徳島大学 / 教育研究者総覧 --- 土肥直哉

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https://researchmap.jp/6g6g (researchmap)

専門分野

○	ライフサイエンス (Life sciences) [ウイルス学 (Virology)]

研究テーマ

著書・論文

(著書・論文等の業績についてはhttps://researchmap.jp/6g6g (researchmap)でも御覧頂けます．)

著書:

1.	Takaaki Koma, Naoya Doi, Le Quoc Bao, Tomoyuki Kondo, Akio Adachi and Masako Nomaguchi : HIV-1 Replication and Pathogenicity: Lessons from Macaque-Tropic HIV-1 Derivatives, IntechOpen, London, Sep. 2023. (出版サイトへのリンク) ● Publication site (DOI): 10.5772/intechopen.1002899 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.5772/intechopen.1002899 (DOI: 10.5772/intechopen.1002899)

学術論文(審査論文):

1.	Takaaki Koma, Osamu Kotani, Keisuke Kamba, Kei Miyakawa, Taiki Morita, Hiromi Nakamura, Masaru Yokoyama, Naoya Doi, Tomoyuki Kondo, Takashi Nagata, Akihide Ryo, Akio Adachi, Akira Ono, Masato Katahira, Masako Nomaguchi and Hironori Sato : Positive correlation between structural disorder of the HIV-1 Gag N-terminal segment and progeny virus particle formation., Journal of Virology, e0088725, 2025. (要約) A class of unstructured peptide segments termed disordered regions plays a crucial role in the regulation of protein structure and function. Although the N-terminal region of the matrix (MA) domain of the HIV-1 Gag precursor protein is composed of an unstructured peptide, the mechanisms underlying the regulation of the unstructured state relating to control of viral phenotypes remain unclarified. We examined, in association, the structural, evolutionary, and biological roles of the MA N-terminal region via mutagenesis. Molecular dynamics simulation of a full-length Gag dimer model suggested that an amino acid residue at position 9 in the MA N-terminal region (MA-9) participates in the Gag dimerization. Information entropy analysis indicated that the MA-9 residue is variable in nature, but the hydrophobic amino acid substitution is evolutionarily maladaptive. Disordered region prediction study suggested that single hydrophobic amino acid substitutions at MA-9 reduce the disordered state of the MA N-terminal region. Consistently, NMR analysis indicated that such substitution reduces motional dynamics of the MA N-terminal region and alters the conformation of the MA domain. A site-directed mutagenesis study showed that hydrophobic amino acid substitutions at the MA-9 residue impair, to different degrees, the elementary and overall processes of virus particle formation in the cells. Importantly, the level of the virus particle formation was positively correlated with the level of disorder of the MA N-terminal region. These results indicate that the maintenance of structural disorder and dynamics of the Gag N-terminal segment is regulated by the MA-9 residue and critical for maintaining the optimal production of HIV-1 particles.IMPORTANCEA class of unstructured peptide segments termed disordered regions plays crucial roles in the regulation of protein structure and function. Although HIV-1 Gag precursor protein has multiple disordered elements, molecular mechanisms underlying regulation of unstructured state and viral phenotypes largely remain elusive. In this study, by analyzing in association the structural, evolutionary, and virological roles of the disordered N-terminal region of the HIV-1 Gag protein, we show that an amino acid residue at position 9 of the Gag is able to modulate the N-terminal disordered state, and the level of disorder of the Gag N-terminal region is positively correlated with the level of virus particle formation. Our findings gain new insights into molecular mechanisms of regulation of Gag structure and highlight the importance of a previously unappreciated survival strategy of HIV-1-namely, preservation of the Gag N-terminal disorder. (出版サイトへのリンク) ● Publication site (DOI): 10.1128/jvi.00887-25 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40956082 ● Search Scopus @ Elsevier (PMID): 40956082 ● Search Scopus @ Elsevier (DOI): 10.1128/jvi.00887-25 (DOI: 10.1128/jvi.00887-25, PubMed: 40956082)
2.	Takaaki Koma, Bao Quoc Le, Khanh Quoc Tran, Naoya Doi, Tomoyuki Kondo, Kei Miyakawa, Akio Adachi and Masako Nomaguchi : The role of HIV-1 Gag and genomic RNA interactions in virion assembly., Frontiers in Microbiology, 16, 1642090, 2025. (要約) The virion assembly represents a critical aspect of producing infectious progenies required for HIV-1 replication. Each step in that process, such as Gag-membrane binding, Gag-genomic RNA binding/packaging, Gag multimerization, and viral particle budding, has been extensively analyzed in a stepwise and specific manner. While Gag proteins are the primary drivers of HIV-1 virion assembly, the interactions between Gag and RNA play a significant role in regulating the process. This article provides an updated overview and perspective on HIV-1 virion assembly, with a particular focus on the role of Gag-RNA interactions. (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2025.1642090 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 40895469 ● Search Scopus @ Elsevier (PMID): 40895469 ● Search Scopus @ Elsevier (DOI): 10.3389/fmicb.2025.1642090 (DOI: 10.3389/fmicb.2025.1642090, PubMed: 40895469)
