Caractérisation moléculaire de l’inhibition de la transcription du VIH dépendante de Tat par la spironolactone

Abstract : Spironolactone (SP) is an aldosterone antagonist used in hypertension treatment for many years. SP treatment is responsible for a rapid and specific degradation of the XPB protein (Alekseev et al., 2014). Jurkat and primary CD4 + T cells infected by HIV-1 or HIV-2 and treated by SP show a strong degradation of the XPB protein and an important inhibition of viral infection. To confirm specificity of SP action on HIV, we have used a structural analogue of SP, Eplerenone (EPL), which can’t degrade XPB. On the contrary, EPL is unable to inhibit infection of cells previously infected by HIV. Otherwise, SP inhibition of HIV seems to be specific of Tat dependent transcription from the HIV promoter, because activation of this promoter with PMA or TNF is not affected by SP. Quantification of viral and cellular RNA show that only LTR transcription is affected by SP. Transcription of other promoters was measured in presence of SP and Tat but no inhibition of gene transcription has been observed. Finally, SP is also able to inhibit HIV LTR reactivation from latently infected T cells. This drug appears as a new anti-HIV compound and gives new perspectives concerning transcriptional inhibitors of HIV replication. This molecule also highlights the cofactor role of XPB during HIV replication in natural target cells.
Keywords : HIV Spironolactone
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Benoît Lacombe. Caractérisation moléculaire de l’inhibition de la transcription du VIH dépendante de Tat par la spironolactone. Virologie. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB137⟩. ⟨tel-02141708⟩

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