Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, New York.
Glia. 2018 Dec;66(12):2563-2574. doi: 10.1002/glia.23511. Epub 2018 Oct 16.
Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV-associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV-positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation. As complement deposition on synapses followed by microglial engulfment has been shown during normal development and disease to be a mechanism for pruning synapses, we have tested whether complement is required for the loss of synapses that occurs after a cortical Tat injection mouse model of HAND. In Tat-injected animals evaluated 7 or 28 days after injection, levels of early complement pathway components, C1q and C3, are significantly elevated and associated with microgliosis and a loss of synapses. However, C1qa knockout mice have the same level of Tat-induced synapse loss as wild-type (WT) mice, showing that the C1q-initiated classical complement cascade is not driving synapse removal during HIV1 Tat-induced neuroinflammation.
小胶质细胞活化、促炎细胞因子产生增加以及突触密度降低是与 HIV 相关神经认知障碍（HAND）相关的关键病理特征。即使接受联合抗逆转录病毒疗法（cART），超过 50%的 HIV 阳性个体仍会出现某种类型的认知障碍。尽管 cART 抑制了病毒复制，但 HIV 蛋白，如 Tat，仍在神经系统内产生，这些蛋白具有神经毒性，参与突触消除，并引发持久的神经炎症。由于补体在突触上的沉积随后被小胶质细胞吞噬，在正常发育和疾病过程中已被证明是一种修剪突触的机制，因此我们检测了补体是否是 HAND 的皮质 Tat 注射小鼠模型中发生的突触丧失所必需的。在 Tat 注射后 7 或 28 天评估的动物中，早期补体途径成分 C1q 和 C3 的水平显着升高，并与小胶质细胞增生和突触丧失相关。然而，C1qa 基因敲除小鼠与野生型（WT）小鼠具有相同水平的 Tat 诱导的突触丢失，表明 C1q 引发的经典补体级联反应不是 HIV1 Tat 诱导的神经炎症期间驱动突触去除的原因。
