University of Colorado, Denver – COPD

Principal Investigator: Andrew Fontenot
Co-Principal Investigators: Thomas Campbell, Brent Palmer

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.

Specific Aims
(1) Determine the effects of HIV-1 infection and smoking on PD-1 expression and IL-10 production by alveolar macrophages (AMs).
(2) Determine the relationship between PD-1 expression on AMs, IL-10 secretion and effector T cell function in the lung.
(3) Determine if HIV-1-related alterations in AMs and their effects on antigen-specific T cell function persist in the lung during long-term ART and are associated with abnormal lung function and a COPD phenotype.

Study Design : Two case-control cohorts
(1) Cohort A: HIV+ smokers (A1), HIV+ non-smokers (A2), HIV- smokers (A3), HIV- non-smokers (A4)
(2) Cohort B: HIV+/COPD+ (B1), HIV+/COPD- (B2), HIV-/COPD+ (B3)
Available Biospecimens: None

Inclusion/Exclusion Criteria
Study Population Overview