Mechanisms of HAD:Role of CCL2 BBB & HIV Infection

HAD的机制：CCL2 BBB的作用

• 批准号: 8262029
• 负责人: Joan Weinberger Berman
• 金额: $ 36.46万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-06 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262029
• 关键词: AIDS neuropathy; ALCAM gene; Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Address; Adherens Junction; Aftercare; Binding; Brain; CCL2 gene; CD31 Antigens; Cell Adhesion Molecules; Cell Communication; Cell model; Cells; Chemotactic Factors; Cultured Cells; Data; Development; Disease; Endothelial Cells; Exposure to; Future; Grant; HIV; HIV Infections; Human; Impairment; In Vitro; Individual; Infection; Infiltration; Inflammation; Intercellular Junctions; Intervention; Leukocyte Trafficking; Leukocytes; Life; Mediating; Membrane; Modeling; Neurocognitive; Pathogenesis; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Population; Predisposition; Prevalence; Principal Investigator; Process; Proteins; Regulation; Role; Route; SIV; Serum; Signal Transduction; T-Lymphocyte; Testing; Tight Junctions; Tissues; Viral; Virus; Virus Diseases; antiretroviral therapy; cadherin 5; chemokine; global health; in vivo; monocyte; neuroinflammation; novel; programs; protein expression; response; success; tissue culture

DESCRIPTION (provided by applicant): The brain becomes infected within days after peripheral HIV infection and viral presence persists despite cART. CNS HIV infection often results in the development of HIV Associated Neurocognitive Disorders, or HAND, that are mediated, at least in part, by ongoing neuroinflammation and low level viral persistence that cause CNS damage. A major mechanism by which virus enters the brain is by the transmigration of HIV-infected monocytes and perhaps T cells across the BBB. Under non-pathological conditions, the transmigration of leukocytes across the CNS vasculature does not disrupt the BBB because specific interactions between adhesion molecules, adherens junction and tight junction proteins (termed "cell junction proteins") on leukocytes and BBB cells maintain the impermeability of these vessels during leukocyte diapedesis. However, during the pathogenesis of NeuroAIDS, leukocyte infiltration into the CNS is associated with BBB compromise. Thus the molecular interactions inherent in leukocyte diapedesis across the BBB are altered, resulting in increased BBB disruption. Our data indicate that HIV infection of monocytes and T cells plus CCL2 as a chemoattractant, but not other chemokines, cause increased transmigration of these cells across a tissue culture model of the BBB and disruption of that barrier. We demonstrated that the virus as well CCL2 induced profound changes in expression, processing and function of diverse cell junction proteins on both leukocytes and brain microvascular endothelial cells. We hypothesize that HIV infection of monocytes and exposure to CCL2 alter their expression, localization, phosphorylation and shedding of cell junction proteins and that these alterations result in aberrant leukocyte/BBB cell interactions, leading to increased transmigration and barrier disruption, contributing to the neuroinflammation and viral damage that characterize NeuroAIDS This renewal is to continue our studies of the mechanisms of transmigration of HIV infected cells across the BBB in response to CCL2, with emphasis on a specific monocyte population that we showed preferentially transmigrates across the BBB in response to CCL2 and is highly susceptible to HIV infection. We will focus on the cell junction molecules PECAM-1, CD99, JAM-A, and ALCAM, as critical proteins involved in dysregulation of monocyte transmigration and disruption of BBB integrity. We also identified additional proteins that may facilitate dysregulated transmigration as well as monocyte susceptibility to HIV infection, and we will examine their expression and function on monocytes. We will examine the contribution of intact and soluble junction proteins to increased transmigration, and determine the route, paracellular or transcellular, of transmigration of uninfected and HIV monocytes. We will demonstrate the in vivo significance of these processes using an SIV model. PUBLIC HEALTH RELEVANCE: HIV infection and HIV associated neurocognitive disorders (HAND) are major emerging global health problems. The prevalence of HAND is increasing as people with AIDS are living longer due to success of antiretroviral therapies (ART). HAND is mediated, at least in part, by inflammation and viral persistence within the CNS, which are present even in many individuals on ART. Our group demonstrated that HIV infected leukocytes transmigrate more exuberantly across the BBB in response to CCL2 as chemoattractant, but not to other chemokines. We propose that CCL2 and/or HIV infection result in profound changes in expression, localization and shedding of the cell junction proteins ALCAM, PECAM-1, JAM- A and CD99 on monocytes and brain microvascular endothelial cells (BMVEC) that enable infected cells to have such increased transmigration across the BBB. In this resubmitted competing renewal we will determine the mechanisms by which these junction proteins are dysregulated on monocytes and BMVEC to result in BBB disruption and increased transmigration in response to CCL2. We propose that targeting these cell junction proteins may be a novel interventional strategy to reduce HIV CNS impairment.

