Deregulation of IRF Menbers in Human Retroviral Infection

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In this study, we focused on the role of Interferon Regulatory Factor ( IRF ) family members in retroviral infection. First we could demonstrate the essential role of LSIRF/IRF-4, an IRF member solely expressed in mature lymphocytes, in T and B function by the development of the gene targeted mouse. In this mutant mouse, the number of T and B lymphocytes is normal, but disable to mount proliferative responses against mitogens or anti-CD3 antibodies or alloantigens. In human, constitutive expression of LSIRF/lRF-4 is found only in cells infected with HTLV-1 , a causative agent of adult leukemia/lymphoma which is prevalent in our Nagasaki area. From clinical analysis, high-expression level is well correlated with the leukemic stage of the patients of ATL, suggesting the possible marker for prognosis in the disease as well as the role of the factor in leukemia as an oncogene. However, many efforts to clone a stable transformant with ectopically expressed LSIRF/lRF-4 is unsuccessful. Developing an inducible expression system of LSIRF/lRF-4, and isolating its associated factor (s) by yeast two-hybrid systems are now in progress.In case of IRF-1 deficient mouse, poor development of NK cells and low expression of IL-1 5 was found. The latter caused by the defect of IRF-1 expression, at least in part, seems to contribute to the impairment of NK cells development. It is interesting to seek physiological conditions of low expression of IRF-1 , by which individuals are susceptible to viral infection in general. On the other hand, this mutant mouse is resistant to a experimental model of human multiple sclerosis, a disease suggestedly caused by retroviral infection, implying that individuals protect themselves against retroviral infection by induction of IRF-1 at the risk of some autoimmune disease involvement.