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

基本信息

批准号：
10668258
负责人：
JANICE E CLEMENTS
金额：
$ 69.34万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10668258
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 Drug abuse Drug usage Exposure to HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Human IL18 gene Immune response Immune system Immunosuppression Impairment Incidence Individual Infection Inflammasome Inflammation Inflammatory Interleukin-1 beta Kidney Diseases Liver diseases Lymphocyte Macaca Macaca mulatta Macrophage 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 chronic inflammatory disease cocaine exposure cocaine use cofactor cytokine drug of abuse insight mathematical model migration monocyte morphine administration mortality non-drug novel opioid abuse recruit response synergism tool

项目摘要

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.

项目概要 HIV/SIV 在急性感染期间感染中枢神经系统中的小胶质细胞和星形胶质细胞，建立病毒库并在 ART 之前，由炎症小体激活介导的中枢神经系统炎症，严重与 HIV 相关。尽管抗逆转录病毒治疗已导致明显的痴呆症（HAD），但大约三分之一的感染患者出现了痴呆症。 HAD 减少，但 50% 的人仍被诊断出较轻形式的 HIV 相关神经认知障碍 (HAND) 尽管 ART 降低了 HIV 相关发病率和死亡率，有证据表明，慢性炎症性疾病在 HIV 感染者中发生得更频繁和/或发生得更早。 HAND 的发病机制尚不清楚，但长期诱发慢性炎症。感染和药物滥用可能是导致病毒感染相关炎症的因素。炎症小体的激活导致 caspase-1 和 caspase-1 的募集和激活。 IL-1β 和 IL-18 的前体裂解为活性的分泌型细胞因子。已知促炎细胞因子可介导炎症，但 IL-18 升高在 HIV 中枢神经系统中的作用。疾病，特别是在长期滥用药物的情况下的影响尚不清楚。滥用可卡因和吗啡对 HIV/SIV 感染期间大脑炎症小体激活的影响尚未得到证实我们建议检查可卡因和吗啡对炎症小体激活的影响。我们的研究显示，在 SIVmac251 感染的恒河猴模型中，有和没有 ART 的病毒感染。表明可卡因和吗啡会影响 SIV 感染中的炎症小体激活。与感染动物相比，SIV 感染前后服用吗啡会导致脑脊液中 IL-18 水平升高我们建议研究长期接触可卡因和吗啡对中枢神经系统的影响。我们还建议首先检查 ART 抑制 SIV 感染的猕猴中的炎症小体激活。时间、急性感染期间炎症小体激活的影响以及可卡因和吗啡对 SIV 感染在大脑中播下种子我们反对 SIV 感染在大脑中导致高水平的病毒。炎症小体激活，长期接触可卡因或吗啡会调节炎症小体特定目标 1 将确定长期使用可卡因或吗啡是否会改变 SIV- 特定目标 2 将确定中枢神经系统中诱导的炎症小体激活是慢性吗啡还是可卡因。 ART 抑制的 SIV 感染猕猴中的给药会影响特定目标 3 的炎症小体激活。将检查长期可卡因或吗啡治疗是否会改变 SIV 感染的进展和/或在大脑中建立/或维持病毒库。