HIV gp120 induces mucus formation in human bronchial epithelial cells through CXCR4/α7-nicotinic acetylcholine receptors

PLoS One. 2013 Oct 14;8(10):e77160. doi: 10.1371/journal.pone.0077160. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiretroviral Therapy, Highly Active
  • Bronchi / pathology*
  • Bronchi / virology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV Infections / therapy
  • HIV Infections / virology
  • Humans
  • Macaca mulatta / virology
  • Mucin 5AC / metabolism
  • Mucus / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Receptors, CXCR5 / metabolism
  • Receptors, GABA-A / metabolism
  • Simian Acquired Immunodeficiency Syndrome / metabolism
  • Simian Acquired Immunodeficiency Syndrome / pathology
  • Simian Acquired Immunodeficiency Syndrome / virology
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • CXCR4 protein, human
  • CXCR5 protein, human
  • HIV Envelope Protein gp120
  • MUC5AC protein, human
  • Mucin 5AC
  • Receptors, CXCR4
  • Receptors, CXCR5
  • Receptors, GABA-A
  • alpha7 Nicotinic Acetylcholine Receptor