Ethanol modulation of SIV infection of the CNS

乙醇调节中枢神经系统 SIV 感染

• 批准号: 6786719
• 负责人: HOWARD S FOX
• 金额: $ 18.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-12 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786719
• 关键词: AIDS dementia complex; HIV infections; Macaca mulatta; alcoholism /alcohol abuse; blood brain barrier; bone marrow; central nervous system; cytokine; disease /disorder model; ethanol; histopathology; immunocytochemistry; in situ hybridization; longitudinal animal study; lymphocyte; macrophage; microglia; neuropathology; neuropharmacology; simian immunodeficiency virus; virus cytopathogenic effect; virus diseases; virus infection mechanism; virus load

DESCRIPTION (provided by applicant): In HIV-induced disease, the central nervous system (CNS) is both a target for virus infection as well as for damage induced by infection. Alcohol abuse is frequent among HIV-infected individuals and those at high risk for contracting HIV infection. Here we propose to examine the interactions of alcohol on the factors controlling SIV infection of the CNS of monkeys, as a model for ethanol effects on HIV in humans. Our working hypothesis is that the toxicity of HIV to the brain is initiated by viral infection of the brain, but is related more to the number and activation state of the brain microglia and macrophages, both of which increase following CNS virus infection. Does alcohol have an effect upon HIV entry and macrophage infiltration into the brain? This key question will be directly addressed here by these studies. This will be studied, in vivo, in the rhesus/SIV model. Events occurring during the acute phase after inoculation may greatly influence the disease induced by SIV. Since the CNS itself is both infected and affected early following inoculation, changes occurring during the acute infection period may dramatically alter CNS disease. Alcohol-treated and non-alcohol treated animals will be infected with SIV, and studied to determine the effect of ethanol on the initial course of SIV infection, and the effect of ethanol on SIV and macrophage entry into the CNS. We will examine the hypothesis that the CNS viral load and CNS macrophage infiltration resulting from SIV infection is altered by ethanol administration. There are numerous convergent processes that can be affected by alcohol and HIWSIV, such as effects on monocytic lineage cells, cytokines, chemokines, oxidative stress, viral infection and cell trafficking, that can result in untoward effects on the CNS. The mechanisms controlling CNS infection and macrophage infiltration will be investigated to pursue the nature of alcohol's effect.

描述（由申请人提供）： 在HIV诱导的疾病中，中枢神经系统（CNS）既是病毒感染的靶标，又是感染造成的损害。艾滋病毒感染的个体和患有艾滋病毒感染的高风险的人经常酗酒。在这里，我们建议将酒精对控制猴子中枢神经系统感染的因素的相互作用，这是对人类对艾滋病毒的乙醇影响的模型。我们的工作假设是，艾滋病毒对大脑的毒性是由大脑病毒感染引发的，但与脑小胶质细胞和巨噬细胞的数量和激活状态更相关，这两种状态都在CNS病毒感染后增加。酒精对艾滋病毒的进入和巨噬细胞浸润有影响吗？这些研究将直接解决这个关键问题。 这将在体内研究恒河类模型。接种后急性期发生的事件可能会极大地影响SIV诱导的疾病。由于CNS本身在接种后早期感染和影响，因此急性感染期间发生的变化可能会大大改变中枢神经系统疾病。经过酒精治疗和非酒精治疗的动物将被SIV感染，并进行了研究以确定乙醇对SIV感染初始过程的影响，以及乙醇对SIV和巨噬细胞进入中枢神经系统的影响。我们将研究以下假设：SIV感染引起的CNS病毒载量和CNS巨噬细胞浸润会通过乙醇给药改变。有许多收敛的过程可能会受到酒精和HIWSIV的影响，例如对单核细胞细胞，细胞因子，趋化因子，氧化应激，病毒感染和细胞运输的影响，这可能会对人o造成不利影响。控制中枢神经系统感染和巨噬细胞浸润的机制将被研究以追求酒精作用的性质。