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

• Published in: Redox biology Vol. 15; no. C; pp. 97 - 108
• Main Authors: El-Amine, Rawan, Germini, Diego, Zakharova, Vlada V., Tsfasman, Tatyana, Sheval, Eugene V., Louzada, Ruy A.N., Dupuy, Corinne, Bilhou-Nabera, Chrystèle, Hamade, Aline, Najjar, Fadia, Oksenhendler, Eric, Lipinski, Marс, Chernyak, Boris V., Vassetzky, Yegor S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2018; Elsevier
• Subjects: B-cell lymphomas; B-Lymphocytes - pathology; B-Lymphocytes - virology; Cancer; DNA damage; DNA Damage - genetics; Glutathione - metabolism; HIV-1; HIV-1 - genetics; HIV-1 - pathogenicity; Humans; Life Sciences; Mitochondria; Mitochondria - genetics; Mitochondria - pathology; NF-kappa B - genetics; Oxidative stress; Oxidative Stress - genetics; Reactive Oxygen Species - metabolism; Research Paper; Signal Transduction; Tat; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; HIV-1; Oxidative stress; Mitochondria; B-cell lymphomas; Tat; DNA damage
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2017.11.024

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. [Display omitted] •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.