3.	Takaaki Koma, Naoya Doi, Bao Quoc Le, Tomoyuki Kondo, Mitsuki Ishizue, Chiaki Tokaji, Chizuko Tsukada, Akio Adachi and Masako Nomaguchi : Involvement of a Rarely Used Splicing SD2b Site in the Regulation of HIV-1 mRNA Production as Revealed by a Growth-Adaptive Mutation., Viruses, 15, 12, 2424, 2023. (要約) We have previously reported an HIV-1 mutant designated NL-Y226tac that expresses Vif at an ultra-low level, being replication-defective in high-APOBEC3G cells, such as H9. It carries a synonymous mutation within the splicing SA1 site relative to its parental clone. In order to determine whether a certain mutant(s) emerges during multi-infection cycles, we maintained H9 cells infected with a relatively low or high input of NL-Y226tac for extended time periods. Unexpectedly, we reproducibly identified a g5061a mutation in the SD2b site in the two independent long-term culture experiments that partially increases Vif expression and replication ability. Importantly, the adaptive mutation g5061a was demonstrated to enhance mRNA production by activation of the SA1 site mediated through increasing usage of a rarely used SD2b site. In the long-term culture initiated by a high virus input, we additionally found a Y226Fttc mutation at the original Y226tac site in SA1 that fully restores Vif expression and replication ability. As expected, the adaptive mutation Y226Fttc enhances mRNA production through increasing the splicing site usage of SA1. Our results here revealed the importance of the SD2b nucleotide sequence in producing mRNA involved in the HIV-1 adaptation and of mutual antagonism between Vif and APOBEC3 proteins in HIV-1 adaptation/evolution and survival. (キーワード) RNA, Messenger / HIV-1 / Cell Line / vif Gene Products, Human Immunodeficiency Virus / Virus Replication / Cytidine Deaminase / Mutation (徳島大学機関リポジトリ) ● Metadata: 2012869 (出版サイトへのリンク) ● Publication site (DOI): 10.3390/v15122424 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38140666 ● Summary page in Scopus @ Elsevier: 2-s2.0-85180515625 (徳島大学機関リポジトリ: 2012869, DOI: 10.3390/v15122424, PubMed: 38140666, Elsevier: Scopus)
4.	Takaaki Koma, Tokifumi Odaka, Sung-il Lee, Naoya Doi, Tomoyuki Kondo, Kazu Okuma, Jun-Ichi Fujisawa, Akio Adachi and Masako Nomaguchi : Humanized mice generated by intra-bone marrow injection of CD133-positive hematopoietic stem cells: application to HIV-1 research, Frontiers in Virology, 3, 2023. (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fviro.2023.1192184 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.3389/fviro.2023.1192184 (DOI: 10.3389/fviro.2023.1192184)
5.	Takaaki Koma, Naoya Doi, Akihiro Suzuki, Kentaro Nagamatsu, Takeshi Yasui, Koji Yasutomo, Akio Adachi, Takeo Minamikawa and Masako Nomaguchi : Major target for UV-induced complete loss of HIV-1 infectivity: A model study of single-stranded RNA enveloped viruses, Frontiers in Virology, 2, 994842, 2022. (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fviro.2022.994842 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.3389/fviro.2022.994842 (DOI: 10.3389/fviro.2022.994842)
6.	Takaaki Koma, Naoya Doi, Mai Takemoto, Kyosuke Watanabe, Hideki Yamamoto, Satoshi Nakashima, Akio Adachi and Masako Nomaguchi : The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process., Viruses, 13, 10, 2021. (要約) HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation. (徳島大学機関リポジトリ) ● Metadata: 2009755 (出版サイトへのリンク) ● Publication site (DOI): 10.3390/v13102079 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34696508 ● Search Scopus @ Elsevier (PMID): 34696508 ● Search Scopus @ Elsevier (DOI): 10.3390/v13102079 (徳島大学機関リポジトリ: 2009755, DOI: 10.3390/v13102079, PubMed: 34696508)
