? ? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Minority Biomedical Research Support Thematic Project Grants (S11)
Project #
5S11NS043499-03
Application #
6773858
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gordon, Alfred W
Project Start
2002-09-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$290,372
Indirect Cost
Name
University of Hawaii
Department
Type
Organized Research Units
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Kang, Wen; Marasco, Wayne A; Tong, Hsin-I et al. (2014) Anti-tat Hutat2:Fc mediated protection against tat-induced neurotoxicity and HIV-1 replication in human monocyte-derived macrophages. J Neuroinflammation 11:195
Wu, Chengxiang; Nerurkar, Vivek R; Lu, Yuanan (2013) New insights into inhibition of human immunodeficiency virus type 1 replication through mutant tRNALys3. Retrovirology 10:112
Cao, Shengbo; Wu, Chengxiang; Yang, Yongbo et al. (2011) Lentiviral vector-mediated stable expression of sTNFR-Fc in human macrophage and neuronal cells as a potential therapy for neuroAIDS. J Neuroinflammation 8:48
Yang, Yongbo; Wu, Jianguo; Lu, Yuanan (2010) Mechanism of HIV-1-TAT induction of interleukin-1beta from human monocytes: Involvement of the phospholipase C/protein kinase C signaling cascade. J Med Virol 82:735-46
Wu, Chengxiang; Lu, Yuanan (2010) High-titre retroviral vector system for efficient gene delivery into human and mouse cells of haematopoietic and lymphocytic lineages. J Gen Virol 91:1909-18
Lu, Yuanan (2009) GFP-lentiviral vectors targeting for neuroAIDS. Methods Mol Biol 515:177-97
Yang, Yongbo; Wu, Chengxiang; Wu, Jianguo et al. (2008) Inhibition of West Nile Virus replication by retrovirus-delivered small interfering RNA in human neuroblastoma cells. J Med Virol 80:930-6
Wu, Chengxiang; Nerurkar, Vivek R; Yanagihara, Richard et al. (2008) Effective modifications for improved homologous recombination and high-efficiency generation of recombinant adenovirus-based vectors. J Virol Methods 153:120-8
Sniderhan, Lynn F; Stout, Angela; Lu, Yuanan et al. (2008) Ankyrin-rich membrane spanning protein plays a critical role in nuclear factor-kappa B signaling. Mol Cell Neurosci 38:404-16
Wu, C; Lu, Y (2007) Inclusion of high molecular weight dextran in calcium phosphate-mediated transfection significantly improves gene transfer efficiency. Cell Mol Biol (Noisy-le-grand) 53:67-74

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