Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

描述（由申请人提供）：截至2010年，全球估计有3400万人感染人类免疫缺陷病毒（HIV）（世界卫生组织和联合国估计）。在初次感染后的早期，即使在抗逆转录病毒时代，艾滋病毒也会进入中枢神经系统，导致30-60%的感染者出现认知和运动障碍。随着感染者寿命的延长，由HIV中枢神经系统感染引起的神经系统并发症的发生率也在增加。HIV-1引起神经发病或神经艾滋病的细胞基础和机制尚不清楚。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。艾滋病毒仅感染这些细胞中的一小部分，并且检测到的病毒产量很少，甚至无法检测到。然而，我们的数据首次表明，HIV感染的星形胶质细胞，通过间隙连接通道和可能的半通道，可以放大炎症和中枢神经系统损伤。我们假设含有间隙连接（GJ）和半通道（uHC）的Cx43将少数HIV感染星形胶质细胞中产生的细胞间信号放大到周围未感染的细胞，从而导致细胞毒性、血脑屏障破坏和DKK1的分泌，导致即使在当前抗逆转录病毒时代病毒复制最小的HIV感染人群中也经常观察到的中枢神经系统功能障碍。为了解决这一假设，我们将扩展我们广泛的初步研究，证明这些通道参与星形胶质细胞，神经元和血脑屏障（BBB）功能障碍，以及细胞激活和炎症的放大

DESCRIPTION (provided by applicant): As of 2010, an estimated 34 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 minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the 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 astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page