The lung compartment HIV infection is characterized by chronic inflammation and severe immunologic derangements. While improvement is seen on highly active antiretroviral therapy (HAART), these patients still are susceptible to lung disease, especially those mediated by chronic inflammation. Furthermore, immune reconstitution is frequently characterized by poorly functioning lymphocytes due to a phenomenon called immunosenescence, or accelerated aging. Immunosenescence is caused by chronic antigenic stimulation, usually by viruses. In this regard, we have shown that HIV can persist in the lung in patients on HAART. Importantly, immunosenescence is associated with a chronic inflammatory state. Thus in this project we hypothesize that persistent antigenic stimulation by whole HIV or HIV proteins leads to an immunosenescent lung phenotype and chronic lung inflammation which contribute to the late complications associated with HIV infection. To address this hypothesis we will make use of two well characterized longitudinal cohorts of HIV-infected subjects we have recruited since 2000 to examine inflammatory and immunologic responses to HAART. We will recruit these subjects back for a longterm follow up visit to assess whether baseline, early HAART findings, or late HAART findings predict the development of long term HIV pulmonary complications. To accomplish our goals we propose the following Specific Aims: (1) To assess HIV-infected subjects who have been on treatment for three years or longer for pulmonary complications using a respiratory questionnaire, pulmonary function testing, chest CT imaging, and bronchoalveolar lavage. (2) To assess the pulmonary and peripheral blood HIV viral load and virome in patients on longterm HAART by measuring acellular HIV and cellular HIV RNA and HIV DNA in bronchoalveolar lavage fluid and blood. (3) To assess lung inflammation in HIV-infected subjects at the genomic level after longterm HAART using nanostring sequencing transcriptome analysis of lung and blood specimens. (4) To assess immune and inflammatory potential in subjects on long-term HAART by measuring cellular activation makers, T cell phenotypes, cytokine and chemokine release, and antigen specific T cell responses. Given our long history of studying HIV-infected subjects we have a large baseline HIV population with well-defined baseline clinical and immunologic characteristics which provide us a unique opportunity to look at longitudinal long term follow-up. Since chronic inflammation is likely at the root of most pulmonary complications in long term HIV infection, this work could have broad reaching implications on the management of these patients.

Public Health Relevance

In this project we will perform long term pulmonary follow up studies on HIV-infected subjects on antiretroviral treatment to determine if immune restoration in the lung is inadequate and results in chronic inflammation leading to complications. These studies will add to our understanding of how viral persistence in the lung, including by HIV itself can lead to long term pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL121831-02
Application #
8743261
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
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$622,323
Indirect Cost
$90,334
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202