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Effets des protéines virales sur l’organisation nucléaire des lymphocytes B du sang périphérique humain

Abstract : An infection with the Human immunodeficiency virus (HIV) is associated with Bcell lymphomas in infected patients. The incidence of some lymphomas remains elevated in HIVinfected individuals whose immune function has been reconstituted under combined antiretroviral therapy. Its contribution to B-cell oncogenesis cells remains enigmatic. HIV-1 is known to induce an oxidative stress and DNA damage (DD) in infected cells via multiple mechanisms. However, it does not infect B lymphocytes. This contrasts with the viral transactivator protein Tat which circulates in the blood of infected individuals and spontaneously penetrates even non infectable cells. We have detected high levels of reactive oxygen species (ROS), mainly from mitochondria, and DDs in Bcells of HIV-infected individuals. We have thus hypothesized that Tat could induce oxidative DD in B-cells thereby promoting genetic instability and malignant transformation in these cells.In B-cells isolated from peripheral blood of healthy donors and incubated in the presence of purified recombinant protein Tat, an oxidative stress has been induced, the antioxidant capacity was decreased due to diminished glutathione levels, the transcription factor NF-κB was activated, and DD and chromosomal aberrations induced. All the effects induced by Tat were shown to depend on its transcriptional activity. To better understand the mechanism(s) of action of this viral protein, crude extracts from endemic plants of Lebanon were tested for their antioxidant potential. The prooxidative effect of Tat was inhibited, as well as the DD and chromosoml aberrations induced by the viral protein. In conclusion, we propose that the oxidative DNA damage and chromosomal aberrations induced by the Tat protein correspond to novel oncogenic factors that favor the development of B-cell lymphomas in HIV-1 infected individuals.
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https://tel.archives-ouvertes.fr/tel-01790346
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Submitted on : Saturday, May 12, 2018 - 1:01:48 AM
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Rawan El Amine. Effets des protéines virales sur l’organisation nucléaire des lymphocytes B du sang périphérique humain. Biochimie, Biologie Moléculaire. Université Paris Saclay (COmUE); École Doctorale des Sciences et de Technologie (Beyrouth), 2017. Français. ⟨NNT : 2017SACLS505⟩. ⟨tel-01790346⟩

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