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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Modified Research Career Development Award (K04)
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AIDS and Related Research Study Section 1 (ARRA)
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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