Patients with human immunodeficiency virus (HIV) are now living to older ages thanks to effective anti-HIV medicines. Despite these gains, many of them suffer from chronic lung disease that greatly impacts their ability to carry out their daily activities and impairs their quality of life. The type of lung disease they face is similar to what longtime smokers develop, a progressive narrowing of the airways and destruction of the lung. However, in HIV, the process appears to be accelerated and more severe. It’s not unusual, for instance, to see patients in their 30s and 40s develop this lung disease (which is approximately 30-40 years earlier than expected). Also, it’s not unusual for HIV patients who have never smoked before to develop this kind of disease. Unfortunately, the traditional medications we use to treat lung disease often interact with anti-HIV medicines, causing severe side effects. Management of breathing symptoms in HIV patients is therefore difficult and it is imperative that we find better agents to combat lung disease in this population. Only by understanding what causes and drives this lung injury process can this goal be achieved, though.
Multiple studies have now shown that smoking alone cannot explain the lung disease phenomenon in HIV. I believe that HIV injures the lung in a two phase process. First, the virus directly breaks down the protective layer of the airway known as the epithelium. Second, over time, as patients develop repeated lung infections due to their weakened immune systems, the bacterial community of the lung or microbiome shifts. I believe that this community disruption results in molecular changes that age the lung faster. My approach is to perform an in-depth investigation into the epithelium of the airway using two innovative methods. To explore the injury that HIV inflicts on the airway, I have created a novel model of the HIV airway using HIV-infected cells co-cultured on a cell culture model of the airway epithelium. We will use this model to see how HIV-infected cells break down the protective barrier of the lung. To explore the shifts in the microbiome, I have collected airway cells from HIV-infected and uninfected patients to not just describe what bacteria exist in the airway but also to determine what effect the community differences between the two groups have on the function of genes in the cells. We will measure how ‘old’ these cells are and compare these findings to uninfected patients.
The work of my laboratory was the first to detect accelerated epigenetic aging and methylation disruptions in the HIV airway epithelium, work that has now been published in the American Journal of Respiratory and Critical Care Medicine, and eBioMedicine.
These insights into accelerated aging in the HIV airway epithelium provide clues into why people living with HIV may be prone to developing chronic lung diseases such as Chronic Obstructive Pulmonary Disease or COPD.
Our work highlights the importance of accelerated aging in HIV, even in patients with well controlled infection. Reversing these aging mechanisms may be critical in the prevention or attenuation of airflow obstruction in this population.
We are continuing to explore mechanisms of early aging in the HIV airway using novel technologies such as magnetic resonance imaging, optical coherence tomography, and single cell sequencing.