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

项目摘要 HIV/SIV在急性感染期间感染CNS中的小胶质细胞和星形胶质细胞，建立病毒储库， 引起由炎性小体活化介导的CNS炎症。在接受抗逆转录病毒疗法之前， 痴呆症（HAD）发生在大约三分之一的感染患者中。尽管ART导致了显著的 尽管HAD的发病率有所下降，但仍有50%的人被诊断出患有较轻形式的HIV相关神经认知障碍（HAND）。 受感染的抗逆转录病毒治疗的个体。虽然抗逆转录病毒疗法降低了与艾滋病毒有关的发病率和死亡率， 有证据表明，慢性炎症性疾病发生更频繁和/或在更早的年龄在艾滋病毒- 感染的人。HAND的发病机制尚不清楚，但长期的慢性炎症反应可导致HAND的发生。 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 炎性小体的激活。炎性小体组装导致半胱天冬酶-1的募集和活化， IL-1β和IL-18的前体形式裂解成活性的分泌细胞因子。IL-1β和IL-18是 促炎细胞因子已知介导炎症。然而，升高的IL-18在HIV CNS中的作用 疾病的影响尚不明确，特别是在长期药物滥用的情况下。常用药物的作用 滥用，可卡因和吗啡，对HIV/SIV感染期间脑中炎性小体激活的影响还没有被证实。 严格审查。我们建议检查可卡因和吗啡对炎性小体激活的影响 和病毒感染的SIVmac 251感染恒河猴模型与ART。 提示可卡因和吗啡影响SIV感染中炎性小体激活。长期接触可卡因 与感染动物相比，SIV感染前/后的吗啡或吗啡导致CSF中IL-18水平升高 没有毒品。我们拟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中的炎性小体激活抑制了SIV感染的猕猴。我们还建议审查，第一， 时间，急性感染时炎性小体激活的影响以及可卡因和吗啡对炎性小体激活的影响。 SIV感染在大脑中的播种。我们假设SIV感染大脑导致高水平的 慢性暴露于可卡因或吗啡将调节炎性小体激活， 大脑中的激活。具体目标1将确定慢性可卡因或吗啡给药是否会改变SIV- 诱导CNS中的炎性小体活化。具体目标2将确定慢性吗啡或可卡因 在ART抑制的SIV感染的猕猴中的施用影响炎性小体活化。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 在脑中建立/或维持病毒储库。

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.