Pulmonary manifestations of HIV infection include both opportunistic infections as well as complications related to primary HIV infection, such as interstitial pneumonitis. The development of interstitial pneumonitis requires targeting of lymphocytes and other inflammatory cells to the lung followed by the adhesion and migration of cells through the endothelial barrier. Adhesion and migration of lymphocytes are mediated through integrins, a class of cell adhesion molecules. We propose that HIV infection of lymphocytes alters the expression and function of integrins. This hypothesis is supported by preliminary data indicating increased expression of the fibronectin receptor, alpha5Beta1 on HIV-infected H9 lymphocytes. Altered expression of integrins may lead to inappropriate accumulation of lymphocytes in the pulmonary interstitium, leading to the development of pneumonitis. We hypothesize that lymphocyte adhesion itself results in upregulation of HIV gene expression. This mechanism may provide a potential route to allow the perpetuation of infected cells within the lung. It is also possible that other stimuli may act in synergy with adhesion and result in increased viral replication. We propose to investigate the effect of HIV infection on lymphocyte integrins. This will be accomplished by examining the surface expression and adhesive function of integrins on chronically infected lymphocytes and acutely infected, primary lymphocytes. We will also determine the effect of individual HIV gene products, including Tat, on integrin expression. The role of lymphocyte adhesion on HIV activation in the lung will also be examined. This will be accomplished by examining the effects of adhesion to pulmonary microvascular endothelial cells and matrix proteins important in the lung. We will determine p24 antigen levels as an indicator of viral gene expression. The ability of adhesion to affect transcription will be tested by examining Jurkat cells transfected with HIV LTR promoter upstream from the luciferase reporter gene. This proposal is designed to increase our understanding of the interactions between HIV-infected lymphocytes and pulmonary microvascular endothelium. This may eventually lead to therapeutic interventions designed to impact on lymphocyte adhesion.
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| Greco, Giampaolo; Pal, Sampa; Pasqualini, Renata et al. (2002) Matrix fibronectin increases HIV stability and infectivity. J Immunol 168:5722-9 |
| Lu, Min; Munger, John S; Steadele, Melissa et al. (2002) Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1. J Cell Sci 115:4641-8 |
