Despite a long list of organ systems adversely affected by aging in HIV, the lung remains relatively understudied, and combined effects of aging and HIV on the lung are unknown. Development of chronic obstructive pulmonary disease (COPD) may be accelerated in HIV despite antiretroviral treatment (ART). Average age of HIV+ individuals with COPD in our cohorts is 51 years compared to 61 years in our HIV- controls (p<0.001 adjusted for smoking). Lung disease may be a novel HIV-associated non-AIDS (HANA) complication related to aging, but rigorously controlled studies have not been performed. Aging in HIV is linked to cellular senescence and maladaptive inflammation. Senescence of lung and immune cells has been implicated in COPD in persons without HIV, but has not been investigated in HIV COPD. Our preliminary data demonstrate 1) increases in senescent and activated systemic T cells, 2) telomere shortening in blood lymphocytes, and 3) increases in peripheral and lung cytokines in HIV COPD;therefore, we hypothesize that aging is important in HIV COPD. Distinct phenotypes are increasingly being recognized as critical in understanding COPD pathogenesis. Our work indicates that HIV+ individuals commonly have different COPD phenotypes. Over 70% of outpatients manifest at least one abnormality with certain abnormalities associated with a greater burden of respiratory symptoms and with mortality. The relative importance of aging and inflammation in these phenotypes has not been examined, and peripheral biomarkers of phenotypes are unknown. Overall goals of the proposal are to evaluate the impact of aging on lung function in HIV, to test the novel hypothesis that COPD in HIV is a manifestation of immune cell and lung cell aging, and to determine peripheral biomarkers of aging and inflammation in HIV COPD. We will test these hypotheses with the following aims:
Aim 1. To test the hypothesis that aging modifies the risk of pulmonary dysfunction in HIV+ individuals.
Aim 2. To test the hypothesis that immune cell and lung cellular aging are increased in HIV COPD.
Aim 3. To establish the significance of patterns of peripheral inflammatory cytokines (the "inflammome") in HIV-associated lung disease. We will recruit HIV+ and HIV- participants from ongoing cohorts with enrichment of individuals over the age of 50. We will examine pulmonary function changes over time and the relationship of pulmonary function to peripheral and pulmonary markers of senescence and inflammation. We are uniquely positioned to investigate lung aging in HIV as we have established cohorts of >600 HIV+ and HIV- participants with thorough physiologic characterization and biological samples. The proposal will fill the gap in knowledge of pulmonary effects of physiologic and cellular aging in HIV and is directly responsive to PA-12-175 (Multidisciplinary Studies of HIV/AIDS and Aging). Results will enhance understanding of pulmonary aging and translate into improvements in prevention and management of HIV pulmonary disease.

Public Health Relevance

Normal age-related declines in lung function and development of chronic obstructive pulmonary disease (COPD) may be accelerated in HIV despite antiretroviral treatment (ART) with an average age of COPD in HIV+ study participants of 51 years compared to 61 years in HIV- controls. The proposed research is relevant to public health and to PA-12-175 (Multidisciplinary Studies of HIV/AIDS and Aging) because it proposes a new paradigm of obstructive lung disease in HIV that links aging and chronic immune activation to lung function abnormalities in HIV-infected persons. The proposal will fill the gap i knowledge of the epidemiology of aging and pulmonary disease in HIV as well as elucidate pulmonary effects of physiologic and cellular aging in HIV. Results will enhance understanding of pulmonary aging and translate into improvements in prevention and management of HIV pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL120398-01
Application #
8594404
Study Section
Special Emphasis Panel (ZRG1-AARR-K (58))
Program Officer
Caler, Elisabet V
Project Start
2013-09-04
Project End
2018-06-30
Budget Start
2013-09-04
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$686,609
Indirect Cost
$184,164
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213