7.	Takaaki Koma, Masaru Yokoyama, Osamu Kotani, Naoya Doi, Nina Nakanishi, Hayato Okubo, Shun Adachi, Akio Adachi, Hironori Sato and Masako Nomaguchi : Species-specific valid ternary interactions of HIV-1 Env-gp120, CD4, and CCR5 as revealed by an adaptive single-amino acid substitution at the V3 loop tip., Journal of Virology, 2021. (要約) Understanding molecular bases for viral entry into cells leads to the elucidation of one of major viral survival strategies, and thus to the development of new effective antiviral measures. As experimentally shown recently, HIV-1 is highly mutable and adaptable in growth-restrictive cells such as those of macaque origin. HIV-1 initiates its infection by sequential interactions of Env-gp120 with two cell surface receptors, CD4 and CCR5. A recent epoch-making structural study has disclosed that CD4-induced conformation of gp120 is stabilized upon binding of CCR5 to the CD4-gp120 complex, whereas its biological significance remains totally unknown. Here, from a series of mutations found in our extensive studies, we identified a single-amino acid adaptive mutation at the V3 loop tip of Env-gp120 critical for its interaction with both CD4 and CCR5 in a host cell species-specific way. This remarkable finding would certainly provoke and accelerate studies to precisely clarify the HIV-1 entry mechanism. (徳島大学機関リポジトリ) ● Metadata: 2009485 (出版サイトへのリンク) ● Publication site (DOI): 10.1128/JVI.02177-20 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33883222 ● Search Scopus @ Elsevier (PMID): 33883222 ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.02177-20 (徳島大学機関リポジトリ: 2009485, DOI: 10.1128/JVI.02177-20, PubMed: 33883222)
8.	Naoya Doi, Takaaki Koma, Akio Adachi and Masako Nomaguchi : Expression Level of HIV-1 Vif Can Be Fluctuated by Natural Nucleotide Variations in the vif-Coding and Regulatory SA1D2prox Sequences of the Proviral Genome., Frontiers in Microbiology, 10, 2019. (徳島大学機関リポジトリ) ● Metadata: 2007405 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2019.02758 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31849897 ● Search Scopus @ Elsevier (PMID): 31849897 ● Search Scopus @ Elsevier (DOI): 10.3389/fmicb.2019.02758 (徳島大学機関リポジトリ: 2007405, DOI: 10.3389/fmicb.2019.02758, PubMed: 31849897)
9.	Naoya Doi, Takaaki Koma, Akio Adachi and Masako Nomaguchi : Role for Gag-CA Interdomain Linker in Primate Lentiviral Replication., Frontiers in Microbiology, 10, 2019. (要約) -modulator to optimize the Gag-related viral replication process. We also have noted, during the course of conducting the research project, that HIV-1 and SIVmac, belonging to distinct primate lentiviral lineages, share a similarly biologically active linker region with each other. In this brief article, we summarize and report the results obtained by mutational studies that are relevant to the functional significance of the interdomain linker of HIV/SIV Gag-CA. Based on this investigation, we discuss about the future directions of the research in this line. (徳島大学機関リポジトリ) ● Metadata: 2007404 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2019.01831 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31440231 ● Search Scopus @ Elsevier (PMID): 31440231 ● Search Scopus @ Elsevier (DOI): 10.3389/fmicb.2019.01831 (徳島大学機関リポジトリ: 2007404, DOI: 10.3389/fmicb.2019.01831, PubMed: 31440231)
10.	Takaaki Koma, Osamu Kotani, Kei Miyakawa, Akihide Ryo, Masaru Yokoyama, Naoya Doi, Akio Adachi, Hironori Sato and Masako Nomaguchi : Allosteric regulation of HIV-1 capsid structure for Gag assembly, virion production, and viral infectivity by a disordered interdomain linker., Journal of Virology, 2019. (要約) HIV-1 particle production and infection are highly ordered processes. Viral Gag proteins play a central role in the assembly and disassembly of viral molecules. Of these, capsid protein (CA) is a major contributor to the Gag-Gag interactions. CA consists of two structured domains, i.e., N-terminal (NTD) and C-terminal (CTD) domains, connected by an unstructured domain named interdomain linker. While multiple regions in the NTD and CTD domains are reported to play roles in virion morphogenesis and infectivity, the roles of the linker region in Gag assembly and virus particle formation remain elusive. In this report, we show by biological and molecular analyses that the linker region functions as an intramolecular modulator to tune Gag assembly, virion production, and viral infectivity. Our study thus illustrates a hitherto unrecognized mechanism, an allosteric regulation of CA structure by the disordered protein element, for HIV-1 replication. (出版サイトへのリンク) ● Publication site (DOI): 10.1128/JVI.00381-19 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31189701 ● Search Scopus @ Elsevier (PMID): 31189701 ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.00381-19 (DOI: 10.1128/JVI.00381-19, PubMed: 31189701)
