VIRAL SANCTUARY IN THE CENTRAL NERVOUS SYSTEM

中枢神经系统中的病毒避难所

• 批准号: 6188322
• 负责人: CAROL K PETITO
• 金额: $ 41.29万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188322
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; HIV infections; SCID mouse; T lymphocyte; antiviral agents; blood brain barrier; choroid plexus; computer assisted sequence analysis; disease /disorder model; extracellular matrix proteins; human tissue; immunocytochemistry; laboratory mouse; latent virus infection; leukocyte activation /transformation; neurotropic virus; postmortem; receptor sensitivity; vascular endothelium permeability; virulence; virus cytopathogenic effect; virus infection mechanism

The central nervous system is often infected by HIV. Not only does this brain infection result in an encephalitis, an infection closely linked to AIDS dementia, but also this brain infection may provide a site that allows HIV to replicate in the setting of highly active anti-retroviral therapy. Our own studies suggest that the choroid plexus may be an important sanctuary for HIV since productive HIV infection develops in monocytes and dendritic cells in this structure even during the period of clinical latency, when brain infection is absent or nonproductive. We found CPx infection in 58% of AIDS cases in whom HIVE was present in only 20%. Similarly, we found Cpx infection in 2 of 7 asymptomatic HIV-infected cases, none of whom had productive brain infection. During the course of these investigations, we detected specific viral sequences from brain isolates that may identify neurotropism although we did not find evidence of sequences identifying neurovirulence in the small population of AIDS cases so studied (n=4). We also have examined in greater detail the biological significance of the AIDS-related breakdown of the blood-brain barrier (BBB), a finding first identified by us in post-mortem brains of AIDS patients several years ago. In this setting, the BBB leak significantly correlated with intramural and perivascular T cell infiltrates in end-stage patients. Although the causal relationship between these two events are not known, we hypothesize that the immune cell entry causes the barrier leak which may, in turn, enhance the immune cell entry. The present application will explore the hypotheses that l) the Cpx is initial hematogenous dissemination of HIV; 2) viral- infected immune cells infect brain after the onset of immunosuppression and AIDS and 3) specific sites provide CNS sanctuary for HIV. These hypotheses will be explored in human autopsy material from controls, asymptomatic HIV-infected and AIDS cases with and without HIVE as well as in animal models combining BBB break with immune cell activation. The hypotheses and their specific aims address the central goal and selective subaims of RFA #NS99-002, "Central Nervous System as the HIV Sanctuary".

中枢神经系统经常被艾滋病毒感染。这种脑部感染不仅会导致脑炎（一种与艾滋病痴呆症密切相关的感染），而且这种脑部感染还可能提供一个位点，使艾滋病毒在高活性抗逆转录病毒治疗的环境中复制。我们自己的研究表明，脉络丛可能是HIV的一个重要避难所，因为即使在临床潜伏期，当大脑感染不存在或非生产性时，生产性HIV感染也会在该结构中的单核细胞和树突状细胞中发展。我们发现58%的艾滋病病例中有CPx感染，而只有20%的艾滋病病例中有HIVE。同样，我们在7例无症状HIV感染者中发现2例Cpx感染，其中无一例有生产性脑感染。在这些调查的过程中，我们检测到特定的病毒序列，从大脑分离，可能会识别嗜神经性，虽然我们没有发现证据的序列识别神经毒力的艾滋病病例的小人口研究（n=4）。我们还更详细地研究了与艾滋病相关的血脑屏障（BBB）破坏的生物学意义，这是我们几年前在艾滋病患者死后的大脑中首次发现的发现。在这种情况下，BBB泄漏与终末期患者的壁内和血管周围T细胞浸润显著相关。虽然这两个事件之间的因果关系尚不清楚，但我们假设免疫细胞进入导致屏障泄漏，这反过来可能会增强免疫细胞进入。本申请将探索以下假设：1）Cpx是HIV的初始血行播散; 2）病毒感染的免疫细胞在免疫抑制和AIDS发作后感染脑;和3）特异性位点为HIV提供CNS避难所.这些假设将在对照组、无症状HIV感染者和有或无HIVE的AIDS病例的人类尸检材料中以及在BBB破裂与免疫细胞活化相结合的动物模型中进行探索。这些假设及其具体目标涉及RFA #NS99-002的中心目标和选择性子目标，即“中枢神经系统是HIV的避难所”。