The hallmark of the acquired immunodeficiency syndrome (AIDS) is a severe derangement of the host's cellular immune system leading to a disease which includes overwhelming, often fatal, opportunistic infections. Recent evidence suggests that the virus that causes AIDS, HIV-1, infects and alters function not only of CD4+ T lymphocytes, but also of monocytes and macrophages. It is possible that the decreased ability of AIDS patients to resist infection by organisms not normally pathogenic is due to alterations in function of both T cells and macrophages. There is evidence that binding of HIV-1, or of its envelop glycoproteins gp120 and gp41, to macrophages significantly alters certain functions, for example chemotactic responses. It is reasonable therefore to question whether or not binding of gp120 and/or gp41 to macrophages alters other effector functions, specifically phagocytosis and killing of certain bacteria. AIDS patients are particularly susceptible to infection by facultative intracellular bacteria of the Mycobacterium avium complex, but curiously not by another facultative intracellular bacterium, Listeria monocytogenes. Resistance to both these pathogens is probably by immune mechanisms in which T cells stimulate macrophages to become efficient effector cells. This implies that there is a defect in T cells and/or macrophages of AIDS patients, expressed at the level of the macrophage, which allows normal resistance to one pathogen, but not the other. Such a defect could occur early, during phagocytosis of the organism, or later, during the microbicidal stage. The purpose of the experiments described here is to test the hypothesis that binding of the HIV-1 envelope glycoproteins gp120 or gp41 to human monocytes or macrophages alters the ability of these cells to phagocytose and/or kill certain bacteria. To test this hypothesis, we will do the following: 1) Determine whether macrophages incubated with gp120, with gp41 peptides synthesized by the core facility, or with both thee ligands, show quantitative alterations in binding or phagocytosis of listeria or Mycobacterium avium. 2) Test whether incubation of macrophages with gp120 and/or gp41 peptides alters the receptors through which M. avium or listeria are phagocytosed. 3) Determine whether incubation with gp120 and/or gp41 peptides alters the ability of normal macrophages to kill M. avium or listeria. 4) Finally, in conjunction with Project 1, determine whether binding of gp120, gp41 peptides, or both to macrophage surfaces alters signal transduction initiated by M. avium.
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