11.	Naoya Doi, Masaru Yokoyama, Takaaki Koma, Osamu Kotani, Hironori Sato, Akio Adachi and Masako Nomaguchi : Concomitant Enhancement of HIV-1 Replication Potential and Neutralization-Resistance in Concert With Three Adaptive Mutations in Env V1/C2/C4 Domains., Frontiers in Microbiology, 10, 2019. (要約) adapts its Env to macaque cells with strongly replication-restrictive nature for HIV-1. While a single and two mutations gave a significantly enhanced replication phenotype in a macaque cell line and also in human cell lines that stably express either human CD4 or macaque CD4, the virus simultaneously carrying the three adaptive mutations always grew best. Entry kinetics of parental and triple mutant viruses were similar, whereas the mutant was significantly more readily inhibited for its infectivity by soluble CD4 than parental virus. Furthermore, molecular dynamics simulations of the Env ectodomain (gp120 and gp41 ectodomain) bound with CD4 suggest that the three mutations increase binding affinity of Env for CD4 in solution. Thus, it is quite likely that the affinity for CD4 of the mutant Env is enhanced relative to the parental Env. Neutralization sensitivity of the triple mutant to CD4 binding site antibodies was not significantly different from that of parental virus, whereas the mutant exhibited a considerably higher resistance against neutralization by a CD4-induced epitope antibody and Env trimer-targeting V1/V2 antibodies. These results suggest that the three adaptive mutations cooperatively promote viral growth via increased CD4 affinity, and also that they enhance viral resistance to several neutralization antibodies by changing the Env-trimer conformation. In total, we have verified here an HIV-1 adaptation pathway in host cells and individuals involving Env derived from a lab-adapted and highly neutralization-sensitive clone. (徳島大学機関リポジトリ) ● Metadata: 2007403 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2019.00002 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30705669 ● Summary page in Scopus @ Elsevier: 2-s2.0-85064397079 (徳島大学機関リポジトリ: 2007403, DOI: 10.3389/fmicb.2019.00002, PubMed: 30705669, Elsevier: Scopus)
12.	Naoya Doi, Tomoyuki Miura, Hiromi Mori, Hiromi Sakawaki, Takaaki Koma, Akio Adachi and Masako Nomaguchi : CXCR4- and CCR5-Tropic HIV-1 Clones Are Both Tractable to Grow in Rhesus Macaques., Frontiers in Microbiology, 9, 2018. (要約) genetic manipulations and viral cell-adaptations, we have successfully generated a series of HIV-1 derivatives with CXCR4-tropism or CCR5-tropism that grow in macaque cells to various degrees. Of these viruses, those with best replicative potentials can grow comparably with a pathogenic SIVmac in macaque cells by counteracting major restriction factors TRIM5, APOBEC3, and tetherin proteins. In this study, rhesus macaques were challenged with CXCR4-tropic (MN4/LSDQgtu) or CCR5-tropic (gtu + A4CI1) virus. The two viruses were found to productively infect rhesus macaques, being rhesus macaque-tropic HIV-1 (HIV-1rmt). However, plasma viral RNA was reduced to be an undetectable level in infected macaques at 5-6 weeks post-infection and thereafter. While replicated similarly well in rhesus peripheral blood mononuclear cells, MN4/LSDQgtu grew much better than gtu + A4CI1 in the animals. To the best of our knowledge, this is the first report demonstrating that HIV-1 derivatives (variants) grow in rhesus macaques. These viruses certainly constitute firm bases for generating HIV-1rmt clones pathogenic for rhesus monkeys, albeit they grow more poorly than pathogenic SIVmac and SHIV clones reported to date. (徳島大学機関リポジトリ) ● Metadata: 2007402 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2018.02510 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30405570 ● Search Scopus @ Elsevier (PMID): 30405570 ● Search Scopus @ Elsevier (DOI): 10.3389/fmicb.2018.02510 (徳島大学機関リポジトリ: 2007402, DOI: 10.3389/fmicb.2018.02510, PubMed: 30405570)
13.	Shoko Nakanishi, Sakimi Watanabe, Naoya Doi, Takaaki Koma, Akio Adachi and Masako Nomaguchi : Virological characterization of HIV-1 CA-NTD mutants constructed in a virus-lineage reflected manner., The Journal of Medical Investigation : JMI, 65, 1.2, 110-115, 2018. (要約) Capsid (CA) protein is a major virion-constituent of all retroviruses including human immunodeficiency virus type 1 (HIV-1), and is essential for early and late phases in viral replication cycle through interaction with numerous cellular factors. In particular, N-terminal domain (NTD) of HIV-1 CA has been frequently and well reported to bind to various host cell proteins that considerably affect viral replication potential. In this study, in order to better define biological bases of the CA-NTD for HIV-1 replication, we performed an extensive mutational analysis in an unprecedented manner. By aligning CA-NTD sequences derived from representative infectious molecular clones of HIV-1, HIV-2, and simian immunodeficiency virus isolated from the rhesus macaque (SIVmac), a number of amino acids specific to HIV-1 were selected, and were replaced with those from SIVmac at the corresponding sites. Mutant viruses thus generated were then examined for multi-cycle infectivity, single-cycle infectivity, and ability to produce progeny virions. While some CA-NTD mutations affected viral replication ability to varying degrees, those in helix 7 abolished viral growth potential without exception. These results highlight functional importance of non-conserved amino acids in helix 7, and give new insights into functionality of HIV-1 CA-NTD. J. Med. Invest. 