Summary: Both retrospective and longitudinal cohort analyses strongly associate HIV infection with the
premature initiation and progression of chronic obstructive pulmonary disease (COPD). Improving long-term
pulmonary outcomes and longevity in people living with HIV (PLWH) will require a better understanding of how
cigarette smoke accelerates COPD in this patient population. We know that exposure to cigarette smoke causes
proliferative and oxidative responses in airway epithelial cells that promote HIV-related COPD. Our prior studies
showed that the HIV protein Tat and chronic smoke exposure both reduced lung levels of the RNA binding
protein human antigen R (HuR), which regulates the balance between decay and translation of multiple mRNA
targets. Similarly, we determined that prolonged smoke exposure reduces HuR levels in primary human airway
epithelial cells (HAECs) isolated from COPD subjects and in lung tissue sections from COPD airways. The loss
of HuR is important since we found that chronic smoke exposure worsened airflow obstruction in airway specific
HuR knockout mice. Moreover, our RNA-seq studies discovered that knocking down HuR in HAECs dysregulates
cell proliferation and reduces antioxidant gene expression. Another line of evidence indicates that the proto-
oncogene tyrosine-protein kinase c-Src negatively regulates HuR expression. We identified enhanced c-Src
activation in HAECs from COPD subjects and in the lungs of EcoHIV infected mice. Thus, we hypothesize that
chronic smoke exposure and HIV induce c-Src to down regulate HuR and thereby impair airway epithelial repair
mechanisms in COPD. This loss of HuR alters the airway transcriptome to promote airflow obstruction in PLWH.
We will test the hypothesis in three aims:
Aim 1: We will use transcriptomic analysis to determine how HIV and cigarette smoke induce COPD by
altering gene expression in human airway epithelial cells from healthy, COPD and HIV/COPD subjects
Aim 2. We will employ in vivo HIV COPD models to ascertain how HuR in the airway epithelium counters
the oxidative damage that promotes airway injury and airflow obstruction in HIV.
Aim 3. We will employ in vitro and in vivo HIV COPD models to determine how c-Src regulates HuR to
alter oxidative and proliferative responses that promote airway injury and airflow obstruction in HIV.
These studies will set the stage for novel pharmacologic interventions that restore HuR expression to counter
the airway epithelial injury that impairs lung function and tissue integrity in HIV infected COPD subjects.