Combined Program on Microbiology and Immunology. Osaka University.

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Research Theme:
Molecular Analysis of Mechanisms of Herpesvirus Infection

Principal Research Scientist
Koichi Yamanishi
Profile:

1968 –1972
Ph.D. candidate at the Research Institute for Microbial Disease, Osaka University.
1973 – 1989
Assistant Professor, Associate Professor, and Professor at the Research Institute for Microbial Disease, Osaka University.
Actively involved in research and education. (School of Medicine, Graduate School of Medicine, Cooperative lectures, Osaka University) Under Prof. Yamanishi's tutelage, ten students earned M.D/Ph.Ds.
1991 – 2005.3
Professor, Osaka University School of Medicine, Graduate School of Medicine.
Actively involved in teaching and conducting research in the field of microbiology at the
Graduate School of Medicine. Under Prof. Yamanishi's tutelage, fifteen students, including eight foreign students, have earned M.D/Ph.D.
2005.4– present
Director General, National Institute of Biomedical Innovation.

Collaborators

Keiji Ueda (Associate Professor, Graduate School of Medicine)
Yasuko Mori (Associate Professor, Graduate School of Medicine)

Kenjiro Tadagaki (Postdoctral Fellow of COE)

Research Summary

In our laboratory, we analyze the mechanisms of human herpesvirus infection and viral latency.
1. Human herpesvirus 6 (HHV-6) is classified into two subvariants, HHV-6A and HHV-6B, based on differences in nucleotide sequence and viral celltropism. The pathology of HHV-6A has not yet been elucidated; however, HHV-6B is known to be a causal agent of exanthema subitum. We have sequenced the complete genome of HHV-6B and have been engaged in molecular biological analyses of various genes encoded by the virus. Recently, human CD46 was identified as a cellular receptor of HHV-6; however, its viral ligand had not yet been identified. We determined that this ligand was indeed the viral envelope glycoprotein (glycoprotein H-glycoprotein L-glycoprotein Q ; gH-gL-gQ ) complex. In addition, we discovered that a portion of this complex, which we designated the gQ, is a conserved glycoprotein encoded only by HHV-6 and human herpesvirus 7 (HHV-7), but not by any other herpesviruses. Furthermore, the ligand molecule gH-gL-gQ complex from HHV-6B does not bind to CD 46. Therefore, CD 46 is the cellular receptor for HHV-6A, but not for HHV-6B. This suggests the existence of an unknown receptor(s) specific for HHV-6B. Additionally, this data indicates that the cellular receptor is one of the factors which determines the celltropism of HHV-6A and HHV-6B. Accordingly, our current research aims to identify the cellular receptor and ligand specific to HHV-6B, and to shed light on the different celltropism among HHV-6 variants.

2. Kaposi's sarcoma-related herpesvirus (KSHV) is an oncogenic herpesvirus closely associated with Kaposi's sarcoma and primary effusion lymphoma. The terminal repeat (Terminal Repeat = TR) element of the KSHV genome functions to initiate replication, and this domain comprises a specific sequence which binds latent infection associated nuclear antigen (LANA). LANA is one of a few viral genes which are expressed during latency, and is an extremely important multifunctional factor for maintenance of latent infection. Recent research on host-virus factors which interact in this domain has revealed that LANA is a key player in recruiting host factors such as the origin recognition complex (ORC), and minichromosome maintenance 2-7 (MCM2-7), which function to initiate replication. By determining the factor(s) which interact with TR-LANA, we believe that the factor(s) in charge of distribution can be identified. On the other hand, only a limited number of viral genes are expressed during latent infection. How is the latency mechanism achieved? The viral genome exists in a so-called heterochromatin domain in the nucleus, and we have found that LANA interacts with Suv39h1, HP1, and MeCP2, which are associated with generating heterochromatin in the host genome, and recruits them to TR. During latent infection, the heterochromatin remains in a repressed and condensed state, which maintains the viral genome in an extremely tight configuration, controlling (suppressing) viral gene expression. We aim to investigate the mechanism of interaction of these factors in detail, to determine the control mechanisms of active and inactive genes during latency.

Publications

1. Ueda, K., K. Ishikawa, K. Nishimura, S. Sakakibara, E. Do, and K. Yamanishi. 2002.
Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Replication and Transcription Factor Activates the K9 (vIRF) Gene through Two Distinct cis Elements by a Non-DNA-Binding Mechanism. J Virol 76:12044-54..

2. Mori, Y., P. Akkapaiboon, X. Yang, and K. Yamanishi. 2003. The Human Herpesvirus 6
U100 Gene Product Is the Third Component of the gH-gL Glycoprotein Complex on the Viral Envelope. J Virol 77:2452-8.

3. Mori, Y., X. Yang, P. Akkapaiboon, T. Okuno, and K. Yamanishi. 2003.
Human Herpesvirus 6 Variant A Glycoprotein H-Glycoprotein L-Glycoprotein Q Complex Associates with Human CD46. J Virol 77:4992-9.

4. Kondo, K., J. Sashihara, K. Shimada, M. Takemoto, K. Amo, H. Miyagawa, and K.
Yamanishi. 2003. Recognition of a novel stage of betaherpesvirus latency in human herpesvirus6. J Virol 77:2258-64.

5. Kondo, K., H. Nozaki, K. Shimada, and K. Yamanishi. 2003. Detection of a gene cluster
that is dispensable for human herpesvirus 6 replication and latency. J Virol 77:10719-24.