This application, submitted in response to RFA-NIH-88-L-15-L, seeks support to initiate studies on alveolar macrophages (AM) and the defense of the lung in AIDS. We will evaluate the hypothesis that cellular alterations caused by HIV-l infection of AM permits development of lung disease in AIDS. AM, like other monocytes, suffer a non-cytopathic, low-level infection with HIV-l. Our initial experiments demonstrate such infection of AM results in altered IL-l activity. Thus, HIV-l- infected AM may contribute to lung disease in AIDS by functional impairment or by acting as a reservoir for further HIV-l infection, or both. To test this hypothesis, we shall study: 1) the frequency of HIv-l infection in AM of AIDS patients and the expression of HIV-l in these cells; 2) the entry and expression of HIV-l in AM in vitro; 3) the impact of HIV-l infection on AM function; 4) effects of modulation of AM activity on HIV-l expression and AM function; 5) transmission of from AM to other cells in the course of immune response. Frequency of HIV-l- infected AM will be determined by PCR. Expression of the HIV-l genome will be determined by detection of latent virus versus evidence for virus production. Entry of HIV-l through CD4, Fc receptors, or phagocytosis will be evaluated through quantitation of HIv-l-AM membrane fusion. To characterize regulation of HIV-l expression, AM will be infected in culture or drawn from HIV-l seropositive individuals and compared for: i) expression of HIV-l p24 antigen, RNA and virions over time; ii) expression of regulatory genes tat and art; iii) modulation of infection through phorbol ester, colony stimulating factors, gamma interferon, LPS, tumor necrosis factor, or lymphocyte supernatants. AM function will be correlated to HIV-l infection by evaluation of the same panel of cells for IL-l and TNF production, and phagocytosis, ant their modulation by inductive agents. Finally, transmission of HIV-l from AM to antigen specific T cells during immune responses to purified protein derivative will be monitored by production of HIV-l and by cell death. The study will utilize expertise in the fields of virology, immunology, clinical medicine and molecular biology. This research will illuminate the mechanisms of generation of HIV-l related lung disease and of immune deficiency.
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