Date Published:
2013
Publication Type:
Journal Article
Authors:
Secondary:
PLoS One
Volume:
8
Pagination:
e77160
Issue:
10
PMID:
24155926
URL:
https://pubmed.ncbi.nlm.nih.gov/24155926
DOI:
10.1371/journal.pone.0077160
Keywords:
alpha7 Nicotinic Acetylcholine Receptor;Animals;Antiretroviral Therapy, Highly Active;Bronchi;Epithelial Cells;External;HIV Envelope Protein gp120;HIV Infections;Humans;Macaca mulatta;Mucin 5AC;Mucus;Receptors, CXCR4;Receptors, CXCR5;Receptors, GABA-A;Simian Acquired Immunodeficiency Syndrome
Abstract:
<p>Lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, and lung infections are major causes of morbidity and mortality among HIV-infected patients even in the era of antiretroviral therapy (ART). Many of these diseases are strongly associated with smoking and smoking is more common among HIV-infected than uninfected people; however, HIV is an independent risk factor for chronic bronchitis, COPD, and asthma. The mechanism by which HIV promotes these diseases is unclear. Excessive airway mucus formation is a characteristic of these diseases and contributes to airway obstruction and lung infections. HIV gp120 plays a critical role in several HIV-related pathologies and we investigated whether HIV gp120 promoted airway mucus formation in normal human bronchial epithelial (NHBE) cells. We found that NHBE cells expressed the HIV-coreceptor CXCR4 but not CCR5 and produced mucus in response to CXCR4-tropic gp120. The gp120-induced mucus formation was blocked by the inhibitors of CXCR4, α7-nicotinic acetylcholine receptor (α7-nAChR), and γ-aminobutyric acid (GABA)AR but not the antagonists of CCR5 and epithelial growth factor receptor (EGFR). These results identify two distinct pathways (α7-nAChR-GABAAR and EGFR) for airway mucus formation and demonstrate for the first time that HIV-gp120 induces and regulates mucus formation in the airway epithelial cells through the CXCR4-α7-nAChR-GABAAR pathway. Interestingly, lung sections from HIV ± ART and simian immunodeficiency virus (SIV) ± ART have significantly more mucus and gp120-immunoreactivity than control lung sections from humans and macaques, respectively. Thus, even after ART, lungs from HIV-infected patients contain significant amounts of gp120 and mucus that may contribute to the higher incidence of obstructive pulmonary diseases in this population.</p>