期刊
JOURNAL OF NEUROSCIENCE
卷 31, 期 26, 页码 9456-9465出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1460-11.2011
关键词
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资金
- National Institute of Mental Health (NIMH) [MH076679, MH075679, MH083497]
- National Institutes of Health (NIH) [R01 NS055648, P01 MH070306, R01 MH069116, R01 NS44815]
- NIH Centers for AIDS Research (CFAR) [AI-051519]
- CFAR at Albert Einstein College of Medicine
HIV infection of the CNS is an early event after primary infection, resulting in neurological complications in a significant number of individuals despite antiretroviral therapy (ART). The main cells infected with HIV within the CNS are macrophages/microglia and a small fraction of astrocytes. The role of these few infected astrocytes in the pathogenesis of neuroAIDS has not been examined extensively. Here, we demonstrate that few HIV-infected astrocytes (4.7 +/- 2.8% in vitro and 8.2 +/- 3.9% in vivo) compromise blood-brain barrier (BBB) integrity. This BBB disruption is due to endothelial apoptosis, misguided astrocyte end feet, and dysregulation of lipoxygenase/cyclooxygenase, BK(Ca) channels, and ATP receptor activation within astrocytes. All of these alterations in BBB integrity induced by a few HIV-infected astrocytes were gap junction dependent, as blocking these channels protected the BBB from HIV-infected astrocyte-mediated compromise. We also demonstrated apoptosis in vivo of BBB cells in contact with infected astrocytes using brain tissue sections from simian immunodeficiency virus-infected macaques as a model of neuroAIDS, suggesting an important role for these few infected astrocytes in the CNS damage seen with HIV infection. Our findings describe a novel mechanism of bystander BBB toxicity mediated by low numbers of HIV-infected astrocytes and amplified by gap junctions. This mechanism of toxicity contributes to understanding how CNS damage is spread even in the current ART era and how minimal or controlled HIV infection still results in cognitive impairment in a large population of infected individuals.
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