Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

描述(由申请人提供)：截至2007年，全球估计有3300万人感染了人类免疫缺陷病毒(HIV)(世界卫生组织和联合国估计)。初次感染后早期，艾滋病毒进入中枢神经系统，导致30%-60%的感染者认知和运动障碍，即使在抗逆转录病毒时代也是如此。随着感染者寿命的延长，由艾滋病毒中枢神经系统感染引起的神经系统并发症的患病率也增加了。HIV-1导致神经发病或神经艾滋病的细胞基础和机制仍不清楚。星形胶质细胞是中枢神经系统中调节血脑屏障完整性、中枢神经系统炎症、免疫反应和神经元存活的关键细胞。艾滋病毒只感染这些细胞中的一小部分，而且病毒产量很低。然而，我们的数据首次表明，感染HIV的星形胶质细胞，通过缝隙连接通道和半脑沟，可以放大炎症和中枢神经系统的损伤。我们的建议假设，含有GJ和半管的Cx43将少数HIV感染的星形胶质细胞产生的细胞内信号放大到周围的未感染细胞，导致细胞毒性、星形胶质细胞增殖、血脑屏障破坏和Dkk1的分泌，导致即使在目前病毒复制最少的抗逆转录病毒时代，HIV感染人群中也经常观察到中枢神经系统功能障碍的增强。为了解决这一假设，我们将扩展我们广泛的初步研究，展示这些通道参与神经元、星形胶质细胞和血脑屏障(BBB)功能障碍，以及HIV感染的星形胶质细胞和未感染细胞的细胞激活和炎症的放大。这些数据将描述脑内艾滋病毒毒性的新途径，并将确定这些途径在星形胶质细胞病毒生命周期中的作用。从这项提议中获得的结果应该表明潜在的新的治疗目标，以限制神经艾滋病的破坏性后果。

DESCRIPTION (provided by applicant): As of 2007, an estimated 33 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60 % of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms, by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and low viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and hemichannels, can amplify inflammation and CNS damage. Our proposal hypothesizes that Cx43 containing GJ and hemichannels amplify intracellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, astrocyte proliferation, BBB disruption and secretion of DKK1 leading to the enhanced CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in neuronal, astrocyte and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes as well as in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels during the viral life cycle in astrocytes. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS.