The Glucocorticoid Receptor in Retroviral Infection

The hope that delivering genes to ailing tissues and organs can treat disease more effectively than drugs or surgery, has fueled the intense interest in gene therapy. Potential uses of gene therapy include replacing mutated genes with healthy ones, inactivating improperly functioning mutated genes, or introducing new genes into the body to help fight a specific disease. While the concept of gene therapy is easy to understand, technical difficulties have limited its practical use. Delivered genes that function admirably in cell culture may not function correctly in vivo, may have unexpected consequences on intracellular signaling pathways, or may transform cells raising the risk of iatrogenic malignancy. Retroviruses play a central role in gene delivery applications because they have a high infection efficiency and are able to induce stable mutagenesis in eukaryotic cells (Yi et al., 2005; Somia & Verma, 2000; Thomas et al., 2003). Stable incorporation of retroviral DNA into the host genome is advantageous, since long-term expression of the transgene, usually a requirement for prolonged therapeutic efficacy, is possible. While they are currently being used for in vitro and (animal) in vivo studies, the clinical use of retroviral vectors to deliver genes is still in its infancy. Among the reasons for the slow progress in adapting retroviruses to deliver genes are the concerns over potential adverse events when introduced into humans and a limited understanding of the mechanisms that affect retroviral function and expression in infected (target) cells. Both wild type and genetically modified retroviruses rely on the host cell to assist during its life cycle. Retroviral infection of cells, followed by integration of its genome into the host genome, is not always a certain process, however, and cellular and extracellular processes can influence these events. Therefore, while retroviral gene delivery is generally successful, the impact of viral infections on target cells remains less predictable and can be considered, basically uncontrollable. Despite the care with which viral vectors are generated, researchers ultimately rely on random events that can yield both positive and negative outcomes. In most eukaryotic cells, steroid hormones regulate a wide variety of physiological functions ranging from inflammation to pregnancy. There are five major classes of steroid hormones: glucocorticoids, mineralocorticoids, estrogens, androgens, and progestins. Steroid hormones from each class can complex with their specific receptors, and often with other transcription factors, to recognize DNA sequences called response elements. This mechanism of gene regulation by steroids is so potent and universal throughout the biosphere that it is not surprising that retroviruses have exploited the host nuclear steroid receptor regulatory system to expand their own genomes and improve their overall functionality.