现IDO诱导。IDO催化色氨酸的氧化分解，该反应对免疫和神经系统产生一系列影响，对HIV神经发病机制具有重要意义。我们推测，在病毒感染的巨噬细胞中IDO的表达为病毒在中枢神经系统中创造了一个安全的避风港，允许感染的持续和传播。在三个提出的具体目标中，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，以揭示这种安全避风港是如何创建的。在这些研究中，我们将探讨三种假设：1)SIV感染巨噬细胞导致IDO诱导，并使细胞在低水平的其他刺激剂下产生IDO；2) SIV和局部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，通过代偿机制保护巨噬细胞的活力和病毒的产生。这些研究将揭示IDO在小胶质细胞和巨噬细胞中调控的分子机制，以及它在HIV感染中的神经发病机制，并导致发现允许这些途径被治疗性地操纵。

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.