Research Project
10406519
PROJECT ABSTRACT Contemporary antiretroviral therapy has transformed HIV infection into a medically manageable chronic condition. However, the longer lifespan of people living with HIV (PLWH) has made them more susceptible to other infections and comorbid diseases. After adjusting for potential confounders, the PLWH are 50-60% more likely to develop the chronic obstructive pulmonary disease (COPD) and that too at a much younger age. Cigarette smoking is highly prevalent among PLWH and smokers living with HIV (SLWH) exhibit an early onset of COPD with an accelerated decline in lung functions. Moreover, HIV is also an independent risk factor for lung pathologies. HIV alters the epithelial homeostasis in multiple organs, including lungs; however, the cellular impact of HIV on lung epithelial inflammatory responses is poorly defined. Previously, using a large animal model, we reported a strong interaction between HIV and CS in affecting the lung pathophysiology. Our data suggested that HIV is a strong independent risk factor in causing epithelial barrier dysfunction and chronic lung pathologies, and CS-exposure synergistically exacerbated the lung epithelial remodeling. Nonetheless, not much is known about the host lung factors contributing to this condition in SLWH. To analyze the genetic determinants of lung epithelial responses, RNA sequencing was performed, and the long noncoding RNAs (lncRNAs) were identified that were significantly associated with epithelial inflammatory responses. Based on the experimental validation and the potential in gene regulation and in modulating inflammation, LncRNA Anti-Sense to ICAM-1 (LASI) was selected for further analyses. Intracellular adhesion molecule 1 (ICAM-1) is a cell surface glycoprotein expressed in epithelial cells, including bronchial epithelia and is associated with airway inflammation and potentially propagates viral infection to other cells and lead to increased susceptibility to chronic diseases. The LASI overlaps with ICAM-1 and is encoded on the antisense strand and was highly upregulated in CS treated normal human airway epithelial cells (HAECs) and in COPD subjects compared to controls. Furthermore, knocking down this lncRNA in HAECs suppressed the inflammatory factors. These data thus posit that lncRNA LASI could be an essential modulator of airway epithelial response and COPD pathogenesis in the context of HIV infection. Therefore, we propose that HIV infection and CS exposure alters the lncRNA LASI expression and subcellular localization in airways resulting in host susceptibility to airway inflammation and COPD exacerbations. We will test this hypothesis by 1) directly modulating the LASI levels in airway epithelial cells by gain- and loss-of-function studies; 2) identifying the mechanisms by which LASI modulates inflammatory responses by analyzing its potential as the precursor for microRNAs or microproteins, or as the sponge that binds the microRNAs. The proposed studies will thus help in improving our understanding of the effect of environmental exposures like CS and HIV in lung epithelial cells and may provide new insights for restoring and improving the pulmonary and overall health of SLWH.
