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

项目总结 HIV/SIV在急性感染期间感染中枢神经系统的小胶质细胞和星形胶质细胞，建立病毒库和 通过激活炎性小体引起中枢神经系统炎症。在接受抗逆转录病毒治疗之前，严重的艾滋病毒相关 痴呆症(HAD)发生在大约三分之一的感染患者中。尽管艺术已经导致了标志 HAD的减少，较轻形式的HIV相关神经认知障碍(HAND)仍有50%被诊断出来 接受抗逆转录病毒治疗的感染者。虽然抗逆转录病毒疗法降低了艾滋病毒相关发病率和死亡率， 有证据表明，慢性炎症性疾病在艾滋病毒患者中发生得更频繁和/或年龄更早- 被感染的人。手部的发病机制尚不清楚，但长期的慢性炎症 感染和药物滥用可能是致病因素。与病毒感染相关的炎症由以下原因引起 炎性小体的激活。炎症小体组装导致caspase-1的招募和激活，并 将前体型的IL-1β和IL-18裂解成活性的、分泌的细胞因子。IL-1β和IL-18分别为 已知可介导炎症的促炎细胞因子。然而，IL-18升高在HIV中枢神经系统中的作用 疾病尚不清楚，特别是在慢性药物滥用的背景下。几种常用药物的药效 滥用可卡因和吗啡对HIV/SIV感染期间脑内炎症体激活的影响尚未得到证实 经过严格审查。我们建议研究可卡因和吗啡对炎性小体激活的影响。 以及SIVmac251感染恒河猴模型中的病毒感染情况。我们的研究 提示可卡因和吗啡影响SIV感染时炎性小体的激活。长期接触可卡因 与感染SIV的动物相比，感染SIV前后的吗啡或吗啡可导致脑脊液中IL-18水平升高 没有毒品。我们建议研究慢性可卡因和慢性吗啡暴露对中枢神经系统的影响 ART对SIV感染猕猴的炎性小体激活有抑制作用。我们还建议第一次审查 急性感染时炎性小体激活的时间、效应及可卡因和吗啡对炎症小体激活的影响 SIV感染在脑内的播种。我们假设SIV在大脑中的感染导致高水平的 炎症小体激活，长期接触可卡因或吗啡将调节炎症小体 大脑中的激活。具体目标1将确定长期服用可卡因或吗啡是否会改变SIV- 诱导中枢神经系统炎性小体激活。特定目标2将确定慢性吗啡或可卡因 ART抑制的SIV感染猕猴的给药会影响炎症体的激活。具体目标3 将检查慢性可卡因或吗啡治疗是否改变SIV感染的进展和/或 在大脑中建立/或维持病毒库。

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.