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A4164 - Smoking Inhibits HIV-Induced CD8+ T Cell Alveolitis by Blocking Macrophage CXCL10 Production
Author Block: J. L. Cho1, B. Corleis2, S. J. Gates2, A. Lisanti2, P. Kohli1, A. K. Dickey1, A. Schiff2, R. Harris1, D. Kwon2, B. D. Medoff1; 1Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States, 2Ragon Institute, Massachusetts General Hospital, Boston, MA, United States.
Rationale: HIV infection results in a CD8+ T cell alveolitis that is only partially reversed by antiretroviral therapy (ART) and is thought to contribute to an increased risk of chronic obstructive pulmonary disease (COPD). Smoking is the single greatest risk factor for development of COPD and is closely associated with CD8+ T cell accumulation in lung tissue. Although 70% of HIV-infected individuals smoke, the lung immune response against HIV in the context of smoking has not been well characterized. Methods: HIV-infected and uninfected subjects on ART who were current and never smokers underwent bronchoscopy with bronchoalveolar lavage (BAL) and airway brushing (n=23 HIV-negative never smokers; n=7 HIV-negative smokers; n=14 HIV-infected never smokers; and n=13 HIV-infected smokers). Lung and blood immune cells were analyzed using flow cytometry. Monocyte derived macrophages (MDMs) were exposed to cigarette smoke extract (CSE) in vitro and chemotactic attraction of T cells was investigated with a transwell assay. Chemokines in BAL were measured by Luminex. Results: We found an HIV-associated increase in the number of CD8+ effector memory T cells in blood and BAL in never smokers. These CD8+ T cells had increased expression of the chemokine receptor CXCR3. Among HIV-infected smokers, an increase in BAL CD8+ T cells was not observed and there was a corresponding decrease in levels of the CXCR3 ligand CXCL10 in BAL fluid. In vitro exposure of MDMs to CSE resulted in decreased CXCL10 production and reduced MDM-mediated recruitment of CD8+ T cells in a transwell assay. However, HIV-infected smokers had an increased frequency of tissue resident CD8+ T cells found in brushing samples from the airways, suggesting impaired trafficking from the lung parenchyma into the airspace. Conclusions: HIV-infected subjects on ART have ongoing recruitment of CD8+ T cells to the airspace. Smoking blocks production of the T cell-specific chemokine CXCL10 by macrophages, which reduces HIV induced CD8+ T cell recruitment into the airspaces but may result in the accumulation of CD8+ T cells in lung tissue, contributing to the development of COPD. Given the high prevalence of smoking in the HIV-infected population, our data suggest a potential mechanism by which smoking contributes to an increased risk of COPD in people living with HIV. Funding: NIH U01HL121827, T32HL116275, and K08AI113083.