Resetting the Clock in HIV associated COPD

Title: Resetting the Clock on HIV associated COPD PROJECT SUMMARY The long-term goal of this proposal is identifying the role of aberrant circadian-coupled gene expression linking HIV and lung inflammation as a fundamental starting point to understand the pathophysiological mechanism in HIV associated COPD. People living with HIV demonstrate increased lung inflammation and incidence of COPD even when compensated for smoking status. Disruption of the lung molecular clock has been implicated in increased lung inflammation observed in COPD and smokers. SIRT1 is a principal circadian deacetylase that serves as a critical link between core clock function and inflammatory responses in the lung. HIV Tat, an immediate early protein of HIV that is secreted extracellularly, upregulates miR-142-5p in primary bronchial epithelial cells. This upregulation results in suppression of SIRT1 and circadian disruption of core clock genes BMAL1 and PER2. Likewise, cigarette smoking has also been shown to suppress SIRT1/BMAL1 pathway and dysregulate the lung molecular clock with consequent increase in secretion of proinflammatory cytokines. A significant proportion of people living with HIV smoke tobacco/cigarettes, possibly exacerbating their lung molecular clock dysfunction. This could be one of the core mechanisms that results in COPD exacerbations in HIV smokers. Therefore, determining the role of lung molecular clock dysfunction in HIV associated lung inflammation and COPD is the goal of this proposal. Resetting the molecular clock could thus help reduce underlying inflammation and/or arrest the lung function decline observed in HIV smokers. We propose three aims. Aim 1 determine that lung molecular clock is dysregulated by HIV Tat and identify the mechanism involved and its impact on inflammation. Aim 2 will test the role of miR-142-5p/SIRT1/BMAL1 axis in lung molecular clock dysfunction in HIV smokers/non smokers and in transgenic mouse models. Aim 3 will test clinically feasible strategies with established potential to neutralize HIV Tat and reset the lung molecular clock in vitro and in transgenic molecular clock mouse models in vivo. Understanding the pathophysiological mechanisms by which HIV disrupts the lung molecular clock will provide therapeutic targets for HIV-associated COPD.