Targeting Brain Macrophages by a novel lentiviral vector

描述（由申请人提供）：HIV-1相关的神经功能障碍是HIV-1感染晚期的常见并发症，被认为是由于感染的巨噬细胞浸润间接损伤神经元。目前，虽然高活性抗逆转录病毒疗法可以抑制病毒复制并降低疾病发病率，但作为一种治疗方法，它并不能消除持续存在于大脑中的病毒库。因此，尽管自实施hart疗法以来该病发病率有所下降，但随着受感染者预期寿命的延长，该病的流行成为一个突出的临床问题。这项建议的目的是开发一种新的治疗方法来靶向和消除大脑中感染的巨噬细胞。该提案的具体目的是测试该系统靶向感染巨噬细胞的可行性。这些特定目的的实验方法是在HIV-1感染的巨噬细胞中实现依赖于HIV-1 Tat和rev的细胞溶解基因——来自炭疽芽孢杆菌的炭疽酶O的表达，以杀死细胞。预计这项研究的结果将促进新的治疗策略的发展，以消除大脑中的病毒库。此外，神经元系统中治疗基因和报告基因的HIV-1依赖性表达的发展将通过提供一种新的工具来跟踪大脑中的病毒感染，从而促进病毒发病机制的研究。

DESCRIPTION (provided by applicant): HIV-1 associated neurological dysfunction is a common complication of late stage of HIV-1 infection, and is believed to be due to indirect neuronal injury by infiltration of infected macrophages. Currently, although the highly active antiretroviral regimen can inhibit viral replication and decrease the incidence of the disease, as a therapy, it does not eliminate the viral reservoir that persists in the brain. As such, despite the decreased incidence of the disease since the introduction of HARRT, with the greater life expectancy of infected people, the prevalence of the disease became a prominent clinical problem. The objectives of this proposal are to develop a novel therapeutic approach to target and eliminate infected macrophages in the brain. The specific aims of the proposal are to test the feasibility of this system in targeting infected macrophages. The experiment methods for these specific aims are to achieve HIV-1 Tat- and Rev-dependent expression of a cytolytic gene, anthralysin O from the bacteria Bacillus anthracis, in HIV-1 infected macrophages for cell killing. It is expected that results from the proposed research will promote the development of novel therapeutic strategies to eliminate viral reservoir in the brain. Additionally, the development of HIV-1 - dependent expression of therapeutic and reporter genes in the neuronal system will facilitate the study of viral pathogenesis by providing a novel tool to track viral infection in the brain.