HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production.
HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production.
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DOI：
10.1016/j.redox.2017.11.024
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发表时间：
2018-05
期刊：
影响因子：
11.4
通讯作者：
Vassetzky YS
中科院分区：
文献类型：
--
作者：
El-Amine R;Germini D;Zakharova VV;Tsfasman T;Sheval EV;Louzada RAN;Dupuy C;Bilhou-Nabera C;Hamade A;Najjar F;Oksenhendler E;Lipinski M;Chernyak BV;Vassetzky YS
人类免疫缺陷病毒（HIV）感染与患者的B细胞恶性肿瘤有关，尽管HIV-1不能感染B细胞。即使在重建免疫功能的联合抗逆转录病毒治疗（cART）下，艾滋病毒感染者的B细胞淋巴瘤发病率仍然很高。因此，HIV-1对B细胞肿瘤发生的作用仍然是个谜。HIV-1通过多种机制，包括病毒达特蛋白，诱导受感染细胞的氧化应激和DNA损伤。我们检测到HIV感染者B细胞中活性氧（ROS）和DNA损伤水平升高。由于达特存在于受感染个体的血液中，并且能够使细胞增殖，我们假设它可以诱导B细胞中的氧化DNA损伤，从而促进遗传不稳定和恶性转化。事实上，从健康供体分离的B细胞与纯化的达特蛋白孵育导致氧化应激、谷胱甘肽（GSH）水平降低、DNA损伤和染色体畸变的出现。达特的作用依赖于其转录活性，并通过激活NF-κB介导。达特主要通过呼吸链复合体I的反向电子流产生线粒体活性氧来刺激B细胞的氧化应激。我们认为Tat诱导的氧化应激、DNA损伤和染色体畸变是HIV-1感染者发生B细胞淋巴瘤的新致癌因素。HIV感染者的B细胞表现出氧化应激、DNA损伤和染色体畸变水平升高。纯化的HIV-1达特蛋白复制了这种作用，并诱导B细胞中的氧化应激和DNA损伤。HIV-1达特诱导线粒体氧化应激并激活B细胞中的NF-κ B。这种情况会增加发生染色体异常和易位的风险。
Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals. B-cells of HIV-infected individuals exhibit elevated levels of oxidative stress, DNA damage and chromosomal aberrations. Purified HIV-1 Tat protein reproduces this effect and induces oxidative stress and DNA damage in B-cells. HIV-1 Tat induces mitochondrial oxidative stress and activates NF-kB in B-cells. This condition increases the risk of developing chromosomal abnormalities and translocations.
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影响因子：
6.6
作者：
Deponte M
通讯作者：
Deponte M
影响因子：
14.9
作者：
Dandekar, DH;Ganesh, KN;Mitra, D
通讯作者：
Mitra, D
影响因子：
3.3
作者：
Curreli S;Krishnan S;Reitz M;Lunardi-Iskandar Y;Lafferty MK;Garzino-Demo A;Zella D;Gallo RC;Bryant J
通讯作者：
Bryant J
影响因子：
4.8
作者：
Anrather, J;Racchumi, G;Iadecola, C
通讯作者：
Iadecola, C
DOI：
10.3324/haematol.2008.002691
发表时间：
2009-06-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Bower, Mark;Fisher, Martin;Sabin, Caroline A.
通讯作者：
Sabin, Caroline A.