Inflammasome activation in an SIV-ART model of chronic drug abuse

慢性药物滥用 SIV-ART 模型中的炎症小体激活

• 批准号: 9934585
• 负责人: JANICE E CLEMENTS
• 金额: $ 71.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934585
• 关键词: AIDS dementia; Adherence; Affect; Age; Animal Model; Animals; Astrocytes; Atherosclerosis; Blood - brain barrier anatomy; Brain; CASP1 gene; CCL2 gene; Cell Culture Techniques; Cells; Central Nervous System Diseases; Chronic; Cocaine; Cocaine Dependence; DNA; Data; Diabetes Mellitus; Diagnosis; Disease; Drug abuse; Drug usage; Exposure to; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Immune response; Immune system; Immunosuppression; Impairment; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Kidney Diseases; Liver diseases; Lymphocyte; Macaca; Macaca mulatta; Maintenance; Measures; Mediating; Microglia; Modeling; Morbidity - disease rate; Morphine; Morphine Abuse; Mus; Neurocognitive Deficit; Opioid; Pathogenesis; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Predisposition; RNA; Role; SIV; Time; Tissues; Viral; Viral Genome; Viral Proteins; Viral reservoir; Virus Diseases; Virus Latency; acute infection; cocaine exposure; cocaine use; cytokine; drug of abuse; insight; macrophage; mathematical model; migration; monocyte; morphine administration; mortality; non-drug; novel; opioid abuse; recruit; response; synergism; tool

PROJECT SUMMARY HIV/SIV infects microglia and astrocytes in the CNS during acute infection establishing viral reservoirs and causing CNS inflammation mediated by activation of inflammasomes. Prior to ART, severe HIV-associated dementia (HAD) occurred in approximately one-third of infected patients. Although ART has led to marked decrease in HAD, milder forms of HIV-associated neurocognitive disorders (HAND) are still diagnosed in 50% of infected ART-treated individuals. Although ART reduced the incidence of HIV-related morbidity and mortality, there is evidence that chronic inflammatory diseases occur more frequently and/or at earlier ages in HIV- infected individuals. The pathogenesis of HAND is unclear, though chronic inflammation induced by long-term infection and drug abuse may be contributing factors. Inflammation associated with viral infections is caused by activation of inflammasomes. Inflammasome assembly results in recruitment and activation of caspase-1 and cleavage of the pro-forms of IL-1β and IL-18 into active, secreted cytokines. IL-1β and IL-18 are proinflammatory cytokines known to mediate inflammation. However, the role of elevated IL-18 in HIV CNS disease is not clear, especially in the context of chronic drug abuse. The effects of commonly used drugs of abuse, cocaine and morphine, on inflammasome activation in brain during HIV/SIV infection have not been rigorously examined. We propose to examine effects of cocaine and morphine on activation of inflammasomes and viral infection in the SIVmac251 infected rhesus macaque model with and without ART. Our studies suggest cocaine and morphine affect inflammasome activation in SIV infection. Long-term exposure to cocaine or morphine before/after SIV infection leads to elevated levels of IL-18 in CSF compared to infected animals without drugs. We propose to study the effects of chronic cocaine and chronic morphine exposure on CNS inflammasome activation in ART suppressed SIV infected macaques. We also propose to examine, for the first time, effects of inflammasome activation during acute infection and the effects of cocaine and morphine on the seeding of SIV infection in brain. We hypothesize that SIV infection in brain results in high levels of inflammasome activation, and that chronic exposure to cocaine or morphine will modulate inflammasome activation in brain. Specific Aim 1 will determine if chronic cocaine or morphine administration alters SIV- induced inflammasome activation in the CNS. Specific Aim 2 will determine if chronic morphine or cocaine administration in ART-suppressed SIV-infected macaques affects inflammasome activation. Specific Aim 3 will examine whether chronic cocaine or morphine treatment alters the progression of SIV infection and/or the establishment of/or maintenance of viral reservoirs in brain.

项目摘要 急性感染期间，中枢神经系统的艾滋病毒/SIV感染小胶质细胞和星形胶质细胞建立病毒储存剂和 引起通过激活炎症介导的CNS炎症。在艺术之前，严重的HIV相关 大约三分之一的感染患者发生痴呆（已有）。虽然艺术导致了标记 减少了HAD，米勒形式的HIV相关神经认知障碍（手）仍在50％中诊断出 尽管ART降低了与HIV相关的发病率和死亡率的事件，但 有证据表明，慢性炎症性疾病发生频率更高和/或HIV-早期。 受感染的人。手的发病机理尚不清楚，尽管长期引起的慢性炎症 感染和药物滥用可能是促成因素。与病毒感染相关的炎症是由 激活炎症。炎性组组装导致caspase-1的募集和激活 将IL-1β和IL-18的促序形式切割成活性的，分泌的细胞因子。 IL-1β和IL-18是 培养基炎症已知的促炎细胞因子。但是，升高IL-18在HIV CNS中的作用 疾病尚不清楚，尤其是在慢性药物滥用的情况下。常用药物的影响 虐待，可卡因和吗啡，在艾滋病毒/SIV感染期间大脑中炎症体激活尚未 严格检查。我们建议检查可卡因和吗啡对炎症激活的影响 在SIVMAC251中，有或没有艺术的恒河猴模型感染了病毒感染。我们的研究 建议可卡因和吗啡会影响SIV感染中的炎性体激活。长期接触可卡因 与感染动物相比 没有毒品。我们建议研究慢性可卡因和慢性吗啡对中枢神经系统的影响 ART中的炎症体激活抑制了SIV感染的猕猴。我们还建议检查第一个 时间，急性感染期间炎性体激活的影响以及可卡因和吗啡对 大脑中SIV感染的播种。我们假设大脑中的SIV感染导致高水平 炎症体激活，并且长期暴露于可卡因或吗啡会调节炎症体 大脑的激活。具体目标1将确定慢性可卡因或吗啡给药是否改变了SIV- CNS诱导的炎性体激活。特定目标2将确定慢性吗啡还是可卡因是 抑制ART抑制的SIV感染猕猴的给药会影响炎症体激活。具体目标3 将检查慢性可卡因或吗啡治疗是否改变SIV感染和/或 在大脑中建立/或维护病毒储存库。