HIV-1 Tat Protein and Cigarette Smoke Mediated ADAM17 Upregulation Can Lead to Impaired Mucociliary Clearance
Kingshuk Panda,
Maria J. Santiago,
Md. Sohanur Rahman,
Suvankar Ghorai,
Stephen M. Black,
Irfan Rahman,
Hoshang J. Unwalla,
Srinivasan Chinnapaiyan
Affiliations
Kingshuk Panda
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Maria J. Santiago
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Md. Sohanur Rahman
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Suvankar Ghorai
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Stephen M. Black
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Irfan Rahman
Department of Environmental Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA
Hoshang J. Unwalla
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Srinivasan Chinnapaiyan
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
Human immunodeficiency virus type-1 (HIV-1) associated comorbidities account for the majority of poor health outcomes in people living with HIV (PLWH) in the era of antiretroviral therapy. Lung-related comorbidities such as chronic obstructive pulmonary disease (COPD) and bacterial pneumonia are primarily responsible for increased morbidity and mortality in PLWH, even when compensated for smoking. Smokers and COPD patients demonstrate cilia shortening, attenuated ciliary beat frequency (CBF), dysfunctional ciliated cells along with goblet cell hyperplasia, and mucus hypersecretion. This is exacerbated by the fact that almost 60% of PLWH smoke tobacco, which can exacerbate inflammation and mucociliary clearance (MCC) dysfunction. This study shows that HIV Tat alters the microRNAome in airway epithelial cells and upregulates miR-34a-5p with consequent suppression of its target, Sirtuin 1 (SIRT1). SIRT1 is known to suppress Metalloproteinase 17 (ADAM17), a protease activating Notch signaling. HIV and cigarette smoke (CS) upregulate ADAM17. ADAM17 upregulation followed by SIRT1 suppression can lead to decreased ciliation, mucus hypersecretion, and attenuated MCC, a hallmark of chronic bronchitis in smokers and COPD. It is, therefore, essential to understand the pathophysiological mechanism resulting in acquired Notch dysregulation and its downstream impact on HIV-infected smokers.
