2021/10/20 更新

写真a

イワナミ ショウヤ
岩波 翔也
IWANAMI Shoya
所属
大学院理学研究科 生命理学専攻 超分子機能学 助教
大学院担当
大学院理学研究科
学部担当
理学部 生命理学科
職名
助教
連絡先
メールアドレス

学位 1

  1. 博士(理学) ( 2020年9月   九州大学 ) 

 

論文 15

  1. Revisiting the guidelines for ending isolation for COVID-19 patients

    Jeong Yong Dam, Ejima Keisuke, Kim Kwang Su, Iwanami Shoya, Bento Ana I, Fujita Yasuhisa, Jung Il Hyo, Aihara Kazuyuki, Watashi Koichi, Miyazaki Taiga, Wakita Takaji, Iwami Shingo, Ajelli Marco

    ELIFE   10 巻   2021年7月

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    記述言語:日本語   出版者・発行元:eLife  

    Since the start of the COVID-19 pandemic, two mainstream guidelines for defining when to end the isolation of SARS-CoV-2-infected individuals have been in use: the one-size-fits-all approach (i.e. patients are isolated for a fixed number of days) and the personalized approach (i.e. based on repeated testing of isolated patients). We use a mathematical framework to model within-host viral dynamics and test different criteria for ending isolation. By considering a fixed time of 10 days since symptom onset as the criterion for ending isolation, we estimated that the risk of releasing an individual who is still infectious is low (0–6.6%). However, this policy entails lengthy unnecessary isolations (4.8–8.3 days). In contrast, by using a personalized strategy, similar low risks can be reached with shorter prolonged isolations. The obtained findings provide a scientific rationale for policies on ending the isolation of SARS-CoV-2-infected individuals.

    DOI: 10.7554/eLife.69340

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  2. Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection

    Kim K.S., Iwanami S., Oda T., Fujita Y., Kuba K., Miyazaki T., Ejima K., Iwami S.

    Life Science Alliance   4 巻 ( 10 )   2021年7月

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    記述言語:日本語   出版者・発行元:Life Science Alliance  

    The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.

    DOI: 10.26508/LSA.202101049

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  3. Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study

    Iwanami Shoya, Ejima Keisuke, Kim Kwang Su, Noshita Koji, Fujita Yasuhisa, Miyazaki Taiga, Kohno Shigeru, Miyazaki Yoshitsugu, Morimoto Shimpei, Nakaoka Shinji, Koizumi Yoshiki, Asai Yusuke, Aihara Kazuyuki, Watashi Koichi, Thompson Robin N., Shibuya Kenji, Fujiu Katsuhito, Perelson Alan S., Iwami Shingo, Wakita Takaji

    PLOS MEDICINE   18 巻 ( 7 ) 頁: e1003660   2021年7月

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    記述言語:日本語   出版者・発行元:PLoS Medicine  

    Background Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials Methods and findings A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d-1 (95% CI: 1.06 to 1.27 d-1), 0.777 d-1 (0.716 to 0.838 d-1), and 0.450 d-1 (0.378 to 0.522 d-1) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. Conclusions In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.

    DOI: 10.1371/journal.pmed.1003660

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  4. Estimation of the incubation period of COVID-19 using viral load data

    Ejima Keisuke, Kim Kwang Su, Ludema Christina, Bento Ana I, Iwanami Shoya, Fujita Yasuhisa, Ohashi Hirofumi, Koizumi Yoshiki, Watashi Koichi, Aihara Kazuyuki, Nishiura Hiroshi, Iwami Shingo

    EPIDEMICS   35 巻   頁: 100454   2021年6月

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    記述言語:日本語   出版者・発行元:Epidemics  

    The incubation period, or the time from infection to symptom onset, of COVID-19 has usually been estimated by using data collected through interviews with cases and their contacts. However, this estimation is influenced by uncertainty in the cases’ recall of exposure time. We propose a novel method that uses viral load data collected over time since hospitalization, hindcasting the timing of infection with a mathematical model for viral dynamics. As an example, we used reported data on viral load for 30 hospitalized patients from multiple countries (Singapore, China, Germany, and Korea) and estimated the incubation period. The median, 2.5, and 97.5 percentiles of the incubation period were 5.85 days (95 % CI: 5.05, 6.77), 2.65 days (2.04, 3.41), and 12.99 days (9.98, 16.79), respectively, which are comparable to the values estimated in previous studies. Using viral load to estimate the incubation period might be a useful approach, especially when it is impractical to directly observe the infection event.

