Central nervous system (CNS) involvement often occurs in individuals infected with human immunodeficiency virus type-1 (HIV-1). The most common clinical syndrome characterized by cognitive, motor, and behavioral disturbances is the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) or HIV- associated dementia (HAD), and is unique to HIV-1 infection. Although anti-retroviral agents (RT and protease inhibitors) are being used in HIV-infected individuals, it is not yet clear how these agents will affect HAD or if these drugs can even penetrate the brain. Thus, a major problem facing HAD patients is the that drugs used to combat systemic viral infection may not influence the CNS, a potential reservoir for virus. Because the physiological status of the brain in AIDS patients cannot be readily sampled, there is a critical need for the development of non-invasive techniques to detect and monitor the extent of HIV- associated cognitive/motor disorders. In this application, we intend to translate basic science findings obtained in the previous grant period to the human, and perform clinical cognitive studies on HIV-infected patients. We will develop non- invasive methodologies, based on 31P nuclear magnetic resonance (NMR) spectroscopy, eventually to investigate how pharmacological and/or immunological manipulations can affect the pathological and psychomotor abnormalities in humans infected with HIV-1. We will also correlate such brain metabolic changes with the degree of dementia in HAD patients. This will be accomplished through he neuropsychological assessment of participants. Thus, a sophisticated array of experimental approaches will be used to define molecular mechanisms underlying the pathophysiology of HAD, which ultimately will be critical for the development and assessment of new therapeutic strategies. There is one specific aim: 1) to test the hypothesis that cerebrospinal fluid (CSF) viral load, CD4+ cells, and/or cytokine content correlates with increases in pH in various regions of the brain, specifically the basal ganglia and cerebellum. In addition, neuropsychological testing will be performed on all subjects enrolled in this study in an effort to a) assess subject neurocognitive/motor status and b) to link the clinical developmental stage of dementia with CSF viral load and brain pH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH050421-10
Application #
6528795
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Kopnisky, Kathy Lynn
Project Start
1993-09-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
10
Fiscal Year
2002
Total Cost
$358,750
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Patton, H K; Chu, W J; Hetherington, H P et al. (2001) Alkaline pH changes in the cerebellum of asymptomatic HIV-infected individuals. NMR Biomed 14:12-8
Lee, S J; Drabik, K; Van Wagoner, N J et al. (2000) ICAM-1-induced expression of proinflammatory cytokines in astrocytes: involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. J Immunol 165:4658-66
Collawn, J F; Benveniste, E N (1999) Regulation of MHC class II expression in the central nervous system. Microbes Infect 1:893-902
Oh, J W; Schwiebert, L M; Benveniste, E N (1999) Cytokine regulation of CC and CXC chemokine expression by human astrocytes. J Neurovirol 5:82-94
Benveniste, E N (1998) Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 9:259-75
Benveniste, E N (1997) Cytokines: influence on glial cell gene expression and function. Chem Immunol 69:31-75
Kwon, J; Lee, S J; Benveniste, E N (1996) A 3' cis-acting element is involved in tumor necrosis factor-alpha gene expression in astrocytes. J Biol Chem 271:22383-90
Patton, H K; Benveniste, E N; Benos, D J (1996) Astrocytes and the AIDS dementia complex. J NeuroAIDS 1:111-31
Rohn, W M; Lee, Y J; Benveniste, E N (1996) Regulation of class II MHC expression. Crit Rev Immunol 16:311-30
Shrikant, P; Benos, D J; Tang, L P et al. (1996) HIV glycoprotein 120 enhances intercellular adhesion molecule-1 gene expression in glial cells. Involvement of Janus kinase/signal transducer and activator of transcription and protein kinase C signaling pathways. J Immunol 156:1307-14

Showing the most recent 10 out of 19 publications