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相关认知/运动复合体或艾滋病痴呆复合体。众所周知，长期使用乙醇会导致免疫功能受损，从而增加对细菌和病毒病原体的易感性。相当数量的HIV-1阳性个人饮酒适中至过量。直接评估酒精在HIV-1神经侵袭和神经发病中的作用的详细研究尚未在相关的动物模型系统中进行。研究人员的实验室已经获得了一种猴-人类免疫缺陷病毒的变种(SHIV500LNV)，在接种到猪尾猕猴后，会导致高病毒负荷，T细胞的CD4+亚群耗尽，以及50%的猕猴出现类似于HIV-1感染人类的神经病理(血管周围袖带、小胶质结节)。在拟议的研究中，研究人员建议使用神经致病的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诱发的脑炎的发生率。为了模拟适度饮酒，16只猕猴被安排在自我给药的酒精饮食中，16只猕猴在9个月内不喝酒精。在这一点上，16只猕猴(8只在酒精饮食和8只在无酒精饮食)将被接种SHIV500LNV，维持在它们的酒精饮食，并在2周后被处死，以确定在感染的初始阶段，即病毒不受限制的复制阶段和宿主尚未对病毒产生有效的免疫反应时，自我注射乙醇是否会导致神经侵袭增加。在第二组16只猕猴(同样是8只酒精饮食和8只无酒精饮食)中，将接种病毒，并跟踪猕猴直到死亡，以确定酒精饮食是否会导致神经系统疾病发生率增加。这些研究结果应该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.