Elucidation of the regulatory basis for alternative splicing towards controlling HIV-1 replication
| Project/Area Number |
17K08860
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
NOMAGUCHI Masako 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (80452647)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | HIV-1 / 同義1塩基置換 / 適応 / Vif / 選択的スプライシング / Vpr / alternative splicing / スプライシング / 変異 / 遺伝子発現 / ウイルス複製 / 変異・適応 / ウイルス / RNAスプライシング |
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| Outline of Final Research Achievements |
Vif is essential for HIV-1 replication by antagonizing host restriction factor APOBEC3. Understanding regulatory bases for Vif expression certainly serves to establish a new anti-HIV-1 strategy. HIV-1 mRNAs are produced by alternative splicing via splicing donors (SD1-SD4) and acceptors (SA1-SA7). We demonstrated by adaptation studies that the nucleotide sequence around SA1 and SD2 (SA1D2prox) is involved in modulating vif mRNA expression. Sequence containing the SA1 site forms a stem loop structure (SLSA1). Mutational analysis showed that the SLSA1 stability and the vif mRNA expression level are inversely correlated, indicating the regulatory association of SLSA1 with vif mRNA production. Furthermore, our virological analysis using different HIV-1 subtypes showed that the region around SA2 and SD3, in addition to SA1D2prox, also determines the vif mRNA expression level. Collectively, we newly identified the genomic region and RNA secondary structure critical for vif mRNA production.
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| Academic Significance and Societal Importance of the Research Achievements |
HIV-1 Vifタンパク質は、宿主細胞のウイルス抑制因子APOBEC3タンパク質群と拮抗するため、ウイルス複製に必須である。Vifの発現量や活性の変化は、ウイルス複製を変動させる主な要因の一つである。したがって、Vifの発現量調節機構の解明は極めて重要であるが、様々なHIV-1ゲノム配列や宿主因子群などが関与するため、その機構は非常に複雑である。本研究における詳細なウイルス学的研究により、Vif発現量調節に関与するゲノム領域と構造を明らかすることができた。今後、Vifの発現量調節機構の全貌解明を尚一層進展させ、Vif発現量を介したHIV-1複製制御手法の確立を目指す。
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Report
(4 results)
Research Products
(26 results)
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[Journal Article] Allosteric Regulation of HIV-1 Capsid Structure for Gag Assembly, Virion Production, and Viral Infectivity by a Disordered Interdomain Linker.2019
Author(s)
2.Koma T, Kotani O, Miyakawa K, Ryo A, Yokoyama M, Doi N, Adachi A, Sato H, Nomaguchi M
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Journal Title
Journal of Virology
Volume: 93 (17)
Issue: 17
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] 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Ia50の役割.2017
Author(s)
Koma, T., Doi, N., Miyakawa, K., Ryo, A., Adachi, A., and Nomaguchi, M.
Organizer
第65回日本ウイルス学会学術集会
Related Report
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[Presentation] HIV-1 vif 産生量とSLSA1の構造・エネルギー庵芸性の連関解析.2017
Author(s)
Adachi, A., Doi, N., Koma, T., Nakanishi, S., Watanabe, S., and Nomaguchi, M.
Organizer
第65回日本ウイルス学会学術集会
Related Report
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[Presentation] 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.2017
Author(s)
Doi, N., Koma, T., Nakanishi, S., Watanabe, S., Nomaguchi, M., and Adachi, A.
Organizer
第65回日本ウイルス学会学術集会
Related Report
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[Presentation] 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.2017
Author(s)
Watanabe, S., Nakanishi, S., Koma, T., Doi, N., Adachi, A., and Nomaguchi, M.
Organizer
第65回日本ウイルス学会学術集会
Related Report
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[Presentation] 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.2017
Author(s)
Nakanishi, S., Watanabe, S., Doi, N., Koma, T., Adachi, A., and Nomaguchi, M.
Organizer
第65回日本ウイルス学会学術集会
Related Report
