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.
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