    DOI: 10.1016/j.epidem.2021.100454

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  5. Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor in vitro

    Shionoya Kaho, Yamasaki Masako, Iwanami Shoya, Ito Yusuke, Fukushi Shuetsu, Ohashi Hirofumi, Saso Wakana, Tanaka Tomohiro, Aoki Shin, Kuramochi Kouji, Iwami Shingo, Takahashi Yoshimasa, Suzuki Tadaki, Muramatsu Masamichi, Takeda Makoto, Wakita Takaji, Watashi Koichi

    FRONTIERS IN MICROBIOLOGY   12 巻   頁: 651403   2021年4月

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    記述言語:日本語   出版者・発行元:Frontiers in Microbiology  

    Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

    DOI: 10.3389/fmicb.2021.651403

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  6. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment

    Ohashi Hirofumi, Watashi Koichi, Saso Wakana, Shionoya Kaho, Iwanami Shoya, Hirokawa Takatsugu, Shirai Tsuyoshi, Kanaya Shigehiko, Ito Yusuke, Kim Kwang Su, Nomura Takao, Suzuki Tateki, Nishioka Kazane, Ando Shuji, Ejima Keisuke, Koizumi Yoshiki, Tanaka Tomohiro, Aoki Shin, Kuramochi Kouji, Suzuki Tadaki, Hashiguchi Takao, Maenaka Katsumi, Matano Tetsuro, Muramatsu Masamichi, Saijo Masayuki, Aihara Kazuyuki, Iwami Shingo, Takeda Makoto, McKeating Jane A., Wakita Takaji

    ISCIENCE   24 巻 ( 4 ) 頁: 102367   2021年4月

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    記述言語:日本語   出版者・発行元:iScience  

    Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling in vitro antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.

    DOI: 10.1016/j.isci.2021.102367

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  7. Time variation in the probability of failing to detect a case of polymerase chain reaction testing for SARS-CoV-2 as estimated from a viral dynamics model

    Ejima Keisuke, Kim Kwang Su, Iwanami Shoya, Fujita Yasuhisa, Li Ming, Zoh Roger S., Aihara Kazuyuki, Miyazaki Taiga, Wakita Takaji, Iwami Shingo

    JOURNAL OF THE ROYAL SOCIETY INTERFACE   18 巻 ( 177 ) 頁: 20200947   2021年4月

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    記述言語:日本語   出版者・発行元:Journal of the Royal Society Interface  

    Viral tests including polymerase chain reaction (PCR) tests are recommended to diagnose COVID-19 infection during the acute phase of infection. A test should have high sensitivity; however, the sensitivity of the PCR test is highly influenced by viral load, which changes over time. Because it is difficult to collect data before the onset of symptoms, the current literature on the sensitivity of the PCR test before symptom onset is limited. In this study, we used a viral dynamics model to track the probability of failing to detect a case of PCR testing over time, including the presymptomatic period. The model was parametrized by using longitudinal viral load data collected from 30 hospitalized patients. The probability of failing to detect a case decreased toward symptom onset, and the lowest probability was observed 2 days after symptom onset and increased afterwards. The probability on the day of symptom onset was 1.0% (95% CI: 0.5 to 1.9) and that 2 days before symptom onset was 60.2% (95% CI: 57.1 to 63.2). Our study suggests that the diagnosis of COVID-19 by PCR testing should be done carefully, especially when the test is performed before or way after symptom onset. Further study is needed of patient groups with potentially different viral dynamics, such as asymptomatic cases.