65:110-115, February, 2018. (徳島大学機関リポジトリ) ● Metadata: 2004624 (出版サイトへのリンク) ● Publication site (DOI): 10.2152/jmi.65.110 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29593179 ● Search Scopus @ Elsevier (PMID): 29593179 ● Search Scopus @ Elsevier (DOI): 10.2152/jmi.65.110 (徳島大学機関リポジトリ: 2004624, DOI: 10.2152/jmi.65.110, PubMed: 29593179)
14.	Masako Nomaguchi, Naoya Doi, Tomoya Yoshida, Takaaki Koma, Shun Adachi, Hirotaka Ode, Yasumasa Iwatani, Masaru Yokoyama, Hironori Sato and Akio Adachi : mRNA Is Modulated by Natural Nucleotide Variations and SLSA1 RNA Structure in SA1D2prox Genomic Region., Frontiers in Microbiology, 8, 2542, 2017. (要約) mRNA level. (徳島大学機関リポジトリ) ● Metadata: 2007400 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2017.02542 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29326677 ● Summary page in Scopus @ Elsevier: 2-s2.0-85038265027 (徳島大学機関リポジトリ: 2007400, DOI: 10.3389/fmicb.2017.02542, PubMed: 29326677, Elsevier: Scopus)
15.	Masako Nomaguchi, Naoya Doi, Takaaki Koma and Akio Adachi : Complete Genome Sequences of Human Immunodeficiency Type 1 Viruses Genetically Engineered To Be Tropic for Rhesus Macaques., Genome Announcements, 5, 39, 2017. (要約) We have constructed two human immunodeficiency type 1 (HIV-1) derivatives, CXCR4 tropic and CCR5 tropic, that replicate in rhesus macaques. They are genetically engineered to be resistant to macaque restriction factors against HIV-1, including TRIM5, APOBEC3, and tetherin proteins. The two HIV-1 variants described here are fundamental clones aiming for rhesus infection studies of HIV-1. (徳島大学機関リポジトリ) ● Metadata: 2008047 (出版サイトへのリンク) ● Publication site (DOI): 10.1128/genomeA.01063-17 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28963223 ● Search Scopus @ Elsevier (PMID): 28963223 ● Search Scopus @ Elsevier (DOI): 10.1128/genomeA.01063-17 (徳島大学機関リポジトリ: 2008047, DOI: 10.1128/genomeA.01063-17, PubMed: 28963223)
16.	Naoya Doi, Yosuke Sakai, Akio Adachi and Masako Nomaguchi : Generation and characterization of new CCR5-tropic HIV-1rmt clones, The Journal of Medical Investigation : JMI, 64, 3,4, 272-279, 2017. (要約) To develop effective non-human primate models for coping with numerous HIV-1/AIDS studies, rhesus macaque-tropic HIV-1 (HIV-1rmt) clones with a variety of biological properties are required. Such clones, if available, are powerful tools to experimentally elucidate HIV-1 replication and pathogenicity in host individuals, and also to develop anti-HIV-1 drugs/vaccines. However, only limited numbers of HIV-1rmt clones have been currently reported. In the present study, we generated new HIV-1rmt clones carrying various CCR5-tropic env (envelope) genes by standard recombinant DNA and intracellular homologous recombination techniques. Resultant virus clones contain the env sequences derived from an AIDS-inducible laboratory or two clinically isolated viral strains. We further constructed their variant clones bearing N160K, S304G, or G310R mutation in Env that potentially can change the viruses to better grow. Newly generated clones were analyzed for their virological properties such as Env expression, single-cycle infectivity, and multi-cycle replication ability. Out of a number of new clones examined, two were found to grow better in macaque cells than the previously constructed clone used for comparison. Our study described here constitutes the initial and essential step towards obtaining CCR5-tropic HIV-1rmt clones useful for various basic and clinical research projects on infected individuals. J. Med. Invest. 64: 272-279, August, 2017. (キーワード) Animals / Cells, Cultured / HIV-1 / Humans / Macaca mulatta / Receptors, CCR5 / Virus Replication / env Gene Products, Human Immunodeficiency Virus (徳島大学機関リポジトリ) ● Metadata: 2004320 (出版サイトへのリンク) ● Publication site (DOI): 10.2152/jmi.64.272 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28954995 ● Search Scopus @ Elsevier (PMID): 28954995 ● Search Scopus @ Elsevier (DOI): 10.2152/jmi.64.272 (徳島大学機関リポジトリ: 2004320, DOI: 10.2152/jmi.64.272, PubMed: 28954995)

