Innate immune memory promotes neural damage in the ART suppressed HIV infected brain

摘要 发达国家抗逆转录病毒疗法(ART)的广泛使用使艾滋病毒感染从 现在基本上是一种可控的慢性感染，是绝症。即使艾滋病毒复制受到抑制 通过抗逆转录病毒治疗，艾滋病毒感染者目前处于一种慢性炎症状态，这种状态被认为是导致 神经学和精神病学的共同病症的发展。越来越多的证据表明， 先天免疫系统，使大脑对与艾滋病毒感染相关的神经损害敏感 其他神经退行性疾病。这种不能分解的炎症/免疫反应会使人变得敏感。 大脑对任何随后的炎症事件的反应，被认为是一种先天免疫记忆，在这种记忆中 小胶质细胞根据它们所受到的刺激和频率来调整它们的表型 他们暴露在这种刺激之下。这种适应是一种先天免疫记忆的形式，可以与 通过长时间的分子重新编程，可以增强或抑制小胶质细胞对 随后的刺激。HIV感染和ART对小胶质细胞重编程的影响尚不清楚。在这里我们 已经鉴定出神经酰胺是由神经鞘蛋白水解酶中性神经鞘蛋白2(NSMase2)产生的 对抗逆转录病毒药物的先天免疫反应的关键调节因子抑制艾滋病毒感染。

ABSTRACT The widespread use of antiretroviral therapy (ART) in developed countries has modified HIV infection from a terminal illness to what is now largely a manageable chronic infection. Even when HIV replication is suppressed with ART, people infected with HIV present with a chronic inflammatory state that is thought to contribute to the development of neurologic and psychiatric co-morbid conditions. A growing body of evidence is implicating the innate immune system with sensitization of the brain to neurological damage associated with HIV infection and other neurodegenerative conditions. This non-resolving inflammatory/immune response sensitizes and primes the brain for any subsequent inflammatory event, and is thought to be a form of innate immune memory in which microglia adapt their phenotype depending on the stimulus they are exposed to, and the frequency with which they are exposed to that stimulus. This adaptation is a form of innate immune memory that can be associated with long-lasting molecular reprogramming that can either enhance or suppress the microglial response to subsequent stimuli. The impact of HIV infection, and ART on microglial reprogramming is unknown. Here we have identified the sphingomyelin hydrolase neutral sphingomyelinase2 (nSMase2) generated ceramide as a critical regulator of the innate immune response to ART suppressed HIV infection.