Adenoviruses (Ads) contain more than 20 genes dedicated to control various aspects of the innate or acquired immune responses of the infected host. Some of these functions are not necessary for the successful replication of the virus in cultured cells; however, they appear to target processes that are essential for the survival of virus during acute or latent infection in vivo (reviewed in Lukashok and Horwitz, 1997; Shenk, 1996; Wold et al., 1999). Many of these immunoregulatory genes are clustered in early region 3 (E3), which contains NF-B-binding sites in the E3 promoter (Deryckere and Burgert, 1996). Proteins encoded in the E3 region can inhibit peptide presentation by class I MHC and cell death by TNF-, Fas-, or TRAIL-induced mechanisms of cytolysis (Wold et al., 1999). Since the activity of the NF-B transcription factor is enhanced after stimulation of the TNF signal transduction pathway, the E3 genes should be activated during the inflammatory response. The focus of this minireview is on two areas of research:(1) A progress report on the nature and function of the cell proteins that interact with one of the Ad E3 proteins (14.7 K), an inhibitor of TNF-induced cytolysis; and (2) the use of the immunoregulatory Ad E3 genes in murine models in vivo to reduce the immune responses to allogeneic islet transplantation and to prevent islet destruction during the autoimmune response that results in type I or insulin-dependent diabetes mellitus (IDDM). There are excellent recent reviews about other aspects of the E3 proteins and other adenoviral proteins that regulate the interferon response, cell death, and the cell cycle (Mahr and Gooding, 1999; Wold et al., 1999). Because viruses have evolved as intracellular parasites over millions of years, they have finely tuned the process of acquiring molecules and targeting pathways to deal with counterattacking host immune responses.

Using the techniques of modern molecular biology and genetics, we have attempted to find the host molecules targeted by the Ad E3-14.7 K viral immunoregulatory protein. In most cases, the host molecules that we identified were novel and involved signaling pathways that had not been sufficiently elucidated to easily explain the function of the Ad E3-14.7 K protein. However, as we and others have contributed to an understanding of these signal transduction pathways, exciting new observations are being made. Before the advent of modern cloning techniques, viruses were critical reagents for discovering and understanding essential cellular processes such as mRNA splicing (Berget et al., 1977), oncogene function (van der Eb et al., 1977), and eukaryotic DNA replication (Challberg and Kelly, 1979; Friefeld et al., 1984). I believe that we have returned in part to such an era of discovery for the study of viral immunoregulatory genes. By determining cell molecules which are the targets of proteins such as Ad E3-14.7 K, viruses can help us bring together the vast amount of knowledge that has been produced by immunologists and cell and molecular biologists into coherent immunoregulatory pathways. These pathways, which control inflammatory responses, can then be used therapeutically to control disease processes. In some cases, the complete mechanistic understanding of the signaling pathways targeted by viral proteins will have to wait for additional data from other areas of biology; however, in the interim it will still be possible to use the viral immunoregulatory proteins in therapeutic or prophylactic ways to alter disease processes. This minireview will attempt to focus on the results as well as the processes by which we have pursued these goals of discovery.