The pathogenesis of HIV-1 infection in the central nervous system (CNS) is uncertain. The role of factors which regulate HIV-1 production in the brain or which actually cause damage to neural cells remains to be defined. Using transgenic mouse technology we will address several hypotheses relevant to the neuropathogenesis of HIV-1 in vivo including: 1. Inflammation in the brain activates HIV-1. Using an established line of transgenic mice in which beta-galactosidase (beta-gal) is expressed in the brain under the direction of HIV-1 long terminal repeat (LTR), we will create inflammation with a cerebral stab wound and herpes simplex virus type 1 encephalitis. beta-gal production will be compared in treated and untreated mice. 2. Tumor necrosis factor-alpha (TNF-alpha) is neurotoxic when secreted in the brain. We will generate transgenic mice which express TNF-alpha under the direction of a brain specific promoter, glial fibrillary acidic protein (GFAP), evaluate offspring mice neuropathologically, and compare the neuropathology to that seen in HIV-1 CNS infection. 3. HIV-1, transactivating protein (tat) is neurotoxic when secreted in the brain. We will create two sets of transgenic mice which express tat in the brain under the direction of GFAP and HIV-1 LTR, evaluate the offspring mice neuropathologically, and compare the neuropathology to that seen in HIV-1 CBS infection. 4. TNF-alpha and tat activate HIV-1 LTR in the brain. Transgenic mice expressing TNF-alpha and tat in the brain will be bred with HIV-1 LTR- beta-gal mice, and offspring carrying both transgenes will be assessed for beta-gal production in comparison to littermates who carry either one or neither transgene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08NS001673-02
Application #
2259724
Study Section
NST-2 Subcommittee (NST)
Project Start
1993-07-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Corboy, J R; Garl, P J (1997) HIV-1 LTR DNA sequence variation in brain-derived isolates. J Neurovirol 3:331-41