Effect of Alcohol on SHIV Neuroinvasion

酒精对 SHIV 神经侵袭的影响

• 批准号: 6555510
• 负责人: Edward Brice Stephens
• 金额: $ 37万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555510
• 关键词: AIDS dementia complex; HIV infections; Macaca nemestrina; T lymphocyte; alcoholic beverage consumption; astrocytes; blood brain barrier; disease /disorder model; ethanol; flow cytometry; histology; human immunodeficiency virus; human immunodeficiency virus 1; immunocytochemistry; microglia; neurons; neuropathology; pathologic process; perfusion; recombinant virus; simian immunodeficiency virus; tissue /cell culture; virus antigen; virus infection mechanism; virus replication

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.

描述（由申请人提供）： 大约 20% 感染 1 型人类免疫缺陷病毒 (HIV-1) 的人会患上一种神经系统疾病，称为 HIV 相关认知/运动复合体或艾滋病痴呆综合征。 众所周知，长期使用乙醇会导致免疫功能低下，从而增加对细菌和病毒病原体的易感性。 相当数量的 HIV-1 阳性个体饮用中度至过量的酒精。 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作用的详细研究。 研究人员的实验室衍生出了一种猿猴-人类免疫缺陷病毒 (SHIV500LNV) 变种，在接种猪尾猕猴后，会导致高病毒负荷、T 细胞 CD4+ 子集耗尽，并且 50% 的猕猴出现与 HIV-1 相似的神经病理学（血管周围套状、小胶质细胞结节） 感染人类。 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 诱发的脑炎的发病率。 16 只猕猴将自行摄入乙醇饮食以模拟适度饮酒，16 只猕猴将在 9 个月内缺乏乙醇。 此时，16只猕猴（8只采用乙醇饮食，8只采用无乙醇饮食）将接种SHIV500LNV，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，该阶段是病毒复制不受限制的时期，并且宿主尚未对病毒产生有效的免疫反应。 病毒。在第二组 16 只猕猴中（同样有 8 只吃乙醇饮食，8 只吃无乙醇饮食），将接种病毒，并对猕猴进行跟踪直至垂死，以确定乙醇饮食是否会导致神经系统疾病的发病率增加。 这些研究的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。