Validation of the Rev-dependent vector for targeting SIV macrophage reservoirs

说明（由申请人提供）：艾滋病毒/艾滋病流行病在全世界造成大约4 000万人的痛苦。艾滋病毒在大脑等解剖学避难所的持续存在阻碍了病毒的根除。巨噬细胞是HIV的主要天然储存库之一，特别是被感染的巨噬细胞浸润到大脑中也会引起神经元损伤。虽然抗逆转录病毒疗法（ART）抑制病毒复制，但它不能选择性地消除病毒库。因此，随着感染者预期寿命的延长，与艾滋病毒相关的神经系统疾病的流行已成为一个突出问题。在这个提议中，我们计划在SIV/恒河猴模型中测试一种新的治疗策略，以选择性地靶向病毒在大脑中的产生和再激活。我们开发了一种新的HIV/SIV rev依赖慢病毒载体，携带治疗基因靶向HIV/SIV感染。使用该系统，我们已经证明了在细胞培养条件下选择性杀死hiv阳性细胞。这项拟议的研究是首次尝试应用这种新技术来减少siv感染动物大脑中的病毒持久性。我们计划在恒河猴身上测试一种治疗性基因，疱疹病毒胸苷激酶（HSV1- tk）。rev介导的HSV1-tk表达具有实际用于治疗HIV感染的潜力，并可能最终导致解决该疾病。

DESCRIPTION (provided by applicant): The HIV/AIDS pandemic inflicts approximately 40 million people worldwide. The persistence of HIV in anatomic sanctuary sites such as the brain prevents viral eradication. One of the major natural reservoirs of HIV is macrophages, in particular infected-macrophages infiltrated into the brain also cause neuronal injury. Although the antiretroviral therapy (ART) inhibits viral replication, it does not selectively eliminate vira reservoirs. As such, with the greater life expectancy of infected people, the prevalence of HIV-associated neurological disorder has become a prominent problem. In this proposal, we plan to test a new therapeutic strategy to selectively target viral production and reactivation in the brai in SIV/rhesus macaque model. We have developed a novel HIV/SIV Rev-dependent lentiviral vector carrying therapeutic genes to target HIV/SIV infection. Using this system, we have demonstrated selective killing of HIV-positive cells in cell culture conditions. The proposed research is the first attempt to apply this novel technology to reduce viral persistence in the brain of SIV-infected animals. We plan to test a therapeutic gene, the herpes virus thymidine kinase (HSV1- tk), in rhesus macaques. The Rev-mediated expression of HSV1-tk has the potential to be practically used for the treatment of HIV infection, and may eventually lead to a solution to the disease.