The relatively low number of investigators in the field of human T cell leukemia/lymphoma viruses types I and II (HTLV-I and HTLV-II), is due, in part, to the higher degree of emergency and funding in the field of human immunodeficiency virus (HIV). This should not obscure the important role that the study of HTLV has played in virology in particular and in biomedical sciences in general. The discovery of HTLV-I in 1980 demonstrated that retroviruses existed in humans. The methods developed to culture T-lymphocytes and isolate HTLV-I were instrumental in the isolation and expansion of the human immunodeficiency virus (HIV), the cause of AIDS, the major pandemic of our time. HTLV-I is associated with adult T cell leukemia/lymphoma (ATL) and with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Understanding the biology of HTLV-I not only helped understand these diseases, but is a model for similar disorders, where an association with this or other viruses has not been demonstrated at present. For instance, HAM/TSP is a model for demyelinating disorders such as multiple sclerosis. The field of HTLV has also spawned or helped development in many areas. It has led to the discovery of interleukin-2 receptor and of the cytokines interleukin (IL)-9 and IL-15. The discovery of the viral transactivator Tax, a protein that increases viral expression and regulates the expression of cellular genes as well as that of Rex, another viral protein that shuttles back and forth from the nucleus and regulates the export of unspliced or singly-spliced mRNA from the nucleus, has opened new areas of research on basic mechanisms of transcriptional and post-transcriptional regulation. These concepts were instrumental in elucidating the key function of proteins with similar function in HIV, such as Tat and Rev. HTLV-I has been used to immortalize T-lymphocytes and this has helped to determine the nature of cytokines produced by T-lymphocytes, for instance chemokines produced by CD8+ T-lymphocytes, that have paved the way to the discovery of HIV coreceptors. The first Tax transgenic mouse model, where neurofibromas develop, helped pinpoint the importance of the constitutive activation of the nuclear factor (NF)-κB pathway as one of the major signal transduction mechanisms of at least some tumoral conditions. The list is not complete and only serves to underscore the major role of HTLV-I research in the biosciences. For this reason we are indebted to Genoveva (Veffa) Franchini, Steve Jacobson and Kuan-Teh Jeang for having organized such an excellent meeting on ‘HTLV-Molecular Biology and Pathogenesis’, that analyzed the current and most important issues in HTLV research, in terms of molecular mechanisms and pathogenesis. This meeting was sponsored by the National Cancer Institute (NCI), the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Allergy and Infectious Diseases (NIAID). What follows is a summary of the different issues that were presented and discussed during the meeting.
HTLV-1 Tax has the following molecular effects: (1) Activation of transcription through interaction of Tax with CBP/p300 (activation of CREB-, NF-κB- and SRF-responsive genes): this leads to increased expression of HTLV-I, interleukin (IL)-2, IL-2-receptor (IL-2R) α, IL-6, tumor necrosis factor (TNF)-α. (2) Repression of transcription through interaction of Tax with CBP/p300: this may lead to decreased expression of cellular genes, such as p18, NF-1, Lck, Bax, DNA polymerase β. (3) Dysregulation by Tax of cell cycle regulatory proteins, such as p16, p15, p53, c-Myb. This leads to disruption of normal regulation of cell cycle and increased proliferation. (4) Increase of genetic instability through repression of p53-dependent transcription and through interaction with hMAD1 (human mitotic checkpoint MAD1 protein, mitotic arrest deficient phenotype) and topoisomerase I. This leads to accumulation of mutations and to an increase in chromosomal anomalies, favoring the development of ATL. Interaction of Tax with hMAD1 leads to decreased expression of DNA polymerase β. Interaction of Tax with topoisomerase I leads to decreased activity of that enzyme. The latter effect is mediated by an inhibition by Tax of relaxation of supercoiled DNA, inhibition of binding of topoisomerase I to DNA and decreased covalent binding of topoisomerase I to chromosomal DNA. The site of action of Tax on topoisomerase I is different from that of camptothecin.
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