Two forms of malignancy are seen in greatly elevated frequency in AIDS and HIV infection: Kaposi's sarcoma (KS) and non-Hodgkin's B cell lymphoma (BCL). In this proposal, studies to examine the effects of HIV-induced immune dysfunction on the development and growth of AIDS-associated BCL are presented.
The specific aims are: 1) to define the nature and mechanism of interleukin 6 (IL-6) overproduction induced by HIV, and to determine the role of IL-6 in the development of B cell malignancies 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 see if treatment with zidovudine (AZT) is associated with a decrease or increase in B cell dysfunction. 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 in the development and growth of AIDS-BCL, on defining the phenotype of pre-neoplastic B cell subsets in AIDS and HIV infection, and on examining the effect of AZT on B cell hyperactivation and T cell immunoregulation. These studies will be done using a various cellular and molecular techniques. The realization of the specific aims will provide valuable information on the relationship between HIV-induced immune dysfunction and the development of AIDS-associated lymphoma. This information could form the foundation for future studies on the role of cytokines in the growth and development of AIDS-associated lymphoma, 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-BCL earlier in the course of tumor development, allowing for earlier clinical intervention. Finally, the results of these studies may indicate if AZT therapy contributes directly to the development of AIDS-BCL.
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