MYCOBACTERIUM AVIUM-INTRACELLULARE INFECTIONS AND AIDS

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The goals of this project are to determine the mechanisms or factors that can effectively activate macrophages (Mphis) to kill or inhibit the growth of Mycobacterium avium-intracellulare (MAI). MAI is a mycobacterium infecting Mphis which causes disseminated disease in immunocompromised individuals such as patients with AIDS and hairy cell leukemia (HCL). We will determine whether MAI infection alters Mphi activation as measured by the expression of the macrophage activation markers HLA-DR and heavy chain of cytochrome B and the production of the monokines TNF-alpha, IL-1beta, and IL-6, important mediators of inflammation. We will investigate whether TNF-alpha and IL-6 play a central role in the defense against MAI and whether the presence of multicatalytic scavenger proteases is a necessary prerequisite for the survival of MAI-infected Mphis. We will also examine the effects of the cytokines MIF, M-CSF, GM-CSF, IL-4, and TGF-beta on their ability to activate Mphis to inhibit growth and kill MAI. Levels of circulating gammabeta T cells in AIDS and HCL patients with and without existing MAI infections will be compared to levels in normal donors. T cell clones reactive to mycobacterial antigens will be developed. These T cells and their lymphokines will then be cultured with MAI-infected Mphis to determine if they have an inhibitory effect on MAI growth. Correlation between HLA type, TNF production and MAI growth in Mphis will be attempted in AIDS and HCL patients and the effects of specific HIV proteins on MAI growth will be examined. These studies are designed to develop or identify an activation scheme which enables MAI-infected Mphis to control intracellular growth of MAI. We have recently found that MIF, a T cell lymphokine with various activating effects on Mphis, almost totally inhibits MAI growth (99%) in Mphis. We think that a treatment regimen involving MIF may lead to specific Mphi activation and subsequent MAI killing and will have considerable practical value in the control of MAI infections in late stage HIV-infected individuals.