Nitric oxide stimulates a PKC-Src-Akt signaling axis which increases human immunodeficiency virus type 1 replication in human T lymphocytes.,Nitric Oxide

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Nitric oxide stimulates a PKC-Src-Akt signaling axis which increases human immunodeficiency virus type 1 replication in human T lymphocytes.
Nitric Oxide ( IF 3.2 ) Pub Date : 2019-09-17 , DOI: 10.1016/j.niox.2019.09.004
Marli F Curcio ₁ , Wagner L Batista ₂ , Eloísa D Castro ₃ , Scheilla T Strumillo ₃ , Fernando T Ogata ₄ , Wagner Alkmim ₅ , Milena K C Brunialti ₁ , Reinaldo Salomão ₁ , Gilberto Turcato ₁ , Ricardo S Diaz ₁ , Hugo P Monteiro ₃ , Luiz Mário R Janini ₆

Affiliation

Human immunodeficiency virus (HIV) infections are typically accompanied by high levels of secreted inflammatory cytokines and generation of high levels of reactive oxygen species (ROS). To elucidate how HIV-1 alters the cellular redox environment during viral replication, we used human HIV-1 infected CD4+T lymphocytes and uninfected cells as controls. ROS and nitric oxide (NO) generation, antioxidant enzyme activity, protein phosphorylation, and viral and proviral loads were measured at different times (2-36 h post-infection) in the presence and absence of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). HIV-1 infection increased ROS generation and decreased intracellular NO content. Upon infection, we observed increases in copper/zinc superoxide dismutase (SOD1) and glutathione peroxidase (GPx) activities, and a marked decrease in glutathione (GSH) concentration. Exposure of HIV-1 infected CD4+T lymphocytes to SNAP resulted in an increasingly oxidizing intracellular environment, associated with tyrosine nitration and SOD1 inhibition. In addition, SNAP treatment promoted phosphorylation and activation of the host's signaling proteins, PKC, Src kinase and Akt. Inhibition of PKC leads to inhibition of Src kinase strongly suggesting that PKC is the upstream element in this signaling cascade. Changes in the intracellular redox environment after SNAP treatment had an effect on HIV-1 replication as reflected by increases in proviral and viral loads. In the absence or presence of SNAP, we observed a decrease in viral load in infected CD4+T lymphocytes pre-incubated with the PKC inhibitor GF109203X. In conclusion, oxidative/nitrosative stress conditions derived from exposure of HIV-1-infected CD4+T lymphocytes to an exogenous NO source trigger a signaling cascade involving PKC, Src kinase and Akt. Activation of this signaling cascade appears to be critical to the establishment of HIV-1 infection.

中文翻译：

一氧化氮刺激PKC-Src-Akt信号转导轴，从而增加人T淋巴细胞中人免疫缺陷病毒1型的复制。

人类免疫缺陷病毒（HIV）感染通常伴随着高水平的分泌性炎性细胞因子和高水平的活性氧（ROS）的产生。为了阐明HIV-1在病毒复制过程中如何改变细胞氧化还原环境，我们使用人类HIV-1感染的CD4 + T淋巴细胞和未感染的细胞作为对照。在存在和不存在NO供体S-亚硝基-N-的情况下，在不同时间（感染后2-36小时）测量ROS和一氧化氮（NO）的产生，抗氧化酶活性，蛋白磷酸化以及病毒和原病毒载量乙酰青霉胺（SNAP）。HIV-1感染增加了ROS的产生并降低了细胞内NO的含量。感染后，我们观察到铜/锌超氧化物歧化酶（SOD1）和谷胱甘肽过氧化物酶（GPx）活性增加，并显着降低了谷胱甘肽（GSH）的浓度。HIV-1感染的CD4 + T淋巴细胞暴露于SNAP会导致细胞内氧化环境日益增加，与酪氨酸硝化和SOD1抑制有关。此外，SNAP处理促进了宿主信号蛋白，PKC，Src激酶和Akt的磷酸化和激活。PKC的抑制导致Src激酶的抑制，强烈表明PKC是该信号级联反应中的上游元素。SNAP治疗后细胞内氧化还原环境的变化对HIV-1复制产生了影响，这反映在原病毒和病毒载量的增加上。在不存在或存在SNAP的情况下，我们观察到与PKC抑制剂GF109203X预孵育的受感染CD4 + T淋巴细胞中病毒载量的降低。综上所述，HIV-1感染的CD4 + T淋巴细胞暴露于外源NO源所产生的氧化/亚硝化应激条件触发了涉及PKC，Src激酶和Akt的信号级联反应。此信号级联的激活似乎对建立HIV-1感染至关重要。

更新日期：2019-09-17

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