総説・解説:

1.	Takaaki Koma, Shun Adachi, Naoya Doi, Akio Adachi and Masako Nomaguchi : Toward Understanding Molecular Bases for Biological Diversification of Human Coronaviruses: Present Status and Future Perspectives., Frontiers in Microbiology, 11, Aug. 2020. (要約) replication for various accessory proteins encoded by the variable 3' one-third portion of the CoV genome mostly remain to be determined. Importantly, the genomic sequences/structures closely linked to the high CoV recombination are poorly investigated and elucidated. Also, determinants for adaptation and pathogenicity have not been systematically investigated. We summarize here these research situations. Among conceivable projects, we are especially interested in the underlying molecular mechanism by which the observed CoV diversification is generated. Finally, as virologists, we discuss how we handle the present difficulties and propose possible research directions in the medium or long term. (徳島大学機関リポジトリ) ● Metadata: 2008527 (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fmicb.2020.02016 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32983025 ● Search Scopus @ Elsevier (PMID): 32983025 ● Search Scopus @ Elsevier (DOI): 10.3389/fmicb.2020.02016 (徳島大学機関リポジトリ: 2008527, DOI: 10.3389/fmicb.2020.02016, PubMed: 32983025)
2.	Masako Nomaguchi, Naoya Doi, Takaaki Koma and Akio Adachi : HIV-1 mutates to adapt in fluxing environments., Microbes and Infection, Oct. 2018. (要約) Human immunodeficiency virus type 1 (HIV-1) is specifically adapted for replication, persistence, transmission, and survival in humans. HIV-1 is highly mutable in nature, and well responds to a variety of environmental pressures by altering its genome sequences. In this review, we have described experimental evidence that demonstrates this phantasmagoric property of HIV-1. (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.micinf.2017.08.003 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28859896 ● Search Scopus @ Elsevier (PMID): 28859896 ● Search Scopus @ Elsevier (DOI): 10.1016/j.micinf.2017.08.003 (DOI: 10.1016/j.micinf.2017.08.003, PubMed: 28859896)

