Unconjugated
In the aging HIV (human immunodeficiency virus)-infected population, comorbid diseases are important determinants of morbidity and mortality. People living with HIV (PLWH) demonstrate increased lung inflammation and incidence of chronic obstructive pulmonary disease (COPD), even after adjusting for smoking status. Disruption of the lung molecular clock has been implicated in the increased lung inflammation observed in COPD and smokers. We hypothesize that the expression of HIV TAT protein in the lungs of PLWHpromotes lung inflammation and features of emphysema due to dysregulation of lung circadian rhythm, determined by the lung molecular clock genes. We demonstrate that HIV TAT upregulates miR-126-3p in primary bronchial epithelial cells and suppresses Sirtuin 1 (SIRT1), resulting in downstream effects on core circadian genes such as BMAL1 and PER2, leading to dysregulation of the lung molecular clock. This study identifies TAT/miR-126-3p/SIRT1 axis as an important mediator of HIV-induced lung inflammation in primary human bronchial epithelial cells, SPC-TAT transgenic mice with lung-specific TAT expression, and lungs from HIV-positive donors. Using single-cell RNA sequencing of lungs from 4-month-old SP-C TAT mice, we further show that these mice already exhibit significant alterations in clock gene expression and elevated expression of proinflammatory markers in their young adult stage. Understanding the pathophysiological mechanisms by which HIV disrupts the lung molecular clock and promotes inflammation may help identify therapeutic strategies to mitigate HIV-associated COPD.
