title: HIV-Tat induces a decrease in IKrand IKsvia reduction in phosphatidylinositol-(4,5)-bisphosphate availability.
abstract: 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 IKrand 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 suggest that Tat sequesters PIP2, leading to a reduction of IKrand IKs, and provide a molecular mechanism for QT prolongation in HIV-infected patients.
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Zeineb
authors: Z
authors: Es-Salah-Lamoureux
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Mariam
authors: M
authors: Jouni
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Olfat A
authors: OA
authors: Malak
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Nadjet
authors: N
authors: Belbachir
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Zeina Reda
authors: ZR
authors: Al Sayed
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Marine
authors: M
authors: Gandon-Renard
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
authors: Guillaume
authors: G
authors: Lamirault
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Chantal
authors: C
authors: Gauthier
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Isabelle
authors: I
authors: Baró
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
authors: Flavien
authors: F
authors: Charpentier
authors: ER045, PRASE, Laboratory of stem cells, Lebanese university, Beirut, Lebanon.
authors: Kazem
authors: K
authors: Zibara
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, CHU Nantes, Nantes, France.
authors: Patricia
authors: P
authors: Lemarchand
authors: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, CNRS, Université de Montpellier, Montpellier, France.
authors: Bruno
authors: B
authors: Beaumelle
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France. Electronic address: nathalie.gaborit@univ-nantes.fr.
authors: Nathalie
authors: N
authors: Gaborit
authors: l'institut du thorax, Inserm, CNRS, Université de Nantes, Nantes, France.
authors: Gildas
authors: G
authors: Loussouarn
mesh_terms: D000200:Action Potentials; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D055724:Electrophysiological Phenomena; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072237:ERG1 Potassium Channel; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: HIV-Tat protein; I(Kr); I(Ks); Induced pluripotent stem cell-derived cardiomyocytes; Long QT syndrome; Phosphatidylinositol-(4,5)-bisphosphate