Tropical spastic paraparesis is caused by
Oncogenic RNA Viruses The study of oncogenic retroviruses in animals has pro- vided spectacular insights into the genetic basis of cancer. However, only one retrovirus, the human T cell lympho- tropic virus-1 (HTLV-1), has been demonstrated to cause cancer in humans. HTLV-1 is associated with a form of T cell leukemia/lymphoma that is endemic in ceain pas of Japan and the Caribbean basin but is found sporadically elsewhere, including the United States. Similar to the human immunodeficiency virus (HIV), HTLV-1 has tropism for CD4+ T cells, and this subset of T cells is the major target for neoplastic transformation. Human infec- tion requires transmission of infected T cells through sexual intercourse, blood products, or breastfeeding. Leukemia develops only in about 3% to 5% of infected persons after a long latent period of 20 to 50 years. There is little doubt that HTLV-1 infection of T lympho- cytes is necessary for leukemogenesis, but the molecular mechanisms of transformation are not clear. The HTLV-1 genome does not contain a viral oncogene, and in contrast with ceain animal retroviruses, no consistent integration site next to a cellular oncogene has been discovered. Indeed, the long latency period between initial infection and devel- opment of disease suggests a multistep process, during which many oncogenic mutations are accumulated. The genome of HTLV-1 contains, in addition to the usual retroviral genes, a unique region called pX. This region contains several genes, including one called TAX. The TAX protein has been shown to be necessary and sufficient for cellular transformation. By interacting with several transcription factors, such as NF-kB, the TAX protein can transactivate the expression of genes that encode cytokines, cytokine receptors, and costimulatory molecules. This inappropriate gene expression leads to autocrine signaling loops and increased activation of promitogenic signaling cascades. Fuhermore, TAX can drive progression through the cell cycle by directly binding to and activating cyclins. In addition, TAX can repress the function of several tumor suppressor genes that control the cell cycle, including CDKN2A/p16 and TP53. From these and other observa- tions, the following scenario is emerging (Fig. 5-31): The TAX gene turns on several cytokine genes and their recep- tors (e.g., the interleukins IL-2 and IL-2R and IL-15 and IL-15R), setting up an autocrine system that drives T cell proliferation. Of these cytokines, IL-15 seems to be more impoant, but much remains to be defined. Additionally, a parallel paracrine pathway is activated by increased pro- duction of granulocyte-macrophage colony-stimulating factor, which stimulates neighboring macrophages to produce other T cell mitogens. Initially, the T cell prolifera- tion is polyclonal, because the virus infects many cells, but because of TAX-based inactivation of tumor suppressor genes such as TP53, the proliferating T cells are at increased risk for secondary transforming events (mutations), which lead ultimately to the outgrowth of a monoclonal neoplas- tic T cell population.
Human T cell lymphotropic virus
Hepatitis B virus
Human immunodeficiency virus
Epstein Barr virus
General anatomy