Interaction of Alcohol with HIV-Protein

描述(申请人提供)：人类免疫缺陷病毒1型(HIV-1)感染是40岁以下成年人痴呆症的最常见原因。酒精是艾滋病毒感染者滥用的一种常见药物，它会加剧与艾滋病毒脑炎有关的额叶功能下降。我们的目标是确定在HIV痴呆的背景下与酒精滥用相关的神经元功能障碍和死亡的机制，这些机制依赖于神经酰胺和神经细胞膜中固醇含量的病理改变。虽然在HIV痴呆中已经发现了许多通道病变，但我们故意将注意力集中在N-甲基-d-天冬氨酸(NMDA)受体功能的变化上，因为这种兴奋性受体在神经元功能障碍和死亡中的重要性。我们的初步发现表明，酒精可以迅速改变神经细胞膜的胆固醇和神经酰胺含量，而HIV-1蛋白gp120和Tat则改变神经鞘磷脂和神经酰胺的组成，并促进NMDA受体向RAFT的转运。基于这些观察，我们假设酒精可能通过扰乱脂筏结构和扰乱RAFT定位的NMDA受体的功能来促进HIV痴呆患者的神经元功能障碍。因此，稳定神经酰胺和胆固醇代谢的药物可能通过防止脂筏的解体而起到神经保护作用。利用HIV-痴呆的体外和体内模型，我们建议确定酒精在急性、慢性和戒断条件下如何调节神经元功能的机制。 与公共卫生相关：酒精是艾滋病毒感染患者中一种常见的滥用药物，会加速痴呆症的发病，并加剧认知能力下降的严重程度。确定酒精如何与病毒产物相互作用损害脑细胞，对于合理设计保护大脑功能的疗法至关重要。

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.