HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS.
HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS.
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DOI：
10.1186/s12974-016-0510-1
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发表时间：
2016-03-02
影响因子：
9.3
通讯作者：
Eugenin EA
中科院分区：
文献类型：
--
作者：
Berman JW;Carvallo L;Buckner CM;Luers A;Prevedel L;Bennett MV;Eugenin EA
尽管进行了有效的抗逆转录病毒治疗和免疫重建，但艾滋病毒相关的神经认知障碍(HAND)仍是至少一半受感染人群的主要并发症。HIV相关的中枢神经系统损伤与活跃的病毒复制无关，而是与调节炎症和神经元损害的机制有关。我们的数据表明，其中一种机制是由缝隙连接通道和/或半通道介导的。正常情况下，缝隙连接通道在炎症条件下关闭，包括病毒疾病。然而，HIV感染上调了连接蛋白43(Cx43)的表达，并通过未知的机制维持缝隙连接通讯(S)。将人原代星形胶质细胞暴露于多种HIV蛋白和HIV，通过免疫印迹、免疫荧光、荧光示踪剂微量注射和染色质免疫沉淀(ChIP)检测连接蛋白43和连接蛋白30通道的表达和功能。在这里，我们证明了艾滋病毒感染增加了体内Cx43的表达。HIV-Tat是病毒的反式激活因子，没有检测到其他HIV蛋白，它增加了Cx43的表达，并维持了人类星形胶质细胞的功能缝隙连接通讯。Cx43的上调是由HIV-Tat蛋白与Cx43启动子结合介导的，而不是与Cx30启动子结合，导致Cx43信使RNA(MRNA)和蛋白质增加以及缝隙连接通讯。我们认为，HIV-TAT通过上调缝隙连接通讯，促进了少数HIV感染细胞产生的细胞内有毒信号向周围未感染细胞的扩散。在目前的抗逆转录病毒时代，艾滋病毒的复制往往被完全抑制，诸如艾滋病毒-TAT等病毒因子仍然会从受感染的细胞中产生和释放。因此，阻断艾滋病毒-TAT的影响可以产生新的战略，以减少艾滋病毒感染中枢神经系统的破坏性后果。
HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s). Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP). Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication. We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS.