VIRAL SANCTUARY IN THE CENTRAL NERVOUS SYSTEM

中枢神经系统中的病毒避难所

• 批准号: 6529477
• 负责人: CAROL K PETITO
• 金额: $ 43.52万
• 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/6529477
• 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".

中枢神经系统经常感染艾滋病毒。这种脑部感染不仅会导致脑炎，这是一种与艾滋病痴呆症密切相关的感染，而且这种脑部感染可能会提供一个场所，允许艾滋病毒在高效抗逆转录病毒治疗的背景下复制。我们自己的研究表明，脉络丛可能是HIV的重要避难所，因为即使在临床潜伏期，当大脑没有感染或不产生感染时，也会在该结构中的单核细胞和树突状细胞中产生生产性HIV感染。我们发现58%的艾滋病患者感染了环磷酰胺，而只有20%的人感染了蜂房。同样，我们发现在7例无症状的HIV感染病例中有2例感染了CPX，这些病例中没有一人有生产性脑感染。在这些调查过程中，我们从脑分离株中检测到可能识别神经嗜性的特定病毒序列，尽管我们没有在所研究的少数艾滋病病例中发现识别神经毒力的序列的证据(n=4)。我们还更详细地研究了与艾滋病有关的血脑屏障(BBB)崩溃的生物学意义，这一发现是我们几年前在艾滋病患者的尸检脑中首次发现的。在这种情况下，终末期患者的血脑屏障渗漏与管壁内和血管周围的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，进而可能增强免疫细胞进入。目前的应用将探索以下假设：L)CPX最初是艾滋病毒的血源性传播；2)病毒感染的免疫细胞在免疫抑制和艾滋病发作后感染大脑，3)特定部位为艾滋病毒提供中枢神经系统的避难所。这些假说将在人类尸检材料中进行探索，这些材料来自对照组、无症状的艾滋病毒感染和艾滋病病例，以及结合血脑屏障断裂和免疫细胞激活的动物模型。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次级目标。