Two forms of malignancy are seen in greatly elevated frequency in AIDS and HIV infection: Kaposi's sarcoma (KS) and non-Hodkin's B cell lymphoma (BCL). In this proposal, studies to examine the effects of HIV-induced immune dysfunction on the development and growth of these AIDS-associated tumors are presented.
The specific aims are: 1) to define the role of interleukin 6 (IL-6) overproduction in B cell hyperactivation and in the development of BCL associated with HIV infection, 2) to delineate changes in B cell subpopulations, and to define the phenotype of the pre-BCL B cell subset, in HIV infection and AIDS, and, 3) to examine the role of IL-6 and other cytokines in AIDS-related KS. While the dominant immune system dysfunction seen in AIDS is the severe functional and numerical CD4 T cell defect, various other immune system changes, including a marked increase in B cell activity, with elevated levels of serum Ig and spontaneous Ig secretion, and in vivo phenotypic B cell changes characteristic of cellular activation, also are seen in AIDS. The high frequency of B cell malignancies seen in HIV infection may result from this in vivo B cell activation: chronic polyclonal B cell stimulation could increase the size of the target cell pool for chromosomal translocations involving the juxtaposition of an oncogene (c-myc) and an Ig gene, resulting in B cell tumors. Studies described in this proposal will focus on determining the role of HIV-induced IL-6 overproduction in AIDS- associated B cell hyperactivation, and on defining the phenotype of pre- neoplastic B cell subsets in AIDS and HIV infection. These studies will be done using a various cellular and molecular techniques. IL-6 also can act as an autocrine/paracrine growth factor in various human malignancies including multiple myeloma and renal cell carcinoma. In preliminary studies, AIDS-KS cells seen to produce and respond to IL-6. Studies aimed at defining the role of IL-6 and other cytokines in the development and growth of AIDS-associated KS also are described in this proposal. The realization of the specific aims will provide valuable information on the relationship between HIV-induced immune dysfunction and the development of AIDS-associated cancers. This information could form the foundation for future studies on the role of cytokines in AIDS-associated tumor growth and development, or could suggest new forms of treatment for AIDS-related diseases. Also, the realization of these specific aims could lead to new screening techniques able to detect AIDS-related BCL or KS much earlier in the course of tumor development, allowing for earlier clinical intervention.
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