描述（由申请人提供）： 大脑在周围HIV感染后的几天内被感染，尽管卡车，病毒存在仍然存在。 CNS HIV感染通常会导致与HIV相关的神经认知障碍或手的发展，这些神经认知障碍至少部分通过持续的神经炎症和低水平的病毒持久性介导，从而造成CNS损害。病毒进入大脑的主要机制是通过艾滋病毒感染的单核细胞的移民，也许是跨BBB的T细胞的迁移。在非病理条件下，CNS脉管系统中白细胞的迁移不会破坏BBB，因为粘附分子之间的特定相互作用，粘附连接和紧密连接蛋白（称为“细胞连接蛋白”）（称为“细胞连接蛋白”）在白细胞和BBB细胞上维持这些血管症的影响。但是，在神经辅助的发病机理中，白细胞浸润到中枢神经系统中与BBB妥协有关。因此，在整个BBB的白细胞尿症中固有的分子相互作用发生了变化，从而导致BBB的破坏增加。我们的数据表明，单核细胞和T细胞的HIV感染加上CCL2作为趋化剂，但没有其他趋化因子，但没有导致这些细胞在BBB的组织培养模型中增加了这些细胞的迁移和该障碍的破坏。我们证明了该病毒和CCL2也引起了白细胞和脑微血管内皮细胞上各种细胞连接蛋白的表达，处理和功能的深刻变化。我们假设单核细胞的HIV感染和暴露于CCL2改变了其表达，定位，磷酸化和细胞连接蛋白的脱落，并且这些改变导致白细胞/BBB细胞相互作用异常HIV感染细胞在BBB响应CCL2的转移机制，重点是特定的单核细胞种群，我们优先显示出对CCL2的跨BBB跨移民，并且对HIV感染非常容易受到HIV感染。我们将重点关注细胞连接分子PECAM-1，CD99，JAM-A和ALCAM，作为​​临界蛋白，涉及单核细胞传播失调和BBB完整性的破坏。我们还确定了可能促进转移失调以及单核细胞对HIV感染的敏感性的其他蛋白质，我们将检查它们在单核细胞上的表达和功能。我们将研究完整和可溶性连接蛋白对增加移民的贡献，并确定未感染和HIV单核细胞迁移的途径，细胞细胞或跨细胞的途径。我们将使用SIV模型来证明这些过程的体内意义。 公共卫生相关性： 艾滋病毒感染和与艾滋病毒相关的神经认知障碍（手）是主要的全球健康问题。由于抗逆转录病毒疗法的成功（ART），随着艾滋病患者的寿命更长，手的普遍性正在增加。手在中枢神经系统内部的炎症和病毒持久性至少部分地介导了手，即使在许多艺术中也存在。我们的小组表明，艾滋病毒感染的白细胞在BBB上更加繁荣，响应于CCL2作为化学吸引剂，而不是其他趋化因子。我们提出，CCL2和/或HIV感染会导致单核细胞和脑微血管内皮细胞（BMVEC）的细胞连接蛋白ALCAM，PECAM-1，JAM-A和CD99的表达，定位和脱落的深刻变化，使感染细胞能够在整个BBB跨BBB跨BBB跨BBB。在这种重新提交的竞争性更新中，我们将确定这些连接蛋白在单核细胞和BMVEC上失调的机制，从而导致BBB破坏和响应CCL2的迁移增加。我们建议将这些细胞连接蛋白靶向可能是减少HIV CNS损害的新型介入策略。