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

描述(申请人提供)：全球约有4000万人感染艾滋病毒/艾滋病。艾滋病毒在大脑等解剖避难所的持续存在阻碍了病毒的根除。HIV的主要天然储存库之一是巨噬细胞，特别是感染的巨噬细胞渗入大脑也会导致神经元损伤。虽然抗逆转录病毒疗法(ART)可以抑制病毒复制，但它并不选择性地消除病毒库。因此，随着感染者预期寿命的延长，艾滋病毒相关神经疾病的流行已成为一个突出的问题。在这项提案中，我们计划测试一种新的治疗策略，在SIV/恒河猴模型中选择性地针对脑内病毒的产生和重新激活。我们开发了一种新型的依赖于HIV/SIV Rev的慢病毒载体，该载体携带治疗性基因来靶向HIV/SIV感染。使用这个系统，我们已经展示了在细胞培养条件下选择性地杀死HIV阳性细胞。这项拟议的研究是首次尝试应用这项新技术来减少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基因--疱疹病毒胸苷激酶(HSV1-tk)。REV介导的HSV1-tk的表达有可能用于HIV感染的治疗，并最终可能导致疾病的解决方案。

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.