The lung has been recognized as one of the main targets of infectious and non-infectious complications of human immunodeficiency virus type 1 (HIV-1) infection. Despite the initiation of anti-retroviral therapy (ART), pulmonary complications of HIV-1/AIDS continue to be a major cause of morbidity and mortality in HIV-1-infected patients, with bacterial pneumonia and chronic obstructive pulmonary disease (COPD) being the most commonly identified pulmonary diseases. Following pneumonia, these individuals experience a decrement in lung function, which is not observed in HIV-1-uninfected populations, and a subset of HIV-1-infected smokers develop an accelerated form of emphysema. However, the mechanisms underlying the increased risk of pneumonia and COPD in HIV-1-infected individuals are not well understood. In this regard, smoking and COPD are associated with a re-programming of alveolar macrophages towards an immune phenotype associated with immunoregulation. In HIV-1-infected subjects, increased expression of the anti-inflammatory cytokine IL-10 in blood and bronchoalveloar lavage (BAL) fluid occurs. Our preliminary data show that alveolar macrophages (AMs) from HIV-1-infected smokers and nonsmokers secrete increased amounts of IL-10 in response to lipopolysaccharide (LPS) compared to uninfected individuals and that cigarette smoke exposure reduced LPS-induced TNF-alpha secretion from AMs. Importantly, a link between increased expression of the coinhibitory receptor programmed death 1 (PD-1) on blood monocytes and IL-10 secretion in HIV-1-infected subjects has been observed. PD-1 is upregulated on T cells in the setting of chronic antigen exposure, contributing to T cell dysfunction and an inability to clear HIV-1. Our preliminary data further show that HIV-1- specific CD4+ and CD8+ T cells in the lung have upregulated expression of PD-1 compared to T cells in blood, resulting in a dysfunctional T cell phenotype. Based on these findings, we hypothesize that the immunoregulatory consequences of increased IL-10 secretion from AMs, a dysfunctional T cell phenotype and HIV-1-induced immunosuppression combine to predispose the HIV-1-infected lung to infection and injury, thereby hastening the development of COPD in HIV-1-infected smokers. Using blood and BAL cells from smokers and nonsmokers with and without HIV-1 infection, we will determine the effects of HIV-1 and smoking on PD-1 expression and IL-10 production by AMs in specific aim 1.
The second aim will evaluate the relationship between PD-1 and IL-10 expression on AMs and their effects on T cell function in the lung before and after ART.
In specific aim 3, we will use a case-control study to evaluate AM and T cell function in relation to physiologic measures of lung function and COPD development. These studies will advance our understanding of the effects of cigarette smoking on innate and adaptive immunity in the HIV- 1-infected lung and the relationship of these responses to the development of chronic lung disease.

Public Health Relevance

This translational study will utilize blood and lung specimens from human subjects with HIV-1 infection to further our understanding of the immune mechanisms that predispose these subjects to the premature development of smoking-related lung disease. The successful completion of these studies will expand our understanding of the combined effects of cigarette smoke and HIV-1 on lung health and may lead to alternative therapeutic options in HIV-1-induced lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL121816-01
Application #
8638762
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Caler, Elisabet V
Project Start
2013-09-26
Project End
2018-07-31
Budget Start
2013-09-26
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$647,522
Indirect Cost
$228,640
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045