HIV infection of lung macrophages may be critical in the pathogens of the pulmonary disease which are major clinical problems in AIDS. Using forms of HIV isolated from lung macrophages, we will examine the interactions between HIV and lung macrophages. The incidence of HIV infection in lung macrophages and the cytological characteristics of the infected cells will be examined using a combination of the polymerase chain reaction (PCR) and cell separation techniques. Lung HIV isolates which preferentially infect macrophages will be molecularly cloned and/or examined using PCR. From a comparative analysis of the sequence information obtained, viral genomic sequences that may be important for macrophage tropism will be identified, and tested by introducing them into infectious clones of HIV to determine whether or not they confer macrophage tropism. Additionally, a panel of six macrophage functions will be tested: production of interleukin-l, tumor necrosis factor, interleukin 6, transforming growth factor beta, and tissue factor, and macrophage anti-mycobacterial activity. Using this panel of assay for macrophage functions which are likely to be disturbed in AIDS, HIV isolates will be screened for their pathogenic effects in lung macrophages. With potentially pathogenic viruses in hand, molecular techniques will be used to determine the genetic basis of HIV virulence for lung macrophages strains. Putative """"""""virulence elements"""""""" will be identified and tested by inserting these sequences into attenuated macrophage- tropic HIV clones. Using PCR techniques, the existence of viral variants in lung macrophages in vivo will be examined, and attempts will be made to correlate specific pulmonary manifestations of HIV infection with particular virulence elements. Finally, the activity of cytokines and antiviral agents capable of modulating the HIV life cycle will be evaluated in lung macrophages in culture. When these studies are complete, the role of lung macrophage dysfunction in AIDS will be better defined and the molecular forms of HIV which infect these cells will be better understood. Additionally, these studies may contribute to our general understanding of lung macrophages, which have been implicated in several lung disease. Armed with this knowledge, the mechanisms which cause HIV infection to progress to disease may be better understood, and novel methods to prevent this progression and to treat HIV-related pulmonary disease may be revealed.
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