title: HIV gp120 induces mucus formation in human bronchial epithelial cells through CXCR4/α7-nicotinic acetylcholine receptors.
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.
authors.affiliation: Respiratory Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Gundavarapu
authors.forename: Neerad C
authors.initials: NC
authors.lastname: Mishra
authors.forename: Shashi P
authors.initials: SP
authors.lastname: Singh
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.forename: Ali Imran
authors.initials: AI
authors.lastname: Saeed
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Julie
authors.initials: J
authors.lastname: Hutt
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Hegde
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Sopori
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001980:Bronchi / Q000473:pathology* / Q000821:virology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology / Q000628:therapy / Q000821:virology; D006801:Humans; D008253:Macaca mulatta / Q000821:virology; D055271:Mucin 5AC / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D054380:Receptors, CXCR5 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology / Q000821:virology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C527276:CXCR4 protein, human; C095085:CXCR5 protein, human; D015699:HIV Envelope Protein gp120; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D011963:Receptors, GABA-A; D064569:alpha7 Nicotinic Acetylcholine Receptor