A Molecular Substrate for Long QT in HIV Patients: Tat Protein Reduces IKR in Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes

Abstract

Compared to the general population, individuals with HIV have a 4.5 fold higher risk of sudden cardiac death, and up to 20% of them present with a long QT syndrome (LQTS). Notably, torsades de pointes arrhythmias have been described even in the absence of drug therapy, suggesting a rather direct implication of HIV in LQTS. The HIV-encoded Tat protein appears as a potential candidate for inducing ventricular arrhythmias, since it was shown to prolong the action potential (AP) of guinea-pig ventricular cardiomyocytes by reducing IKr. Tat protein serves as a transactivator of transcription required for HIV replication. Tat is released from infected cells and is found circulating in the blood of HIV-infected patients.The aim of this study was to evaluate the human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CMs) as a model to study the cellular mechanisms involved in the Tat-dependent alteration of cardiac electrical activity in human.Our data show that Tat incubation reduces IKr in hiPS-CMs while it does not alter IhERG in transfected COS-7 and HEK293 cellular models. hERG protein expression was reduced only in Tat-incubated hiPS-CMs; such reduction likely contributes to IKr reduction. Ventricular AP durations (APD70 and APD90) were significantly increased in hiPS-CMs incubated with Tat compared to buffer incubation. In addition, most Tat-treated cells showed a higher APD90 dispersion which resulted from AP duration and amplitude alternans. Alternans were exacerbated at faster stimulation rates.This work highlights that Tat-treated hiPS-CMs recapitulate alterations of the cardiomyocyte electrical activity, consistent with the arrhythmias observed in HIV patients. hiPS-CMs represent a relevant model for further investigations of the cellular mechanisms involved in AIDS, and, more generally, in cardiac non-genetic diseases.