Most patients with HIV infection will have an infectious pulmonary complication at some point during the course of their disease. However, these are usually a late manifestation of HIV infection, not appearing until CD4 counts fall well below 500 cells/ul and often below 200 cells/ul. HIV-infected patients frequently have an accumulation of CD8+ cytotoxic T lymphocytes (CTL) in the alveolar space which appears early and persists until late in their disease course when they are replaced by CD8+ suppressor cells. This switch heralds the rapid progression of end stage HIV disease and is associated with an increased incidence of pulmonary infections. The changing CD8+ population could reflect a shift in phenotype from CTL to suppressor cells under the influence of cytokines and cells in the alveolar space, expansion of the suppressor cell population, or loss of CTL. Any of these changes may be mediated by HIV itself or in concert with other organisms raising the intriguing possibility that pulmonary infections themselves can induce the switch from CTL to suppressor cells in the alveolar space. For this proposal they hypothesize that the fundamental change in the lung environment which leads to an AIDS defining pulmonary infection occurs when CD8+ CTL are replaced by CD8+ suppressor cells. They propose to address this hypothesis using an in vitro Mycobacterium tuberculosis infection model. They speculate that the switch is caused by a complex interplay between cytokines, cells, HIV and infectious organisms in the alveolar space. In this proposal they will 1. Examine changes in alveolar cell immune function in patients at different stages of HIV infection with regards to cytokine secretion and the induction of cellular immune responses, 2. Determine if these changes mediate the CD8+ CTL to suppressor cell switch through apoptosis of CTL, expansion of suppressor cells, or induction of a direct phenotypic switch from one cell type to the other, 3. Determine if the switch from CD8+ CTL CD8+ suppressor cells in the alveolar space impairs the ability to kill Mycobacterium tuberculosis, and 4. Determine if Mycobacterium tuberculosis can induce the CD8+ CTL to CD8+ suppressor cell switch through alteration of alveolar macrophage and T cell function, induction of CD8+ suppressor cell expansion, induction of CD8+ CTL apoptosis, and/or upregulation of HIV expression. Understanding mechanisms behind the change in the alveolar compartment in HIV-infected patients with advanced disease will contribute substantially to our understanding about late HIV infection and its attendant increase in pulmonary morbidity as well as offer suggestions on novel immune based therapeutic strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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AIDS and Related Research Study Section 5 (ARRE)
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Twigg 3rd, Homer L; Knox, Kenneth S (2013) Impact of antiretroviral therapy on lung immunology and inflammation. Clin Chest Med 34:155-64
Twigg, Homer L; Schnizlein-Bick, Carol T; Weiden, Michael et al. (2010) Measurement of antiretroviral drugs in the lungs of HIV-infected patients. HIV Ther 4:247-251
Wood, Karen L; Twigg 3rd, Homer L; Doseff, Andrea I (2009) Dysregulation of CD8+ lymphocyte apoptosis, chronic disease, and immune regulation. Front Biosci (Landmark Ed) 14:3771-81
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
Twigg Iii, Homer L; Weiden, Michael; Valentine, Fred et al. (2008) Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects. J Infect Dis 197:109-16
Twigg, Homer L; Knox, Kenneth S (2007) HIV-Related Lung Disorders. Drug Discov Today Dis Mech 4:95-101
Knox, Kenneth S; Day, Richard B; Kohli, Lisa M et al. (2006) Functional impairment of CD4 T cells despite normalization of T cell number in HIV. Cell Immunol 242:46-51
Wood, Karen L; Knox, Kenneth S; Wang, Yana et al. (2005) Apoptosis of CD57+ and CD57- lymphocytes in the lung and blood of HIV-infected subjects. Clin Immunol 117:294-301
Day, Richard B; Wang, Yana; Knox, Kenneth S et al. (2004) Alveolar macrophages from HIV-infected subjects are resistant to Mycobacterium tuberculosis in vitro. Am J Respir Cell Mol Biol 30:403-10
Wood, Karen L; Hage, Chadi A; Knox, Kenneth S et al. (2003) Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 167:1279-82

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