HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production
Rawan El-Amine,
Diego Germini,
Vlada V. Zakharova,
Tatyana Tsfasman,
Eugene V. Sheval,
Ruy A.N. Louzada,
Corinne Dupuy,
Chrystèle Bilhou-Nabera,
Aline Hamade,
Fadia Najjar,
Eric Oksenhendler,
Marс Lipinski,
Boris V. Chernyak,
Yegor S. Vassetzky
Affiliations
Rawan El-Amine
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Diego Germini
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Vlada V. Zakharova
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Tatyana Tsfasman
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Eugene V. Sheval
LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, 94805 Villejuif, France, 119334 Moscow, Russia
Ruy A.N. Louzada
UMR 8200, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Corinne Dupuy
UMR 8200, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Chrystèle Bilhou-Nabera
Biological Hematology Service-U.F. of Onco-Hematology Cytogenetics-Hôpital Saint-Antoine, 75012 Paris, France
Aline Hamade
Department of Life and Earth Sciences, Faculty of Sciences II/Doctoral School of Sciences and Technology (EDST), Lebanese University, Jdeidet El Metn-Fanar, Lebanon
Fadia Najjar
Department of Chemistry and Biochemistry, Faculty of Sciences II/EDST, Lebanese University, Jdeidet El Metn-Fanar, Lebanon
Eric Oksenhendler
Department of Clinical Immunology, Hôpital Saint-Louis, 75010 Paris, France
Marс Lipinski
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
Boris V. Chernyak
LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, 94805 Villejuif, France, 119334 Moscow, Russia
Yegor S. Vassetzky
UMR 8126, Paris Saclay University, Paris-Sud University, Institut Gustave Roussy, CNRS, Villejuif 94805, France
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.
