Combined Program on Microbiology and Immunology. Osaka University.

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Research Theme :
Analysis of Molecular Mechanisms of Viral infection

Principal Research Scientist
Kazuyoshi Ikuta
Profile:

[Research/Education]

April, 1979 - February, 1989
Research Associate, Research Institute for Microbial Diseases
March, 1984 - February, 1986
Research Associate, Louisiana State University Medical Center
February, 1989 - April, 1989
Associate Professor, Research Institute for Microbial Diseases
May, 1989 - October, 1998
Professor, Hokkaido University, Institute of Immunological Science
April, 1990 - March, 1992
Visiting Professor, Tokyo Medical and Dental University
November, 1998 – present
Professor, Research Institute for Microbial Diseases

Collaborators

Keizo Tomonaga, Shotaro Tsuji, Wataru Kamitani

Akikazu Sakudo (Postdoctral Fellow of COE)

Cooperation given by

Etsuro Ono (Institute for Genetic Medicine, Hokkaido University)
Hiroyuki Taniyama (RAKUNO GAKUEN UNIVERSITY, School of Veterinary Medicine)

Research Summary

We have been investigating viruses which cause persistent infections, with particular emphasis on the mechanisms of viral replication and pathogenesis. HIV is known to target the immune system. Using HIV we found that the mutations of accessory genes, which do not affect the viral replication that causes apoptosis, are involved in establishing persistent infection following the initial acute infection. In addition, we have conducted a series of analyses of HIV-like viruses using animal models of HIV in the cat and horse, and have reported information which may be valuable in the development of an HIV vaccine. In particular, we have found that controlling genomic mutation, which is a characteristic of HIV, is crucial for HIV vaccine development. Using an animal model of equine infectious anemia virus (EIAV), we further discovered that the genetic variability is rather limited despite the continuous generation of escape variants. We have also collaborated with the Thai NIH for more than ten years in ongoing investigations of non-B subtype HIV, which differs from subtype B HIV, the most prevalent form of HIV in North America and Western Europe.
Since 1995, we have also been investigating Borna disease virus (BDV), which causes persistent infection of the central nervous system (CNS). BDV is a causative agent for encephalitis in horse and sheep, and research on BDV has been carried out for a long time in Germany and the neighboring countries. In 1985, the relevance of BDV to human psychiatric disorders was presented for the first time by a German research group through a seroepidemiological study. In Japan, the presence of BDV was not recognized until we reported an epidemiological survey of BDV infection in animals and patients with psychiatric disorders. We conducted an epidemiological survey of horse, sheep, cattle, cat, and humans with psychiatric disorders, and demonstrated dramatic epidemics of BDV infection for the first time. We then analyzed autopsied brain tissues from patients with various CNS diseases, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease, and were able to isolate BDV from the brain tissue of patient with psychiatric disorder. Furthermore, we successfully produced a transgenic mouse strain which expresses only a single BDV protein, and demonstrated that such transgenic mice exhibited an enhanced intermale aggressiveness and a spatial reference memory deficit. We are currently investigating persistent infection by BDV and the molecular pathogenesis of CNS disorders using these animal models.

Comparison of X4 HIV-1 sensitivity between T-cell subsets (CD4+ CD38+ and CD4+CD38-)
The number of CD4+ T cells in HIV-1 infected patients decreases as the disease progresses. However, the percentage of CD38+ T cells among CD4+ T-cell population is known to significantly increase in many patients. We have clarified that the CD38+ subset exhibits higher sensitivity to X4 HIV-1. We have also demonstrated that endogenous IL-4 is involved in this sensitivity. In addition, we analyzed the mechanism of X4 HIV-1 replication in the CD38 subsets. No differences in sensitivity during the processes of attachment, entry and integration were observed between the CD38 subsets; however, an apparent difference in sensitivity was observed during transcription. No difference was apparent in the activation of transcription factors such as STAT6 and NF- kappa B in the subsets, and no relevance of activation (CD25) or proliferation (Ki-67) markers was observed. On the other hand, the activation of AP-1 was observed in the CD38+ subset in an IL-4 dependent manner. Identification of genes specifically expressed either in the IL-4-treated CD38+ subset or in the IL-4-treated CD38- subset is currently underway using GeneChip analysis. We intend to utilize these host genes to develop a method to control HIV replication.

We found that BDV phosphoprotein (p24) binds to neurite promoting factor (HMGB1) and attempted to generate transgenic mice which express this protein only in glial cells. We were able to produce 5 strains; among these strains one transgenic mouse strain which exhibited high p24 expression shows increased aggression, decreased capacity of learning/memory function and apparent neurologic manifestations (spontaneous movement was not affected). We also observed decreased levels of the neurotrophic factor BDNF, a decrease in synapse number, and deviations in serotonin receptor levels (decreased levels of 5HTR1A and 5TR1B, normal levels of 5HTR1C). In addition, using the animal model of BDV intracranial infection (neonatal stage), we demonstrated that two factors, persistent intracranical infection of BDV and stress (stress was induced by intraperitoneal injection of LPS at 8 weeks of age), caused an apparent manifestation of disease state. Persistent BDV infection in neurons and glial cells in the brain results in a weakening of CNS cells, thereby disrupting the normal response to stress.

Publications

1. Komoto, S., Tsuji, S., Ibrahim, M.S., Li, Y.-G., Warachit, J., Taniguchi, K. and Ikuta, K.:
The Vpu protein of human immunodeficiency virus type 1 plays a protective role against viral induced apoptosis in primary CD4+ T lymphocytes. J. Virol. 77, 10304-10313, 2003.

2. Zhang, G., Kobayashi, T., Kamitani, W., Komoto, S., Yamashita, M., Baba, S., Yanai, H.,
Ikuta, K. and Tomonaga, K.: Borna disease virus phosphoprotein represses p53-mediated transcriptional activity by interference with HMGB1. J. Virol. 77, 12243-12251, 2003.

3. Kobayashi, T., Zhang, G., Lee, B.-J., Baba, S., Yamashita, M., Kamitani, W., Yanai, H.,
Tomonaga, K. and Ikuta, K.: Modulation of Borna disease virus phosphoprotein nuclear localization by the viral protein X encoded in the overlapping open reading frame. J. Virol. 77, 8099-8107. 2003.

4. Kamitani, W., Ono, E., Yoshino, S., Kobayashi, T., Taharaguchi, S., Lee, B-J., Yamashita,
M., Kobayashi, T., Okamoto, M., Taniyama, H., Tomonaga, K. and Ikuta, K.: Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice. Proc. Natl. Acad. Sci. USA 100, 8969-8974, 2003.

5. Ibrahim, M.S., Watanabe, M., Palacios, J.A., Kamitani, W., Komoto, S., Kobayashi, T.,
Tomonaga, K. and Ikuta, K.: Varied persistent life cycles of Borna disease virus in a human oligodendroglioma cell line. J. Virol. 76, 3873-3880, 2002.