Human immunodeficiency virus type -1 (HIV-1) infection is the commonest cause of dementia in adults less than 40 years of age. Alcohol is a common drug of abuse in HIV-infected patients that can worsen the decline of frontal lobe function that is associated with HIV encephalitis. Our goals are to determine the mechanisms of neuronal dysfunction and death associated with alcohol abuse in the setting of HIV-dementia that are dependent on the pathological modification of ceramide and sterol content in neuronal membranes. Although a number of channelopathies have been identified in HIV-dementia, we have deliberately focused our attention on alterations in N-methyl-d-aspartate (NMDA) receptor function because of the importance of this excitatory receptor in neuronal dysfunction and death. Our preliminary findings suggest that the alcohol can rapidly alter the cholesterol and ceramide content of neuronal membranes, while the HIV-1 proteins gp120 and Tat alter the sphingomyelin and ceramide composition, and promote the trafficking of NMDA receptors to rafts. Based on these observations we hypothesize that alcohol may promote neuronal dysfunction in HIV-dementia by disorganizing the structure of lipid rafts and perturbing the function of raft-located NMDA receptors. Accordingly, pharmacological agents that stabilize ceramide and cholesterol metabolism may be neuroprotective by preventing the disorganization of lipid rafts. Using in vitro and in vivo models of HIV-dementia, we propose to determine the mechanisms of how alcohol dysregulates neuronal function in acute, chronic and withdrawal conditions. ? ? Public Health Relevance: Alcohol is a common drug of abuse in HIV-infected patients that can hasten the onset of dementia and worsen the severity of cognitive decline. Determination of how alcohol interacts with viral products to damage brain cells is critical for the rational design of therapeutics designed to protect brain functions. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA017408-01
Application #
7425495
Study Section
Special Emphasis Panel (ZAA1-BB (12))
Program Officer
Noronha, Antonio
Project Start
2007-09-27
Project End
2012-08-31
Budget Start
2007-09-27
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$375,199
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Tovar-Y-Romo, Luis B; Kolson, Dennis L; Bandaru, Veera Venkata Ratnam et al. (2013) Adenosine triphosphate released from HIV-infected macrophages regulates glutamatergic tone and dendritic spine density on neurons. J Neuroimmune Pharmacol 8:998-1009
Saleem, Mahwesh; Bandaru, Veera V Ratnam; Herrmann, Nathan et al. (2013) Ceramides predict verbal memory performance in coronary artery disease patients undertaking exercise: a prospective cohort pilot study. BMC Geriatr 13:135
Haughey, Norman J; Zhu, Xiaomao; Bandaru, Veera Venkata Ratnam (2013) A biological perspective of CSF lipids as surrogate markers for cognitive status in HIV. J Neuroimmune Pharmacol 8:1136-46

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