Interaction of Alcohol with HIV-Protein

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DESCRIPTION (provided by applicant): 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.