The majority of infectious complications of AIDS result f rom the loss of mechanisms which hold in check opportunistic microorganisms present in the lung. The alveolar macrophage is thought to play a important role in this process, and it is known to be a target for HIV infection. We propose to directly study how HIV infection of alveolar macrophages (AM) and related phagocytic cells affects their capacity to phagocytose, inhibit and kill Cryptococcus neoformans, Mycobacterium avium-intracellulare and Mycobacterium tuberculosis. Experiments will be conducted with AMs recovered from the lungs of AIDS patients undergoing diagnostic bronchoscopy as well as normal AM and peripheral blood monocytes infected with HIV in vitro. The antimicrobicidal activity of these cells will be correlated with changes in specific functional parameters and cell surface antigens. The molecular mechanisms of virus-induced dysfunction will be determined by studying the effects of individual viral proteins (gp12O, gp4l, p24, tat, nef) added exogenously to AM cultures or expressed intracellularly from vectors transfected into monocytes and U937 cells. Conversely, we will evaluate how the binding of cryptococci and mycobacteria to HIV-infected phagocytic cells affects virus expression and cytopathicity in these cells. These studies are expected to provide fundamental insights into the mechanisms by which opportunistic infections arise in the lungs of HIV-infected persons, and may suggest new lines of investigation for the treatment of the pulmonary complications of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044846-03
Application #
3363613
Study Section
Special Emphasis Panel (ARR (V3))
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1992-04-27
Budget End
1993-03-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Means, T K; Jones, B W; Schromm, A B et al. (2001) Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. J Immunol 166:4074-82
Keane, J; Remold, H G; Kornfeld, H (2000) Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol 164:2016-20
Ieong, M H; Reardon, C C; Levitz, S M et al. (2000) Human immunodeficiency virus type 1 infection of alveolar macrophages impairs their innate fungicidal activity. Am J Respir Crit Care Med 162:966-70
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
Wu, P; Phillips, M I; Bui, J et al. (1998) Adeno-associated virus vector-mediated transgene integration into neurons and other nondividing cell targets. J Virol 72:5919-26
Nau, G J; Guilfoile, P; Chupp, G L et al. (1997) A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci U S A 94:6414-9
Reardon, C C; Kim, S J; Wagner, R P et al. (1996) Interferon-gamma reduces the capacity of human alveolar macrophages to inhibit growth of Cryptococcus neoformans in vitro. Am J Respir Cell Mol Biol 15:711-5
Reardon, C C; Kim, S J; Wagner, R P et al. (1996) Phagocytosis and growth inhibition of Cryptococcus neoformans by human alveolar macrophages: effects of HIV-1 infection. AIDS 10:613-8
Harrison, T S; Kornfeld, H; Levitz, S M (1995) The effect of infection with human immunodeficiency virus on the anticryptococcal activity of lymphocytes and monocytes. J Infect Dis 172:665-71
Sugar, A M; Picard, M; Wagner, R et al. (1995) Interactions between human bronchoalveolar macrophages and Blastomyces dermatitidis conidia: demonstration of fungicidal and fungistatic effects. J Infect Dis 171:1559-62

Showing the most recent 10 out of 17 publications