    DOI: 10.1098/rsif.2020.0947

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  8. A quantitative model used to compare withinhost SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2

    Kim K.S., Ejima K., Iwanami S., Fujita Y., Ohashi H., Koizumi Y., Asai Y., Nakaoka S., Watashi K., Aihara K., Thompson R.N., Ke R., Perelson A.S., Iwami S.

    PLoS Biology   19 巻 ( 3 )   2021年3月

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    記述言語:日本語   出版者・発行元:PLoS Biology  

    The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2-3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARSCoV- 2 and may be useful for development of antiviral therapies.

    DOI: 10.2110/JSR.2020.113

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  9. Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma

    Iwanami Shoya, Kitagawa Kosaku, Ohashi Hirofumi, Asai Yusuke, Shionoya Kaho, Saso Wakana, Nishioka Kazane, Inaba Hisashi, Nakaoka Shinji, Wakita Takaji, Diekmann Odo, Iwami Shingo, Watashi Koichi

    PLOS BIOLOGY   18 巻 ( 7 ) 頁: e3000562   2020年7月

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    記述言語:日本語   出版者・発行元:PLoS Biology  

    Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying (“stay-strategy”) or is packaged into a progeny virion that will be released extracellularly (“leave-strategy”). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.

    DOI: 10.1371/journal.pbio.3000562

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  10. Revealing uninfected and infected target cell dynamics from peripheral blood data in highly and less pathogenic simian/human immunodeficiency virus infected Rhesus macaque

    Hara Akane, Iwanami Shoya, Ito Yusuke, Miura Tomoyuki, Nakaoka Shinji, Iwami Shingo

    JOURNAL OF THEORETICAL BIOLOGY   479 巻   頁: 29 - 36   2019年10月

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    記述言語:日本語   出版者・発行元:Journal of Theoretical Biology  

    Since chimeric simian and human immunodeficiency viruses (SHIVs) used here, that is, SHIV-#64 and -KS661 utilize both CCR5 and CXCR4 chemokine receptors, they have broad target cell properties. A highly pathogenic SHIV strain, SHIV-KS661, causes an infection that systemically depletes the CD4+ T cells of Rhesus macaques, while a less pathogenic strain, SHIV-#64, does not cause severe symptoms in the macaques. In our previous studies, we established in vitro quantification system for virus infection dynamics, and concluded that SHIV-KS661 effectively produces infectious virions compared with SHIV-#64 in the HSC-F cell culture. However, in vivo dynamics of SHIV infection have not been well understood. To quantify SHIV-#64 and -KS661 infection dynamics in Rhesus macaques, we developed a novel approach and analyzed total CD4+ T cells and viral load in peripheral blood, and reproduced the expected dynamics for the uninfected and infected CD4+ T cells in silico. Using our previous cell culture experimental datasets, we revealed that an infection rate constant is different between SHIV-#64 and -KS661, but the viral production rate and the death rate are similar for the both strains. Thus, here, we assumed these relations in our in vivo data and carried out the data fitting. We performed Bayesian estimation for the whole dataset using MCMC sampling, and simultaneously fitted our novel model to total CD4+ T cells and viral load of SHIV-#64 and -KS661 infection. Our analyses explained that the Malthusian parameter (i.e., fitness of virus infection) and the basic reproduction number (i.e., potential of virus infection) for SHIV-KS661 are significantly higher than those of SHIV-#64. In addition, we demonstrated that the number of uninfected CD4+ T cells in SHIV-KS661 infected Rhesus macaques decreases to the significantly lower value than that before the inoculation several days earlier compared with SHIV-#64 infection. Taken together, the differences between SHIV-#64 and -KS661 infection before the peak viral load might determine the subsequent destiny, that is, whether the systemic CD4+ T cell depletion occurs or the host immune response develop.

