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A7245 - Mucoobstructive Lung Disease in the Era of Antiretroviral Therapy - A One-Two Blow of Tobacco Smoke Exposure and HIV Infection
Author Block: H. S. Chand1, R. Vazquez Guillamet2, S. P. Singh3, S. S. Hussain4, K. Rudolph3, C. M. Royer5, N. C. Mishra3, E. G. Barrett3, S. E. Callen6, M. Nair4, S. Buch6, M. L. Sopori3; 1Immunology, Florida International University, Miami, FL, United States, 2Internal Medicine, University of New Mexico, Albuquerque, NM, United States, 3Lovelace Respiratory Research Institute, Albuquerque, NM, United States, 4Immunology, Florida International University, MIAMI, FL, United States, 5UC Davis, Walnut Creek, CA, United States, 6University of Nebraska, Omaha, NE, United States.
Rationale: Effective antiretroviral therapy (ART) has increasingly shifted the focus toward long-term comorbidities affecting HIV patients. Chronic lung diseases including chronic bronchitis (CB) are among the most prevalent mucoobstructive disorders found increasingly among HIV-infected patients. Cigarette smoke (CS) exposure is one the well-recognized confounding factor for CB and smoking is very common among HIV-positive population. HIV infection has also been implicated in the development chronic lung diseases. Therefore, to investigate a potential interaction between CS and HIV in ensuing CB, cynomolgus monkeys were exposed to CS and/or simian-human immunodeficiency virus (SHIV), and were treated with ART to control viremia. Methods: Twenty five cynomolgus monkeys were exposed to mainstream CS or filtered-air (FA) for 11 weeks, and group of FA- and CS-exposed monkeys (n=7) were infected with SHIV89.6 and received ART (tenofovir + emtrictabine). SHIV infection and/or CS exposure were continued for 16 more weeks altogether, the animals received CS for 27 weeks and SHIV + ART for 16 weeks. Lung functions were determined by plethysmography using FlexiVent and upper airway wall thickening was measured by ultrasound imaging of extrathoracic tracheal rings. Airway mucous pathology were assessed by histological (AB-PAS), immunological (MUC5AC and MUC5B) and molecular (MUC5AC, MUC5B, SPDEF and FOXA3 mRNA levels) analyses. Bronchial epithelial integrity was analyzed by assessing tight junction proteins, occludin (OCLN) and zonula occludins 1 (ZO-1). Results: Following SHIV infection, animals exhibited viral loads of over 107 copies/ml plasma at 2 weeks post infection. The viral replication was responsive to ART, eliminating viral load by over 99.9% and promoting a weight gain. Surprisingly, even after a successful ART, SHIV infected animals showed HIV-gp120 immunoreactivity in airway epithelial cells (AECs) with higher number of alveolar AECs that were HIV-gp120+ than bronchial AECs. The number of HIV-gp120+ AECs were remarkably increased upon CS exposure. SHIV independently promoted goblet cell hyperplasia (GCH) and mucous phenotype, that were significantly higher than CS alone, and the combination of CS+SHIV induced a dramatic exacerbation of these mucous responses. SHIV and CS disrupted the bronchial epithelial barrier resulting in impaired lung function and exacerbated chronic bronchitis. Ultrasound imaging of tracheal rings correlated positively with mucous pathology and GCH, and the lung function decline. Conclusion: Together, these data suggest that HIV and CS independently promote bronchitis, and the combination exposure of CS and HIV further deteriorates muco-obstructive pulmonary disease despite a successful ART treatment. Study supported by NIH (HL125000 and AI117560) and ALA RG306208.