Non-Hodgkin's B cell lymphoma (AIDS-lymphoma)is seen in greatly-evaluated frequency in AIDS and HIV infection. In this proposal, studies to delineate immune system changes in HIV infection, relevant to the development of AIDS-lymphoma, are presented. While the dominant immune system change seen in AIDS is a severe functional and numerical loss of CD4 T cells, various other immune system changes are seen, including a marked increase in polyclonal B cell activation. The high frequency of B cell lymphoma seen in HIV infection may result, in part, from this chronic polyclonal B cell stimulation. Also, loss of immunoregulatory control of y-herpesvirus (EBV, HHV8) infected/activated B cells may contribute to AIDS-lymphoma. HHV8 encodes a viral IL6 homologue (vIL6). Studies described in this proposal will examine how vIL6 interacts with human B cells, in terms of receptor utilization, signal transduction, and biological effects. In other preliminary studies, key IL6 receptor element, IL6-Rx'CD126' was seen to be over- expressed in HIV infection, and to be involved in aberrant signaling (huIL6). Studies to define factors that could enhance IL6Rx expression, or modulate IL6Rx-mediated signaling, are proposed. Finally, preliminary studies indicate that people with advanced HIV disease show marked phenotypic changes in circulating B cells and CD8 T cells, including the over-expression of B/T cell surface stimulatory molecules. Studies to examine mechanisms that may be involved in the up-regulation of these molecules are proposed.
The specific aims are to: 1) define the biological effects of vIL6, and the receptor elements and signaling pathways utilized by this viral cytokine, on human B lymphocytes, 2) elucidate factors that contribute to IL6Rx over-expression on B cells and monocytes, and modulate IL6 receptor-mediated signaling, in HIV infection, and 3) characterize changes in immune cell subpopulations associated with enhanced B cell hyper-stimulation, or with the development of lymphoma, which are seen in people with advanced HIV disease. The accomplishment of these specific aims will provide information on HIV-induced immune dysfunction and the development of AIDS-lymphoma, may suggest new avenues for treatment, and could lead to screening technologies for the early detection of lymphoma.
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