HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

Redox Biology

Chrystèle Bilhou-Nabera¹  Fadia Najjar²  Eric Oksenhendler³  Aline Hamade⁴  Eugene V. Sheval⁵  Boris V. Chernyak⁵  Diego Germini⁶  Vlada V. Zakharova⁶  Tatyana Tsfasman⁶  Rawan El-Amine⁶  Yegor S. Vassetzky⁶  Marс Lipinski⁶  Ruy A.N. Louzada⁷  Corinne Dupuy⁷ 

[1]Biological Hematology Service-U.F. of Onco-Hematology Cytogenetics-Hôpital Saint-Antoine, 75012 Paris, France

[2]Department of Chemistry and Biochemistry, Faculty of Sciences II/EDST, Lebanese University, Jdeidet El Metn-Fanar, Lebanon

[3]Department of Clinical Immunology, Hôpital Saint-Louis, 75010 Paris, France

[4]Department of Life and Earth Sciences, Faculty of Sciences II/Doctoral School of Sciences and Technology (EDST), Lebanese University, Jdeidet El Metn-Fanar, Lebanon

[5]LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, 94805 Villejuif, France, 119334 Moscow, Russia

[6]UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France

[7]UMR 8200, Institut Gustave Roussy, CNRS, Villejuif 94805, France

关键词: HIV-1;    Tat;    Oxidative stress;    Mitochondria;    DNA damage;    B-cell lymphomas;   

DOI  :  10.1016/j.redox.2017.11.024

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown