VIRAL SANCTUARY IN THE CENTRAL NERVOUS SYSTEM

中枢神经系统中的病毒避难所

• 批准号: 6394241
• 负责人: CAROL K PETITO
• 金额: $ 42.39万
• 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/6394241
• 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（一种与艾滋病痴呆密切相关的感染），而且这种脑部感染可能会提供一个允许艾滋病毒在高效抗逆转录病毒治疗中复制的场所。我们自己的研究表明，脉络丛可能是艾滋病毒的重要避难所，因为即使在临床潜伏期，当脑部感染不存在或没有感染时，该结构中的单核细胞和树突状细胞也会产生生产性艾滋病毒感染。我们发现 58% 的 AIDS 病例中存在 CPx 感染，而只有 20% 的病例中存在 HIVE。同样，我们在 7 名无症状 HIV 感染者中发现了 2 名 Cpx 感染，但没有一人出现有效的脑部感染。在这些调查过程中，我们从大脑分离物中检测到了可能识别神经毒性的特定病毒序列，尽管我们在所研究的一小部分艾滋病病例中没有发现识别神经毒力的序列证据（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大脑中首次发现的发现。在这种情况下，BBB 渗漏与终末期患者的壁内和血管周围 T 细胞浸润显着相关。尽管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，这反过来可能增强免疫细胞进入。本申请将探讨如下假设：l) Cpx 是 HIV 最初的血行传播； 2）病毒感染的免疫细胞在免疫抑制和艾滋病发病后感染大脑，3）特定部位为艾滋病毒提供中枢神经系统庇护所。这些假设将在来自对照、无症状艾滋病毒感染者和艾滋病病例（有或没有艾滋病毒）的人体尸检材料以及结合血脑屏障破坏和免疫细胞激活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“中枢神经系统作为艾滋病毒庇护所”的中心目标和选择性子目标。