|1.Research Institution||Kyoto University|
|2.Research Area||Life Sciences|
|3.Research Field||Infectious Diseases and Bioregulation|
|4.Term of Project||FY 1997 〜 FY 2001|
|6.Title of Project||Molecular Mechanism of Biological Defense against Retrovirus and Hepatitis Virus Infection|
|Name||Institution,Department||Title of Position|
|Junji, Yodoi||Kyoto University, Institute for Virus Research||Professor|
|Names||Institution,Department||Title of Position|
|Kunitada, Shimotohno||Kyoto University, Institute for Virus Research||Professor|
|Arimichi, Takabayashi||Kyoto University, Graduate School of Medicine||Associate Professor|
9.Summary of Research Results
We have demonstrated that members of the thioredoxin (TRX) system including TRX, mitochondria specific TRX2 plays important roles in the
regulation of viral persistent infection and cell death by redox regulation. We showed that the TRX2 gene is essential for cell survival and
regulates apoptosis using the DT-40 knock out system. We also studied extracellular functions of TRX and clarified that TRX suppresses
neutrophil extravasation into inflammatory site. Influenza-induced pneumonia and Listeria infection as well as cytokine -induced interstitial
pneumonia was suppressed in TRX transgenic mice, suggesting a protective role of TRX against inflammation. We also revealed the regulatory
mechanism of the TRX gene through the antioxidant responsive element, suggesting the coordinated role of the TRX system and the glutathione
system against oxidative stress. We newly identified TRX binding protein-2/ vitamine D3 up-regulated protein 1 (VDUP-1) as a negative regulator
of TRX. TBP-2 expression was markedly abrogated in HTLV-I infected cell lines. Loss of TBP-2 expression was associated with loss of IL-2
dependency in these cell lines. TBP-2 also has a growth suppressing activity, indicating a role of TBP-2 as a tumor suppressor. Therefore, analysis
of TBP-2/VDUP-1 family genes seems very important for creating a new diagnostic and therapeutic approach in HTLV-I infection.
We established an assay system for assessing natural killer (NK) cell activity by measuring the mitochondrial membrane potential (Dym). The levels of Dym, in NK cells were decreased in HCV infected patients and virus-positive patients, suggesting that NK cells in the patients who could not eliminate HCV may have impaired functions.
We analyzed the role of HCV core and non-structural protein, NS5A in the regulation of cell proliferation. We showed that core protein expressing cells were resistant to apoptotoic stimulation and this ability was correlated with the ability of core to activate NF-κB. NS5A interferes the PKR function so that the NS5A expressing cells become resistant to interferon treatment. We revealed that the C-terminal region of NS5A is involved in this regulation.
Inefficient replication of HCV in a tissue culture hampers to study the pathogenic role of this virus. We established the cell line in which a part of HCV genome replicates efficiently. This system may provide a new clue for HCV research.
(4)HCV、(5)ATL、(6)thioredoxin binding protein-2 (TBP-2)/VDUP-1