Mycobacterium avium is the most frequent cause of disseminated bacterial infection in patients infected with human immunodeficiency virus (HIV) and is associated with morbidity and shortened survival. It is not clear why M. avium infection is more common in HIV-infected persons than in other groups of immunocompromised individuals and reaches such high levels in tissues (10 9- 10/g). The regulation of the growth of M. avium within mononuclear phagoytes and the infected host is the subject of AI25799. Colonial morphotype is a reliable determinant of the potential for intracellular replication. Smooth, flat-transparent (SmT) isolates are phagocytosed less well, but undergo more intracellular replication than smooth domed-opaque (SmD) colonies, and differ in their capacity to induce expression of interleukin-1, and tumor necrosis factor, but not IL-6. Cytokines have bidirectional effects on the intracellular growth of M. avium; and IL-1 alpha and IL-6 also promote extracellular growth. Purified gp120 protein of HIV also appears to modulate phagocytosis and intracellular growth of M. avium, and multinucleated giant cell formation by monocytes. These observations suggest that differential induction of cytokines by M. avium colonial morphotypes, possibly as modulated by HIV- products, determines the growth characteristics of M. avium in the mononuclear phagocyte, and in the tissues of patients infected with HIV. Testing of this hypothesis and initial exploration of its potential relevance in the HIV-infected host will require in vivo and in vitro studies in healthy and HIV-infected persons. Accordingly, the Specific Aims to test this hypothesis are: (1) To explore whether the growth- enhancing properties of IL-1 and IL-6 for M. avium are associated with binding to receptors on the organisms, and account for intracellular growth characteristics; and whether these cytokines promote M. avium growth in the monocytes and tissues of HIV-infected persons. (2) To examine the potential role of glycopeptidolipids and lipoarabinomannans of M. avium in the differential induction of cytokines by SmT and SmD strains; and the effects of these organisms and their constituents on the intracellular pathways of cytokine expression within the mononuclear phagocyte. (3) To determine the basis for the interference by HIV gp120 with the phagocytosis and intracellular growth inhibition of M. avium by human monocytes and with multinucleated giant cell formation, in terms of modulation of cell surface receptors, cytokine expression, and effector function. These studies should provide novel insights into the pathogenesis of and potential therapeutic approaches to M. avium in HIV-infected subjects, and the means by which viral products and induction of host cytokines contribute to successful parasitism.
Showing the most recent 10 out of 15 publications
