HIV Tat Protein Induces the TGF‐β Signaling Pathway and Suppresses the CFTR Biogenesis and Activity by microRNA‐Regulated Gene‐Silencing Mechanism

Abstract

The advent of combination antiretroviral therapy (cART) has led to a dramatic decline in morbidity and mortality from HIV/AIDS. HIV infected subjects are still six times more likely to contract pneumonia compared to non‐infected age matched controls. Mortality, following an episode of bacterial pneumonia was also four times higher in HIV infected subjects compared to non‐infected controls. Thus, pneumonia can also contribute to HIV progression. Understanding the pathophysiological mechanisms that lead to microbial colonization of the airways in HIV infected patients is therefore important to public health. HIV Tat and CS can suppress CFTR function, which is a critical determinant of ASL depth and this can lead to depressed MCC and consequent microbial colonization. Our study showed that HIV‐infected cells in the airway namely alveolar macrophages, other immune cells or bronchial epithelial cells can serve as reservoirs and a source of HIV proteins like Tat which upregulates TGF‐beta mRNA in primary human bronchial epithelial cells with a corresponding decrease in CFTR mRNA. Chromatin immunoprecipitation with RNA Polymerase II demonstrated that transcription from the CFTR promoter is unaffected and blocking the miRNA processing pathway with Aurin Tricarboxylic acid (ATA) restore CFTR inhibition caused by TGF‐ beta. Our data showed that HIV infection suppress CFTR mRNA and function and blocking TGF‐beta signaling rescues this. Together this posits a strong role for (TGF‐beta induced) miRNA in Tat mediated CFTR gene silencing.Support or Funding InformationFlight Attendant Medical Research Institute (FAMRI)HypothesisFigure 1HIV Tat suppresses CFTR via common TGF‐beta signalingFigure 2