    DOI: 10.1016/j.jtbi.2019.07.005

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  11. 骨髄球バイパスを含む造血システムの数理モデルを用いた1細胞移植実験のデータ解析 (第14回生物数学の理論とその応用 : 構造化個体群ダイナミクスとその応用)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   ( 2087 ) 頁: 77 - 85   2018年8月

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    記述言語:日本語   出版者・発行元:京都大学数理解析研究所  

    CiNii Article

  12. 骨髄球バイパスを含む造血システムの数理モデル (第13回生物数学の理論とその応用 : 連続および離散モデルのモデリングと解析)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   ( 2043 ) 頁: 102 - 108   2017年9月

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    記述言語:日本語   出版者・発行元:京都大学数理解析研究所  

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  13. A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture

    Iwanami Shoya, Kakizoe Yusuke, Morita Satoru, Miura Tomoyuki, Nakaoka Shinji, Iwami Shingo

    THEORETICAL BIOLOGY AND MEDICAL MODELLING   14 巻 ( 1 ) 頁: 9   2017年4月

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    記述言語:日本語   出版者・発行元:Theoretical Biology and Medical Modelling  

    Background: The host range of human immunodeficiency virus (HIV) is quite narrow. Therefore, analyzing HIV-1 pathogenesis in vivo has been limited owing to lack of appropriate animal model systems. To overcome this, chimeric simian and human immunodeficiency viruses (SHIVs) that encode HIV-1 Env and are infectious to macaques have been developed and used to investigate the pathogenicity of HIV-1 in vivo. So far, we have many SHIV strains that show different pathogenesis in macaque experiments. However, dynamic aspects of SHIV infection have not been well understood. To fully understand the dynamic properties of SHIVs, we focused on two representative strains - the highly pathogenic SHIV, SHIV-KS661, and the less pathogenic SHIV, SHIV-#64 - and measured the time-course of experimental data in cell culture. Methods: We infected HSC-F with SHIV-KS661 and -#64 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for 9 days. The experiments were repeated at two different multiplicities of infection, and a previously developed mathematical model incorporating the infectious and non-infectious viruses was fitted to the full dataset of each strain simultaneously to characterize the infection dynamics of these two strains. Results and conclusions: We quantified virological indices including virus burst sizes and basic reproduction number of both SHIV-KS661 and -#64. Comparing the burst size of total and infectious viruses (viral RNA copies and TCID50, respectively), we found that there was a statistically significant difference between the infectious virus burst size of SHIV-KS661 and -#64, while there was no significant difference between the total virus burst size. Furthermore, our analyses showed that the fraction of infectious virus among the produced SHIV-KS661 viruses, which is defined as the infectious viral load (TCID50/ml) divided by the total viral load (RNA copies/ml), is more than 10-fold higher than that of SHIV-#64 during overall infection (i.e., for 9 days). Taken together, we conclude that the highly pathogenic SHIV produces infectious virions more effectively than the less pathogenic SHIV in cell culture.

    DOI: 10.1186/s12976-017-0055-8

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  14. A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2

    Kim Kwang Su, Ejima Keisuke, Iwanami Shoya, Fujita Yasuhisa, Ohashi Hirofumi, Koizumi Yoshiki, Asai Yusuke, Nakaoka Shinji, Watashi Koichi, Aihara Kazuyuki, Thompson Robin N., Ke Ruian, Perelson Alan S., Iwami Shingo, Roberts Roland G., Roberts Roland G., Roberts Roland G.

    PLOS BIOLOGY   19 巻 ( 3 ) 頁: e3001128   2021年3月

  15. Quantitative immunology by data analysis using mathematical models

    Iwanami S.

    Encyclopedia of Bioinformatics and Computational Biology: ABC of Bioinformatics   1-3 巻   頁: 984 - 992   2018年1月

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    出版者・発行元:Encyclopedia of Bioinformatics and Computational Biology: ABC of Bioinformatics  

    DOI: 10.1016/B978-0-12-809633-8.20250-1

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▼全件表示

書籍等出版物 1

  1. Quantitative immunology by data analysis using mathematical models

    Iwanami S., Iwami S.

