HIV infection of astrocytes compromises inter-organelle interactions and inositol phosphate metabolism: A potential mechanism of bystander damage and viral reservoir survival.
HIV infection of astrocytes compromises inter-organelle interactions and inositol phosphate metabolism: A potential mechanism of bystander damage and viral reservoir survival.
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DOI：
10.1016/j.pneurobio.2021.102157
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发表时间：
2021-11
影响因子：
6.7
通讯作者：
Eugenin EA
中科院分区：
文献类型：
--
作者：
Malik S;Valdebenito S;D'Amico D;Prideaux B;Eugenin EA
在一半以上的艾滋病毒感染者中观察到与艾滋病毒相关的神经功能障碍，即使在目前的抗逆转录病毒时代也是如此。HIV介导CNS功能障碍的机制尚不清楚，但与持久HIV储库的存在有关。在中枢神经系统中，巨噬细胞/小胶质细胞和少量星形胶质细胞携带病毒。然而，HIV感染细胞的低数量与高度损伤无关，这表明可能涉及损伤放大机制。在这里，我们表明，HIV感染的细胞和周围未感染细胞的凋亡的生存机制是由线粒体/高尔基体/内质网系统和相关的IP 3和钙介导的信号之间的细胞器间的相互作用调节。我们发现潜伏性HIV感染的星形胶质细胞具有升高的细胞内IP 3水平，IP 3是一种主要的调节剂第二信使，其通过间隙连接扩散到邻近的未感染的星形胶质细胞中，导致其凋亡。此外，使用激光捕获显微切割，我们证实了未感染的星形胶质细胞的旁观者凋亡和HIV感染的星形胶质细胞的存活依赖于线粒体功能，细胞内钙离子和IP 3信号。阻断间隙连接通道并不能阻止HIV感染细胞中IP 3或细胞器间功能障碍的增加，但能减少未感染邻近细胞的凋亡扩增。我们的数据为幸存的感染细胞诱导的旁观者损伤提供了一种机制解释，这些细胞作为病毒储存库，并为减少艾滋病毒在大脑中的破坏性后果的干预措施提供了潜在的靶点。尽管有有效的抗逆转录病毒治疗，但艾滋病毒认知障碍仍影响到至少一半的艾滋病毒感染者。HIV感染人群的脑部疾病机制与病毒储库和未知的损伤机制有关。我们已经确定，即使在没有病毒复制的情况下，HIV也使用间隙连接通讯来传播CNS毒性。我们认为，HIV感染的星形胶质细胞通过改变质膜（PM）、线粒体和ER之间的相互作用（1，2）、Nef与IP 3R 1的结合（3）以及不导致钙和凋亡的细胞内IP 3水平升高（4）而在感染后存活。含有GJ的Cx43的维持使得IP 3能够扩散到邻近的未感染细胞中（5），导致ER中的适当信号传导（6），增加钙（7），并激活凋亡过程（8）。间隙连接通道通过细胞器间和IP 3介导的机制将凋亡从仅少数HIV感染的星形胶质细胞放大到周围未感染的星形胶质细胞。
HIV-associated neurological dysfunction is observed in more than half of the HIV-infected population, even in the current antiretroviral era. The mechanisms by which HIV mediates CNS dysfunction are not well understood but have been associated with the presence of long-lasting HIV reservoirs. In the CNS, macrophage/microglia and a small population of astrocytes harbor the virus. However, the low number of HIV-infected cells does not correlate with the high degree of damage, suggesting that mechanisms of damage amplification may be involved. Here, we demonstrate that the survival mechanism of HIV-infected cells and the apoptosis of surrounding uninfected cells is regulated by inter-organelle interactions among the mitochondria/Golgi/endoplasmic reticulum system and the associated signaling mediated by IP3 and calcium. We identified that latently HIV-infected astrocytes had elevated intracellular levels of IP3, a master regulator second messenger, which diffuses via gap junctions into neighboring uninfected astrocytes resulting in their apoptosis. In addition, using laser capture microdissection, we confirmed that bystander apoptosis of uninfected astrocytes and the survival of HIV-infected astrocytes were dependent on mitochondrial function, intracellular calcium, and IP3 signaling. Blocking gap junction channels did not prevent an increase in IP3 or inter-organelle dysfunction in HIV-infected cells but reduced the amplification of apoptosis into uninfected neighboring cells. Our data provide a mechanistic explanation for bystander damage induced by surviving infected cells that serve as viral reservoirs and provide potential targets for interventions to reduce the devastating consequences of HIV within the brain. HIV cognitive impairment affects at least half of the HIV-infected population despite effective antiretroviral therapy. The brain disease mechanism in the HIV-infected population has been associated with viral reservoirs and unknown damage mechanisms. We have identified that HIV uses gap junctional communication to spread CNS toxicity, even in the absence of viral replication. We propose that HIV-infected astrocytes survive infection by altering the interactions between the plasma membrane (PM), mitochondria, and the ER (1, 2), binding of Nef to the IP3R1 (3), and increased intracellular IP3 levels (4) that do not result in calcium and apoptosis. The maintenance of Cx43 containing GJ enables the diffusion of IP3 into neighboring uninfected cells (5), resulting in proper signaling in the ER (6), increasing calcium (7), and activating the apoptotic process (8). Gap junction channels amplify apoptosis from only a few HIV-infected astrocytes into surrounding uninfected astrocytes by an inter-organelle and IP3 mediated mechanism.
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影响因子：
3.1
作者：
Aktas, Orhan;Schulze-Topphoff, Ulf;Zipp, Frauke
通讯作者：
Zipp, Frauke
DOI：
10.1073/pnas.0409650102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Boehning, D;van Rossum, DB;Snyder, SH
通讯作者：
Snyder, SH
DOI：
10.1126/science.aab1370
发表时间：
2015-07-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung J;Torta F;Masai K;Lucast L;Czapla H;Tanner LB;Narayanaswamy P;Wenk MR;Nakatsu F;De Camilli P
通讯作者：
De Camilli P
DOI：
10.1124/jpet.106.112045
发表时间：
2006-12-01
影响因子：
3.5
作者：
Bai, Donglin;del Corsso, Cristiane;Spray, David C.
通讯作者：
Spray, David C.
影响因子：
9.3
作者：
Berman JW;Carvallo L;Buckner CM;Luers A;Prevedel L;Bennett MV;Eugenin EA
通讯作者：
Eugenin EA