Recent findings make it clear that there is no true """"""""latency phase"""""""" associated with HIV disease, at least in the strict sense of the term. Active virus replication is ongoing throughout the long clinical asymptomatic period which typically follows initial infection. These findings make it likely that the virus itself plays a key role in the clinical deterioration of the infected individual. Both in vitro and in vivo data demonstrate the ability of tissue macrophages to be infected by and harbor HIV. These cells may serve both as long-lived mobile reservoirs for spreading the virus and as the mediators of some of the major clinical syndromes associated with advanced HIV disease. There has been considerable speculation that they play a pivotal role in the pathogenesis of AIDS, although relatively little is understood regarding their role in the development of AIDS-associated opportunistic infections. In the unique environment of the lung, where alveolar macrophages represent the principal mediators of the host cell immune response against lung pathogens, the influence of HIV infected cells upon pulmonary defense systems is particularly pertinent. The overall objective of this research program is to delineate the mechanisms by which HIV infection of alveolar macrophages contributes to the pulmonary dysfunction that ultimately results in opportunistic infections. These mechanisms encompass both the effects of HIV upon the functioning of the alveolar macrophage, and interactions between HIV and other pathogens found in the immunocompromised lung. With regard to the alveolar macrophage itself, this project is specifically oriented towards understanding the dysregulation of cytokine production in alveolar macrophages resulting from HIV infection and its pathophysiological consequences. Within this project, we will also address the role of CMV, the other virus most commonly associated with AIDS in impairing lung defense mechanisms. Aspects of alveolar macrophage function with respect to infection by P. carinii and mycobacteria will be also investigated within the context of collaborative projects in the program.
Our aim i s to develop data on the operative dynamics within the pulmonary system of HIV infected individuals, both between different invading organisms and between those organisms and the host tissue, in sufficient molecular detail to then pursue specific strategies designed to interfere with these destructive processes. One specific strategy for intervention is presented which utilizes gene therapy as an outgrowth of the reagents and knowledge base generated in this project.
|Saukkonen, Jussi J; Bazydlo, Beth; Thomas, Michael et al. (2002) Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Infect Immun 70:1684-93|
|Ghosh, S; Frisardi, M; Rogers, R et al. (2001) How Giardia swim and divide. Infect Immun 69:7866-72|
|Yang, Y M; Hatch, W C; Liu, Z Y et al. (2001) Beta-chemokine induction of activation protein-1 and cyclic AMP responsive element activation in human myeloid cells. Cell Growth Differ 12:211-21|
|Stehle, S E; Rogers, R A; Harmsen, A G et al. (2000) A soluble mannose receptor immunoadhesin enhances phagocytosis of Pneumocystis carinii by human polymorphonuclear leukocytes in vitro. Scand J Immunol 52:131-7|
|Venkatakrishnan, G; Salgia, R; Groopman, J E (2000) Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. J Biol Chem 275:6868-75|
|Koziel, H; Li, X; Armstrong, M Y et al. (2000) Alveolar macrophages from human immunodeficiency virus-infected persons demonstrate impaired oxidative burst response to Pneumocystis carinii in vitro. Am J Respir Cell Mol Biol 23:452-9|
|Trujillo, J R; Goletiani, N V; Bosch, I et al. (2000) T-tropic sequence of the V3 loop is critical for HIV-1 infection of CXCR4-positive colonic HT-29 epithelial cells. J Acquir Immune Defic Syndr 25:10-Jan|
|Rees, D D; Rogers, R A; Cooley, J et al. (1999) Recombinant human Monocyte/Neutrophil elastase inhibitor protects rat lungs against injury from cystic fibrosis airway secretions. Am J Respir Cell Mol Biol 20:69-78|
|Park, I W; Wang, J F; Groopman, J E (1999) Expression and utilization of co-receptors in HIV and simian immunodeficiency virus infection of megakaryocytes. AIDS 13:2023-32|
|Koziel, H; Kim, S; Reardon, C et al. (1999) Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 160:2048-55|
Showing the most recent 10 out of 98 publications