    Encyclopedia of Bioinformatics and Computational Biology: ABC of Bioinformatics  2018年1月  ( ISBN:9780128114148

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    記述言語:日本語

    Mathematical models have been widely used for analysis of experimental data in immunology, which can describe the interactions among cells or antigens. Many mathematical modeling studies have provided novel insights into immune systems. These researches adopt a generalized mathematical model based on population dynamics, which is frequently used in ecology or demography. By discussing several studies of cell differentiation, lymphocyte turnover and virus dynamics, we demonstrate the applicability of the generalized mathematical model to immunology data analysis.

    DOI: 10.1016/B978-0-12-809633-8.20250-1

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科研費 1

  1. 組織維持を担う細胞群個体群動態の理解と定量的データ解析

    研究課題/研究課題番号:19J12319  2019年4月 - 2021年3月

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    担当区分:その他 

    生体内の異なる階層・タイムスケールを繋ぐ数理モデルを構築し、細胞間相互作用の強弱や細胞の性質の変化を比較することで、組織の恒常性を破綻させる要因を定量的に明らかにする。まず、造血幹細胞の加齢に伴い変容する造血組織を再現する確率シミュレータの構築し、細胞分化での細胞個体の振る舞いから造血組織の変容を理解する。次に、骨代謝の履歴から骨量変動を計算する積分方程式による数理モデルの構築し、骨量代謝の細胞間相互作用を表すパラメータを比較することで骨組織の変容を理解する。構築した数理モデルから他の組織で汎用性のある、細胞と組織をつなぐ理論を構築する。
    生体内では、細胞群が相互に影響を与え合いながら組織の恒常性を維持している。ここでは、幹細胞が維持する組織として老化の研究が盛んに行われている造血組織と、細胞が組織を形成と破壊のバランスを取りながら維持している骨組織に着目した。
    造血幹細胞は全ての血液細胞と免疫細胞に分化する能力を持ち、生涯にわたって造血組織を維持すると考えられている。また、造血幹細胞の分化機構について、様々な研究結果から複数のモデルが提唱されている。さらに、加齢による造血幹細胞の能力の変化が、造血組織の老化を引き起こすという研究成果が報告されている。造血幹細胞が造血組織を維持し、老化するメカニズムを解明するために、造血幹細胞分化を記述する数理モデルを開発した。この数理モデルを用いて、若齢マウスと老齢マウスから取得された造血幹細胞を移植したときの末梢血中での各細胞系統の変動を解析した。このとき、非線形混合効果モデルの手法を取り入れ、マウスでの移植実験のデータのばらつきを統計的に扱うことが可能な解析手法を構築した。若齢マウスと老齢マウスの造血幹細胞の能力を比較し、老化に伴って骨髄球の産生が多くなることを説明した。今後は、造血幹細胞分化の確率シミュレータを開発し、細胞の分化と組織の維持の関係性の定性的・定量的な解釈を目指す。
    骨組織は骨芽細胞と破骨細胞が相互に作用し合うことで、骨形成と骨吸収のバランスをとりながら維持され、一般に、加齢と共に骨量が減少する。また、重力変化や閉経などの摂動によって骨量が変化することが示唆されている。ここでは、マウスで取得された骨代謝マーカーと骨量変動の長期の時系列データと、人工的に重力をかけられたマウスのデータを同時に解析し、骨代謝マーカーの変動から骨量の変動を説明することに成功した。今後は、他の摂動実験を説明しうる数理モデルを開発していく。
    造血幹細胞移植の実験データと骨量変動の時系列データの解析に成功し、細胞と組織の変化を説明する枠組みは構築できた。細胞分化を網羅的に捉える確率シミュレータの開発に取り掛かっており、当初の計画通りに研究は進んでいると考えられる。
    当初の計画に従って、造血幹細胞分化を捉える確率シミュレータと、骨代謝の履歴から骨量変動を計算する積分方程式による数理モデルを構築する。細胞群の変化と組織の変化をつなぐ原理を見出すために、大規模な計算機実験と、他の摂動を加えた実験データの解析を行う。