Activation of T cells leads to the synthesis of set of coordinately expressed gene products, including several lymphokines. The expression of human immunodeficiency virus (HIV) also increases following activation of T cells containing this virus. We have shown that a transcription factor, NF-kB, becomes activated in T cells to cause this induction. A major goal of this proposal is to understand how DNA binding proteins regulate the expression of HIV in T cells and to identify agents which might modulate HIV expression without affecting inducible lymphokines, particularly interleukin (IL)-2. The proteins which bind to regulatory regions of these inducible genes will be identified and the functional role of their binding sites assessed by mutational analysis. The relevant proteins and their respective binding sites will be compared to those in y-interferon (y-IFN), IL-3, and IL-4 to identify common transcription factors and sites which may coordinately regulate these genes. A DNA binding protein which negatively regulates the expression of IL-2 has been found whose binding site is present also in a regulatory region of y-IFN and IL-4. The regulation of this DNA binding protein in comparison to NF-kB will be analyzed. The mechanism of activation for HIV will also be explored further using viral transactivator genes from herpesvirus, adenovirus, papovavirus, or HTLV-I. The expression of HIV enhancer mutants with altered sites in the HIV promoter and enhancer will be tested using the herpesvirus ICPO, adenovirus E1A, papovavirus E2, or HTLV-I tat transactivators. Changes in binding of NF-kB, other HIV regulatory proteins, or 2 DNA binding proteins will also be determined in response to treatment with different physiologic or pharmacologic activators. Finally, agents which might prevent the binding and action of these transcription factors, such as glucocorticoids, cyclosporin A or synthetic oligonucleotide analogues will be examined. Understanding the molecular basis of this coordinate gene expression will help to develop strategies to prevent the expression of HIV selectively in T cells.
| Osborn, L; Kunkel, S; Nabel, G J (1989) Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 86:2336-40 |
