HIV-Tat induces a decrease in I Kr and I Ks via reduction in phosphatidylinositol-(4,5)-bisphosphate availability
Résumé
Patients with HIV present with a higher prevalence of QT prolongation, of which molecular
bases are still not clear. Among HIV proteins, Tat serves as a transactivator that stimulates
viral genes expression and is required for efficient HIV replication. Tat is actively secreted
into the blood by infected T-cells and affects organs such as the heart. Tat has been shown to
alter cardiac repolarization in animal models but how this is mediated and whether this is also
the case in human cells is unknown. In the present study, we show that Tat transfection in
heterologous expression systems led to a decrease in hERG (underlying cardiac IKr) and
human KCNE1-KCNQ1 (underlying cardiac IKs) currents and to an acceleration of their
deactivation. This is consistent with a decrease in available phosphatidylinositol-(4,5)-
bisphosphate (PIP2). A mutant Tat, unable to bind PIP2, did not reproduce the observed
effects. In addition, WT-Tat had no effect on a mutant KCNQ1 which is PIP2-insensitive,
further confirming the hypothesis. Twenty four-hour incubation of human induced pluripotent
stem cells-derived cardiomyocytes with Wild-type Tat reduced IKr and accelerated its
deactivation. Concordantly, this Tat incubation led to a prolongation of the action potential
(AP) duration. Events of AP alternans were also recorded in the presence of Tat, and were
exacerbated at a low pacing cycle length. Altogether, these data obtained on human K+
channels both in heterologous expression systems and in human cardiomyocytes strongly
suggest that Tat sequesters PIP2, leading to a reduction of IKr and IKs, and provide a molecular
mechanism for QT prolongation in HIV-infected patients.
Key
Domaines
Biologie cellulaire
Origine : Fichiers produits par l'(les) auteur(s)
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