国際会議:

1.	Noriaki Minakawa, Noriko Saito-Tarashima, Takaaki Koma, NAOTO Hinotani, Keigo YOSHIDA, Moka OGASA, AKIHO Murai, Shuya INOUE, Tomoyuki Kondo, Naoya Doi, Koichi Tsuneyama and Masako Nomaguchi : 3-Deazaguanosine exhibits anti-SARS-CoV-2 activity and blocks the development of COVID-19 pneumonis in hamsters, Supra FIBER International Summit for Nucleic Acids (S-FISNA) 2024, Mar. 2024.

国内講演発表:

1.	駒貴明, 土肥直哉, LE Bao Quoc, TRAN Khanh Quoc, 近藤智之, 足立昭夫, 野間口雅子 : HIV-1A4Y1Env-CT, 第71回日本ウイルス学会学術集会, 2024年11月.
2.	TRAN Khanh Quoc, LE Bao Quoc, 駒貴明, 近藤智之, Marissa Sayako JONES, 前原礼佳, 足立昭夫, 野間口雅子, 土肥直哉 : PIMキナーゼによるHIVウイルスタンパク質発現抑制機構の解析, 第71回日本ウイルス学会学術集会, 2024年11月.
3.	LE Bao Quoc, TRAN Khanh Quoc, 近藤智之, 土肥直哉, UTSUMI Aoi, 得津成次郎, 足立昭夫, 野間口雅子, 駒貴明 : HIV-1Env-gp120beta20-21内のE433K変異はV2領域の適応変異と協働してウイルス複製を促進する, 第71回日本ウイルス学会学術集会, 2024年11月.
4.	近藤智之, 駒貴明, 土肥直哉, Le Quoc Bao, TRAN QUOC KHANH, 浅井大輝, 足立昭夫, 野間口雅子 : HIV-1複製能を変動させるSA3周辺の新規塩基配列領域の解析, 第71回日本ウイルス学会学術集会, 2024年11月.
5.	近藤智之, 駒貴明, 土肥直哉, Le Quoc Bao, TRAN QUOC KHANH, 浅井大輝, 内海葵, ジョ-ンズマリッサ清子, 得津成次郎, 前原礼佳, 足立昭夫, 野間口雅子 : SA3周辺の塩基配列がHIV-1の複製能に与える影響の解析, 第38回中国四国ウイルス研究会, 2024年7月.
6.	Le Quoc Bao, 横山勝, 土肥直哉, 一ノ宮匠海, 薦田奈々子, 近藤智之, 足立昭夫, 小谷治, 佐藤裕徳, 野間口雅子, 駒貴明 : R5指向性HIV-1複製におけるEnv V3内ITI tripletモティーフの重要性, 第70回日本ウイルス学会学術集会, 2023年9月.
7.	駒貴明, Le Quoc Bao, 土肥直哉, 薦田奈々子, 一ノ宮匠海, 近藤智之, 足立昭夫, 野間口雅子 : HIV-1集合における Gag-NCとgRNAの相互作用の意義, 第70回日本ウイルス学会学術集会, 2023年9月.
8.	近藤智之, 駒貴明, 土肥直哉, Le Quoc Bao, 薦田奈々子, 一ノ宮匠海, 足立昭夫, 野間口雅子 : Vpr領域内の同義1塩基置換がHIV-1複製に及ぼす影響, 第70回日本ウイルス学会学術集会, 2023年9月.
9.	土肥直哉, 駒貴明, Le Quoc Bao, 薦田奈々子, 一ノ宮匠海, 近藤智之, 足立昭夫, 野間口雅子 : PIMキナーゼによるHIVウイルス産生抑制の解析, 第70回日本ウイルス学会学術集会, 2023年9月.
10.	駒貴明, 小谷治, 土肥直哉, 近藤智之, 横山勝, 足立昭夫, 佐藤裕徳, 野間口雅子 : HIV-1 Gag MAのGag二量体化における役割の解明, 第36回日本エイズ学会, 2022年11月.
11.	近藤智之, 駒貴明, 足立昭夫, 野間口雅子, 土肥直哉 : PIMキナーゼによるHIV型特異的な遺伝子発現調節の解析, 第36回日本エイズ学会学術集会・総会, 2022年11月.
12.	土肥直哉, 駒貴明, 後藤田知里, 長坂麻里, 近藤智之, 足立昭夫, 野間口雅子 : HIV-1遺伝子発現におけるvpr塩基配列の重要性, 第69回日本ウイルス学会学術集会, 2022年11月.
13.	近藤智之, 駒貴明, 宇田川明郁, 奥村希, 足立昭夫, 野間口雅子, 土肥直哉 : PIMによるHIV種特異的な遺伝子発現制御機構の解析, 第69回日本ウイルス学会学術集会, 2022年11月.
14.	駒貴明, 小谷治, 土肥直哉, 近藤智之, 横山勝, 足立昭夫, 佐藤裕徳, 野間口雅子 : HIV-1 Gag-MAにおけるGag前駆体二量体化部位のウイルス学的解析, 第69回日本ウイルス学会, 2022年11月.
15.	近藤智之, 駒貴明, 足立昭夫, 野間口雅子, 土肥直哉 : PIMキナーゼ及びPIM阻害剤によるHIV種特異的な遺伝子発現と複製への影響, 第265回徳島医学会学術集会, 2022年7月.
16.	駒貴明, 土肥直哉, 近藤智之, 野間口雅子 : HIV-1 matrixタンパク質のウイルス粒子集合初期過程における役割解明, 第266回徳島医学学術集会, 2022年.
17.	駒貴明, 礎光希, 塚田知寿子, 戸梶智耀, 足立昭夫, 野間口雅子, 土肥直哉 : PIMキナーゼ阻害剤がHIV種特異的に複製に及ぼす影響の解析(若手優秀演題), 第35回日本エイズ学会学術集会・総会, 2021年11月.
18.	駒貴明, 土肥直哉, 塚田知寿子, 戸梶智耀, 礎光希, 足立昭夫, 野間口雅子 : HIV-1 vpr塩基配列の同義一塩基置換がウイルス複製に与える影響, 第68回日本ウイルス学会, 2021年11月.
