Development of gene transfer approaches for neuroAIDS

描述（由申请人提供）： 人类免疫缺陷病毒（HIV）是中枢神经系统（CNS）的主要疾病，其影响约20%的HIV感染者。HIVD的治疗是有限的，部分原因是许多抗逆转录病毒药物无法穿透血脑屏障（BBB）;因此需要新的方法。 一种这样的方法可以是靶向通常穿过BBB的细胞，例如血液单核细胞。该建议的假设是，有可能对bold单核细胞进行遗传修饰，并将其用作“特洛伊木马”递送系统，以实现基因转移到CNS中，用于治疗neuroAIDS。 该项目将作为夏威夷大学和罗切斯特大学的研究人员之间的综合协调合作进行。本项目的申请人部分将侧重于测试和比较分析不同病毒载体对血液单核细胞的潜在能力;还将评估载体对单核细胞穿越血脑屏障的作用。还将进行实验以确定（1）用缺陷型干扰慢病毒载体（DLV）转导的单核细胞是否不太允许感染性HIV-1复制，以及（2）DLV是否可以被感染性HIV-1动员、扩增并扩散至未转导的旁观者细胞。本申请的合作者部分将重点分析载体转导的单核细胞是否释放与细胞活化相关的可溶性神经毒性因子。此外，该合作者构建了一种编码可溶性神经保护因子的病毒载体，并将确定用该载体转导的单核细胞是否能够促进暴露于明确定义的候选HIV神经毒素的旁观者神经元的存活。整个项目是一个紧密结合的整体，将使调查人员的互补专长能够以最有效和互利的方式得到应用。这项合作也将为PI及其学生和研究员提供充足的机会，以获得神经科学和各种相关技术的培训。总的来说，这项工作预计将导致对治疗神经艾滋病和其他神经系统疾病的新方法的重大见解。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) is a primary disorder of the central nervous system (CNS) that affects about 20% of individuals infected with HIV. Treatment for HIVD are limited, in part because many antiretroviral drugs fail to penetrate the blood-brain barrier (BBB); novel approaches are therefore needed. One such approach may be to target cells that normally traffic across the BBB- such as blood monocytes. The hypothesis of this proposal is that it may be possible to genetically modify bolld monocytes and to use them as a "Trojan horse" delivery system, to effect gene transfer into the CNS, for treatment of neuroAIDS. This project will be conducted as an integrated, coordinated collaboration between investigators at the University of Hawaii and the University of Rochester. The applicant component of this project will focus on the testing and comparative analysis of different virus vectors for their potential ability to transduce blood monocytes; vectors will also be evaluated with respect to their efforts on monocyte transmigration across the blood-brain barrier. Experiments will also be conducted to determine (1) whether monocytes transduced with a defective interfering lentivirus vector (DLV) are less permissive for replication of infectious HIV-1, and (2) whether the DLV can be mobilized, amplified and spread to untransduced bystander cells by infectious HIV-1. The collaborator component of this application will focus on analyzing whether vector-transduced monocytes release soluble neurotoxic factors associated with cellular activation. In addition, the collaborator with construct a virus vector encoding a soluble neuroprotective factor, and will determine if monocytes transduced with this vector are capable of promoting the survival of bystander neurons exposed to well-defined candidate HIV- neurotoxins. The entire project comprises a tightly integrated whole, and will allow for the complementary expertise of the investigators to be applied in a maximally productive and mutually beneficial way. The collaboration will also provide ample opportunitites for the PI, and his students and fellows, to obtain training in neuroscience and a wide range of related techniques. Overall, the work is expected to result in significant insight into new approaches for treatment of neuroAIDS and other neurologic diseases.