Effect of Alcohol on SHIV Neuroinvasion

描述（由申请人提供）： 大约20%感染人类免疫缺陷病毒1型（HIV-1）的人会发展成一种神经系统疾病，称为HIV相关的认知/运动综合征或AIDS痴呆综合征。 已知长期使用乙醇可导致免疫功能低下状态，从而导致对细菌和病毒病原体的易感性增加。 相当多的HIV-1阳性者饮用适量至过量的酒精。 尚未在相关动物模型系统中进行直接评估酒精对HIV-1神经侵袭和神经发病机制的作用的详细研究。 研究者的实验室已经推导出一种猴-人免疫缺陷病毒（SHIV 500 LNV）的变体，该变体在接种到猪尾猕猴中后，导致高病毒负荷、T细胞的CD 4+亚群耗竭以及50%的猕猴中的神经病理学（血管周围套囊、小胶质细胞结节），这与在HIV-1感染的人中观察到的相似。 在拟议的研究中，研究人员建议使用神经致病性SHIV/猕猴模型来确定酒精是否可以直接影响神经侵袭的早期事件以及SHIV诱导的脑炎的发生率。 将16只猕猴置于自我施用乙醇饮食以模拟适度饮酒，并将16只猕猴置于缺乏乙醇9个月。 在这一点上，十六只猕猴（8只接受乙醇饮食，8只接受无乙醇饮食）接种SHIV 500 LNV，维持其乙醇饮食，并在2周时处死，以确定在感染的初级阶段，自我施用乙醇是否会导致神经侵袭增加，这是病毒复制不受限制的时期，此时宿主还没有产生针对病毒的有效免疫应答。在第二组16只猕猴（8只喂食乙醇饮食，8只喂食无乙醇饮食）中，接种病毒，并跟踪猕猴直至濒死，以确定乙醇饮食是否会导致神经系统疾病的发病率增加。 这些研究结果将为乙醇对灵长类慢病毒神经侵袭和神经发病机制的影响提供直接证据。

DESCRIPTION (provided by applicant): Approximately 20% of humans infected with human immunodeficiency virus type 1 (HIV-1) develop a neurological disease known as HIV-associated cognitive/motor complex or AIDS dementia complex. It is known that chronic use of ethanol can lead to an immunocompromised state that results in increased susceptibility to bacterial and viral pathogens. A significant number of HIV-1 positive individuals drink moderate to excessive amounts of alcohol. Detailed studies directly assessing the role of alcohol on HIV-1 neuroinvasion and neuropathogenesis have not been performed in a relevant animal model system. The investigator's laboratory has derived a variant of simian-human immunodeficiency virus (SHIV500LNV) that following inoculation into pig-tailed macaques, results in high virus burdens, depletion of the CD4+ subset of T cells, and a neuropathology (perivascular cuffing, microglial nodules) in 50% of the macaques that is similar to that seen in HIV-1 infected humans. In the proposed studies, the investigators propose to use the neuropathogenic SHIV/macaque model to determine if alcohol can directly affect the early events of neuroinvasion as well as the incidence of SHIV-induce encephalitis. Sixteen macaques will be placed on a self-administered ethanol diet to model moderate drinking and sixteen macaques on lacking ethanol for 9 months. At this point, sixteen macaques (eight on the ethanol diet and eight on the ethanol free diet) will be inoculated with SHIV500LNV, maintained on their ethanol diet and sacrificed at 2 weeks to determine if self-administered ethanol will result in increased neuroinvasion during the primary phase of infection, which is a period of unrestricted virus replication and when the host has not yet developed an effective immune response against the virus. In the second group of sixteen macaques (again eight on the ethanol diet and eight on the ethanol-free diet), the virus will be inoculated and macaques followed until moribund to determine if an ethanol diet will result in an increased incidence of neurological disease. The results of these studies should provide direct evidence on the effect of ethanol on primate lentivirus neuroinvasion and neuropathogenesis.