19.	横山勝, 小谷治, 土肥直哉, 駒貴明, 野間口雅子, 佐藤裕徳 : アミノ酸配列の統計解析により推定されたHIV-1エンベロープのセクター, 第42回日本分子生物学会年会, 2019年12月.
20.	横山勝, 小谷治, 土肥直哉, 駒貴明, 野間口雅子, 佐藤裕徳 : HIV-1 エンベロープにおける脆弱部位の推定, 第33回日本エイズ学会学術集会, 2019年11月.
21.	小谷治, 駒貴明, 宮川敬, 梁明秀, 横山勝, 土肥直哉, 足立昭夫, 野間口雅子, 佐藤裕徳 : HIV-1カプシド ''disorder'' 領域の構造機能解析, 第33回日本エイズ学会学術集会, 2019年11月.
22.	駒貴明, 土肥直哉, 足立昭夫, 野間口雅子 : HIV-1 Gag集合初期に関わる内在性集合促進因子の探索, 第33回日本エイズ学会学術集会, 2019年11月.
23.	駒貴明, 土肥直哉, 中嶋敏司, 足立昭夫, 野間口雅子 : HIV-1 Gag 集合初期に関わる集合促進因子の探索, 第67回日本ウイルス学会学術集会, 2019年10月.
24.	野間口雅子, 駒貴明, 土肥直哉, 山本秀樹, 渡部京介, 竹本真依, 足立昭夫 : HIV-1ゲノムのSA1D2prox変異と適応変異によるVif発現量決定機構の解析, 第67回日本ウイルス学会学術集会, 2019年10月.
25.	土肥直哉, 駒貴明, 足立昭夫, 野間口雅子 : CCR5指向性HIV-1のEnv V3 tip内1アミノ酸変異による種特異的増殖促進の分子基盤, 第67回日本ウイルス学会学術集会, 2019年10月.
26.	駒貴明, 小谷治, 土肥直哉, 宮川敬, 梁明秀, 横山勝, 佐藤裕徳, 足立昭夫, 野間口雅子 : リンカードメインによるGag集合・ウイルス産生・感染性に関わるHIV-1カプシド構造のアロステリック制御, 第34回中国四国ウイルス研究会, 2019年6月.
27.	野間口雅子, 土肥直哉, 駒貴明, 吉田和子, 足立昭夫 : SA1D2proxに関するHIV-1 Vif低発現変異体NL-gatは，Vif発現量適応変異あるいはenv変異の獲得により増殖能を向上させる, 第66回日本ウイルス学会学術集会, 2018年10月.
28.	足立昭夫, 土肥直哉, 駒貴明, 大久保隼人, 吉田和子, 野間口雅子 : SA1D2prox領域に関するHIV-1 Vif超低発現変異体 NL-tacのAPOBEC3G高発現下における適応過程の解析, 第66回日本ウイルス学会学術集会, 2018年10月.
29.	駒貴明, 小谷治, 土肥直哉, 宮川敬, 梁明秀, 横山勝, 佐藤裕徳, 足立昭夫, 野間口雅子 : HIV-1複製後期過程におけるGag-CAリンカードメインの役割, 第66回日本ウイルス学会学術集会, 2018年10月.
30.	土肥直哉, 駒貴明, 中西仁奈, 足立昭夫, 野間口雅子 : 馴化型R5-tropic HIV-1rmtで同定されたEnvによる増殖促進の解析, 第66回日本ウイルス学会学術集会, 2018年10月.
31.	中西祥子, 渡邊咲仁, 土肥直哉, 駒貴明, 足立昭夫, 野間口雅子 : HIV-1 Env V1/C4 domain内の1アミノ酸変異は協調的にCD4親和性を増加させ，ウイルス増殖を促進する, 第65回日本ウイルス学会学術集会, 2017年10月.
32.	渡邊咲仁, 中西祥子, 駒貴明, 土肥直哉, 足立昭夫, 野間口雅子 : HIV-1 SA1D2prox Vif低発現変異体は複製抑制下で適応しVif発現を回復する, 第65回日本ウイルス学会学術集会, 2017年10月.
33.	土肥直哉, 駒貴明, 中西祥子, 渡邊咲仁, 野間口雅子, 足立昭夫 : Env domain swappingにより増殖効率が向上した馴化型R5-tropic HIV-1rmtの構築, 第65回日本ウイルス学会学術集会, 2017年10月.
34.	足立昭夫, 土肥直哉, 駒貴明, 中西祥子, 渡邊咲仁, 野間口雅子 : HIV-1 vif産生量とSLSA1の構造・エネルギー安定性の連関解析, 第65回日本ウイルス学会学術集会, 2017年10月.
35.	駒貴明, 土肥直哉, 宮川敬, 梁明秀, 足立昭夫, 野間口雅子 : HIV-1複製後期過程におけるGag-CAリンカー領域内アミノ酸残基S149及びI150の役割, 第65回日本ウイルス学会学術集会, 2017年10月.

特許:

1.	野間口雅子, 駒貴明, 土肥直哉, 近藤智之, 横山勝, 佐藤裕徳, 小谷治 : ウイルスタンパク質のセクター同定方法及び同定されたセクターの利用, (2024年6月), 特許第2024-094047号 (2024年6月).

科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

PIMキナーゼのタイプ特異的な遺伝子発現制御によるHIV粒子産生抑制機構の解析 (研究課題/領域番号: 24K11655 )
PIM阻害剤によるHIVタイプ特異的な複製能調節機構の解明 (研究課題/領域番号: 21K08491 )
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土肥 直哉

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総説・解説:

国際会議:

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特許:

科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

土肥直哉