Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells.
Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells.
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DOI：
10.1186/1742-4690-10-60
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发表时间：
2013-06-06
期刊：
影响因子：
3.3
通讯作者：
Pauza CD
中科院分区：
文献类型：
--
作者：
Li H;Pauza CD
在病毒附着过程中，细胞表面受体 CD4 和 CCR5 结合 CCR5 倾向的 HIV 包膜 (Env) 糖蛋白。这些相同的受体具有与正常免疫细胞功能相关的信号传导活动。我们还知道，Env 与 CD4 阴性 γδ T 细胞上高水平存在的 CCR5 结合，通过 p38 MAP 激酶发出信号，激活 caspase 和 Fas 依赖性细胞死亡。在这里，我们询问通过细胞受体的 Env 信号传导是否导致未感染的 CD4+/CCR5+ T 细胞死亡，以及 Env 对可能影响 HIV 感染的 CD4+/CCR5-阴性细胞有何影响。从信号转导和对细胞激活或细胞死亡途径的影响方面分析 Env 结合的结果。 Env 通过 Erk 和 Akt 激酶与 CD4 信号结合。 Erk/Akt 的激活会因 CCR5 结合而抑制 p38，并允许细胞存活。当可溶性 CD4 或蛋白激酶抑制剂阻断 CD4 信号传导时，未感染的 CD4+ CCR5+ T 细胞中 p38 激活和 Fas 依赖性细胞死亡增加。我们还注意到 CD4 信号传导对扁桃体淋巴细胞培养物中 CCR5 阴性 CD4 T 细胞的特定影响。暴露于 CCR5 倾向性 HIV Env（BaL 株）会增加 CXCR5、PD-1、Fas 和 FasL 的表达。在表达高水平 CXCR5 和 PD-1 的 CD4+/CCR5- T 细胞中，存在大量 Fas 依赖性细胞死亡。 CXCR5 和 PD-1 表达的增加被可溶性 CD4 或 Akt 激酶的特异性抑制剂阻断，显示 CD4 信号传导、T 细胞激活和 Fas 依赖性细胞死亡之间的直接关系。特异性抑制 Akt 激活会增加 CCR5+ CD4 T 细胞的 Env 依赖性细胞死亡。同样的抑制剂、阻断 gp120 上 CD4 结合位点的抗体或可溶性 CD4 也可以阻止 CXCR5 或 PD-1 表达的增加，并降低 Fas 依赖性细胞死亡的水平。 Akt 激酶和相关信号传导事件是生产性感染所需的细胞存活的关键，并且可能是抗病毒药物开发的目标。 Akt 的特异性抑制剂可通过在病毒附着至 CD4+ CCR5+ 靶细胞期间促进细胞死亡来减少生产性感染，并减少免疫激活，以防止未感染的 CXCR5+ PD-1+ CD4 T 细胞（包括共享此表型的滤泡辅助 T 细胞）发生 Fas 依赖性死亡。
The cell surface receptors CD4 and CCR5 bind CCR5-tropic HIV Envelope (Env) glycoprotein during virus attachment. These same receptors have signaling activities related to normal immune cell functions. We also know that Env binds to CCR5 present at high levels on CD4-negative γδ T cells where it signals through p38 MAP kinase to activate caspases and Fas-independent cell death. Here, we asked whether Env signaling through cellular receptors is responsible for death among uninfected CD4+/CCR5+ T cells and what are the effects of Env on CD4+/CCR5-negative cells that might impact HIV infection. The outcomes of Env binding are analyzed in terms of signal transduction and the effects on cell activation or cell death pathways. Env binding to CD4 signals through Erk and Akt kinases. Activation of Erk/Akt suppresses p38 due to CCR5 binding, and allows cell survival. When CD4 signaling was blocked by soluble CD4 or protein kinase inhibitors, p38 activation and Fas-independent cell death were increased among uninfected CD4+ CCR5+ T cells. We also noted specific effects of CD4 signaling on CCR5-negative CD4 T cells in tonsil lymphocyte cultures. Exposure to CCR5-tropic HIV Env (BaL strain) increased expression of CXCR5, PD-1, Fas and FasL. Among CD4+/CCR5- T cells expressing high levels of CXCR5 and PD-1, there were substantial amounts of Fas-dependent cell death. Increased CXCR5 and PD-1 expression was blocked by soluble CD4 or specific inhibitors of the Akt kinase, showing a direct relationship between CD4 signaling, T cell activation and Fas-dependent cell death. Specific inhibition of Akt activation increased Env-dependent cell death of CCR5+ CD4 T cells. The same inhibitor, antibodies blocking the CD4 binding site on gp120, or soluble CD4 also prevented the increase in expression of CXCR5 or PD-1, and reduced the levels of Fas-dependent cell death. The Akt kinase and related signaling events, are key to cell survival that is needed for productive infection, and may be targets for the development of antivirals. Specific inhibitors of Akt would decrease productive infection, by favoring cell death during virus attachment to CD4+ CCR5+ target cells, and reduce immune activation to prevent Fas-dependent death of uninfected CXCR5+ PD-1+ CD4 T cells including T follicular helper cells that share this phenotype.
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影响因子：
20.3
作者：
De Milito, A;Nilsson, A;Chiodi, F
通讯作者：
Chiodi, F
影响因子：
6.4
作者：
FOX, CH;TENNERRACZ, K;FAUCI, AS
通讯作者：
FAUCI, AS
影响因子：
64.8
作者：
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Siliciano, RF
影响因子：
3.7
作者：
Biard-Piechaczyk, M;Robert-Hebmann, V;Devaux, C
通讯作者：
Devaux, C
影响因子：
3.3
作者：
Ahr B;Robert-Hebmann V;Devaux C;Biard-Piechaczyk M
通讯作者：
Biard-Piechaczyk M