Understanding of the impact of infection microenvironment in HIV reactivation and cell-to-cell transmission
| Project/Area Number |
20H03498
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 49060:Virology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
RYO Akihide 横浜市立大学, 医学研究科, 客員教授 (20363814)
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| Co-Investigator(Kenkyū-buntansha) |
中林 潤 東京医科歯科大学, 統合教育機構, 教授 (80322733)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | HIV / エイズ / 感染症 / 微小環境 / 宿主因子 / AIDS / 二次リンパ組織 / ＨＩＶ |
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| Outline of Research at the Start |
本研究課題では、複数の細胞種が積層された生体環境に近い構造を持つ3次元感染細胞培養モデルを用いて、潜伏感染細胞からのウイルスの再活性化や細胞間伝播を可視化・定量化することで、ストレス刺激に伴うウイルスの挙動をリアルタイムに解析する。 取得したデータを基に数理モデルを構築し、不均一な細胞集団下でのHIV伝播予測や薬効予測に役立てる。また、ウイルスの挙動変化を規定する責任因子をマルチオミクス解析により包括的に明らかにすることで、HIV伝播を制御する新たな分子機構の解明と、根治を目指した新規治療法の創出を目指す。
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| Outline of Final Research Achievements |
In this research project, we found that treatment of three-dimensional infected cell models with type I interferon markedly reduced the amount of viral cell-to-cell spread from infected to uninfected cells. A protein-protein interaction analysis revealed that the transmembrane protein MAL accumulated HIV-1 Gag protein in the host endosomal compartment, leading to its degradation in lysosomes. We searched for host factors that are cleaved by HIV-encoded proteases. We found that PR specifically cleaved the TBK1 and markedly reduced the kinase activity of TBK1. In fact, in HIV PR-expressing cells, nuclear translocation of IRF3 and production of type I IFN were reduced upon innate immune signals. We analyzed the molecular mechanism of HIV-2 latency under hypoxia and found that the hypoxia-inducible factor HIF-1α induces multiple long non-coding RNAs bound to the transcriptional regulatory region of HIV-2 and suppressed HIV-2 gene expression through an epigenetic regulatory mechanism.
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| Academic Significance and Societal Importance of the Research Achievements |
HIV感染症は死亡率が劇的に改善したが、体内に残存するHIV潜伏感染細胞がしばしば再活性化するため根治療法は未だ存在しない。３次元微小環境培養モデルを用いて、ウイルスの再活性化及び細胞間伝播を可視化・定量化し数理モデルを構築、また、ウイルスの挙動変化を規定する責任因子をマルチオミクス解析により包括的に明らかにすることで、HIV伝播を制御する新たな分子機構の解明とHIV感染症の根治を目指した新規治療法を創出することが期待される。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] Development of a Monoclonal Antibody Targeting HTLV-1 Envelope gp46 Glycoprotein and Its Application to Near-Infrared Photoimmuno-Antimicrobial Strategy.2022
Author(s)
Hatayama Y, Yamaoka Y, Morita T, Jeremiah SS, Miyakawa K, Nishi M, Kimura Y, Mitsunaga M, Iwase T, Kimura H, Yamamoto N, Takaori-Kondo A, Hasegawa H, Ryo A.
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Journal Title
Viruses
Volume: 14(10)
Issue: 10
Pages: 2153-2153
DOI
Related Report
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[Journal Article] Antimicrobial strategy for targeted elimination of different microbes, including bacterial, fungal and viral pathogens.2022
Author(s)
Mitsunaga M, Ito K, Nishimura T, Miyata H, Miyakawa K, Morita T, Ryo A, Kobayashi H, Mizunoe Y, Iwase T.
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Journal Title
Commun Biol
Volume: 5(1)
Issue: 1
Pages: 647-647
DOI
Related Report
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