Downmodulating Monocyte/Macrophage Activation for HAND

描述（由申请人提供）：hiv相关神经认知障碍（HAND）即使在接受art治疗的人群中也是一个主要问题，并且随着人们接受治疗的时间延长，患病率也在增加。HAND是由激活的单核/巨噬细胞（M/M）谱系细胞引起的慢性炎症引起的。血液中CD16+/CD163+单核细胞的扩增被认为会侵入中枢神经系统（也可能携带病毒进入大脑）。在大脑中，被激活和/或感染的M/M的积累会释放损伤神经元的细胞因子、小分子或病毒蛋白，以及吸收额外M/M的趋化因子，如MCP-1。最近的数据表明，尽管抗逆转录病毒抑制，神经炎症和慢性全身性免疫激活仍然存在，这主要是由受损肠道屏障的微生物易位以及残留的病毒表达驱动的。因此，持续性M/M激活是治疗或预防HAND的辅助治疗的关键靶点。他汀类药物是一种降胆固醇药物，广泛用于治疗或预防动脉粥样硬化。通过阻断HMG-coA还原酶，他汀类药物还可以阻止细胞内信号分子的异戊二烯化，从而产生免疫调节活性，这也有助于临床获益。活化的M/M细胞是动脉粥样硬化的主要炎症细胞，也是他汀类药物免疫调节的重要靶点。HAND中的M/M激活与动脉粥样硬化中的M/M激活有几个惊人的相似之处，几个体外和体内研究小组的研究以及我们在体外的初步数据表明，他汀类药物下调与HAND发病有关的M/M激活模式，包括lps诱导的CD16和CD163上调，向MCP-1的迁移，以及M/M和星形胶质细胞产生MCP-1。我们假设他汀类药物会抑制ART治疗的感染者中与HAND相关的残留M/M激活，并在机制上参与其中，因此将成为预防和治疗神经认知障碍的有价值的辅助手段。在这个项目中，我们将(1)确定他汀类药物如何在体外调节单核细胞活化、细胞内信号通路和与HAND发病机制有关的功能；(2)在一项双盲安慰剂对照交叉研究中确定阿托伐他汀对hiv感染/ART治疗受试者中单核细胞活化的影响；(3)明确ART治疗对象中残余单核细胞活化的基因表达模式和他汀类药物的调节；(4)评估他汀类药物对art治疗患者中枢神经系统免疫激活标志物和神经认知功能的影响。

DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorder (HAND) is a major problem even in ART-treated people, and increasing in prevalence as people live longer on therapy. HAND results from chronic inflammation driven largely by activated monocyte/macrophage (M/M) lineage cells. An expansion of CD16+/CD163+ monocytes occurs in blood that is thought to invade the CNS (and may also carry virus into the brain). In the brain the accumulation of activated and/or infected M/M releases cytokines, small molecules or viral proteins that injure neurons, as well as chemokines such as MCP-1 that recruit additional M/M. Recent data indicate that despite antiretroviral suppression, there is persistence of both neuroinflammation and chronic systemic immune activation, driven largely by microbial translocation from a damaged gut barrier as well as residual viral expression. Persistent M/M activation is thus a critical target for adjunctive therapy to treat or prevent HAND. Statins are cholesterol lowering agents widely used to treat or prevent atherosclerosis. By blocking HMG-coA reductase, statins also prevent isoprenylation of intracellular signaling molecules, resulting in immunomodulatory activity believed also to contribute to clinical benefit. Activated M/M are principal inflammatory cells in atherosclerosis and important targets of statin immunomodulation. M/M activation in HAND has several striking parallels to that in atherosclerosis, and work by several groups in vitro and in vivo, as well as our preliminary data in vitro, show that statins downregulate M/M activation patterns implicated in HAND pathogenesis, including LPS-induced CD16 & CD163 upregulation, migration to MCP- 1, and MCP-1 production by M/M as well as astrocytes. We hypothesize that statins will suppress residual M/M activation associated with and mechanistically involved in HAND in ART- treated infected individuals and as such will be valuable adjuncts for prevention & treatment of neurocognitive disorders. In this project we will (1) Determine how statins modulate monocyte activation, intracellular signaling pathways and functions implicated in the pathogenesis of HAND in vitro; (2) Define the effect of atorvastatin on monocyte activation in HIV-infected/ART- treated subjects in a double-blind placebo- controlled crossover study; (3) Define gene expression patterns of residual monocyte activation in ART- treated subjects and modulation by statins, and; (4) Assess statin effects on CNS immune activation markers and neurocognitive function in ART-treated subjects. PUBLIC HEALTH RELEVANCE: Activation and inflammation involving monocyte/macrophage cells are a key component driving cognitive and neurological deficits in people with HIV infection, and these neurocognitive complications persist even if virus replication is suppressed by antiretroviral treatment. Statins are drugs widely used to treat atherosclerosis, and evidence suggests that part of their beneficial effect in that disease is through down-regulating monocyte/macrophage activation and inflammation. We will test if statins down-regulate monocyte/macrophage activation in HIV- infected people on antiretroviral therapy, and define the mechanisms behind this effect.