Most patients with Human Immunodeficiency Virus (HIV) infection will have a pulmonary complication at some point during the course of their disease. The advent of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of pulmonary infections. Although infections still predominate, some patients have a paradoxical worsening after initiation of HAART despite evidence of a recovering immune system. This phenomenon is termed immune restoration disease (IRD) and can affect up to 25% of patients who initiate HAART. IRD can be fatal and frequently mimics active pulmonary infection. As such, it can be a difficult diagnosis and contribute to morbidity and excessive clinical testing. Early pulmonary IRD is usually caused by latent or unrecognized infections at the time HAART is initiated. These infectious agents provide the substrate for the immunopathological response in IRD. However, late pulmonary IRD frequently manifests as sarcoidosis and is caused by unknown antigens. Stratifying people at risk for IRD and assessing their long term outcome is thus increasingly important, especially as the number of patients treated with HAART increases worldwide. We hypothesize that pulmonary IRD is clinically underrecognized and mediated by unbalanced Th1 responses. We propose to address this hypothesis by performing sequential CT scans, clinical assessment and bronchoscopies to harvest lung T cells in patients starting HAART therapy. Cytokine measurements, flow cytometry, and TREC analysis will be performed on lung and blood T cell subsets to assess if naive or memory cells are responsible for Th1-mediated IRD.
Specific aims i nclude: 1. To define a large, well-characterized clinical cohort of HIV-infected subjects for longitudinal study of IRD. 2. To determine the mechanisms of CD4 repopulation of the lung and 3. To define predictors of early and late pulmonary IRD based on clinical and immunological parameters. This work will have significant implications on clinical issues in HIV infected subjects, including predicting who is at risk for IRD and the 3 year outcome of patients with IRD. These studies also will provide the immunologic foundation for treatment strategies. Public Health Statement: As more patients worldwide are treated with anti-HIV drugs, the """"""""side effects"""""""" of these drugs require study. Patients who are at risk for these therapy-related problems need to know if their long term health is affected.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Peavy, Hannah H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Twigg 3rd, Homer L; Knox, Kenneth S (2013) Impact of antiretroviral therapy on lung immunology and inflammation. Clin Chest Med 34:155-64
Knox, Kenneth S; Vinton, Carol; Hage, Chadi A et al. (2010) Reconstitution of CD4 T cells in bronchoalveolar lavage fluid after initiation of highly active antiretroviral therapy. J Virol 84:9010-8
Crouser, Elliott D; Culver, Daniel A; Knox, Kenneth S et al. (2009) Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis. Am J Respir Crit Care Med 179:929-38
Brenchley, J M; Knox, K S; Asher, A I et al. (2008) High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage. Mucosal Immunol 1:49-58
Brenchley, Jason M; Paiardini, Mirko; Knox, Kenneth S et al. (2008) Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112:2826-35
Twigg, Homer L; Knox, Kenneth S (2007) HIV-Related Lung Disorders. Drug Discov Today Dis Mech 4:95-101