AIDS patients experience an additional risk of lymphoma between 60 and 100 times that expected in the HIV-negative population. Regulation of cellular genes by human retroviruses is likely to be a crucial link in their pathogenic activities. Deregulated expression or overexpression of B-cell mitogenic cytokines like IL-6 and IL-10 patients infected with HIV has been proposed as a potential mechanism leading to the development of B cell lymphomas in these patients. The only previously discovered way in which human retroviruses can interact with host cellular genes is via the trans-activator gene products tax or tat. In preliminary studies, a new way in which human (and murine) retroviruses aberrantly regulate B cell mitogenic cytokine gene expression infected cells has been identified. A new trans-activating activity encoded in the LTR of these viruses has been discovered. The cellular genes regulated by the viral LTR include those encoding IL-6 and IL-10 (and other cytokines, including MCP-1), MHC antigens, lymphocyte activation antigens, and proteases. Furthermore, ways of circumventing this control, and reversing the trans-activation process, have been demonstrated. The immediate objectives of this project are to elucidate, at a molecular level, the mechanisms by which murine and human retroviral LTRs trans- activate the cellular cytokine genes IL6 and IL10 infected cells, and the consequences of this trans-activation. The trans-acting mechanism encoded in the LTR of HIV will be defined. Next, the cis-acting elements of the IL-6 and IL-10 genes which mediate the LTR trans-activation will be mapped. The biological consequences of this aberrant host gene control, and how this dysregulation contributes to the pathogenicity or life cycle of the virus, will be studied. Finally, the mechanism of inhibition of LTR trans-activation of cytokine genes induced by oncogenes will be analyzed, those oncogenes which suppress trans-activation of cellular cytokine genes by retroviral LTRs will be identified, and the molecular mechanisms by which oncogenes alter the trans-activation of cellular genes by HIV will be determined. the long-term aim is to develop ways of circumventing this abnormal regulation of gene expression, to permit and facilitate destruction of the virus and prevention of HIV-associated lymphoma.
