Project/Area Number |
18K15170
|
Research Category |
Grant-in-Aid for Early-Career Scientists
|
Allocation Type | Multi-year Fund |
Review Section |
Basic Section 49060:Virology-related
|
Research Institution | Kumamoto University |
Principal Investigator |
Toyoda Mako 熊本大学, ヒトレトロウイルス学共同研究センター, 特任助教 (70771129)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
|
Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
Keywords | HIV-1 / SERINC5 / Nef / 感染者コホート / SERINC3/5 / 宿主制限因子 / ウイルス蛋白質 / 細胞膜 / ウイルス / HIV / 感染症 |
Outline of Final Research Achievements |
HIV-1 Nef plays an essential role in enhancing virion infectivity by antagonizing the host restriction molecule SERINC5. Because Nef is highly polymorphic due to the selective forces of host cellular immunity, we hypothesized that certain immune-escape polymorphisms may impair Nef’s ability to antagonize SERINC5 and influence viral fitness in vivo. To test this, we identified 58 Nef polymorphisms that were overrepresented in HIV-infected patients in Japan sharing the same HLA genotypes. Specifically, we found that a number of the HLA-B*51:01-associated Y120F/Q125H mutations were most significantly associated with a reduced plasma viral load. A series of experiments showed that Y120F/Q125H impaired Nef’s ability to antagonize SERINC5 and associated with decreasing virion infectivity and viral replication. Our results suggest that the differential ability of Nef to counteract SERINC5 by naturally occurring immune-associated mutations was associated with the plasma viral load in vivo.
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Academic Significance and Societal Importance of the Research Achievements |
本研究成果によって、生体内で選択されるNef変異は、宿主因子であるSERINC5に拮抗する能力を損なうことでウイルスの感染性および複製能力を弱め、血漿ウイルス量の低下に寄与するものと示唆された。個体内でのウイルス蛋白質と宿主因子の相互機能解明は、宿主に本来備わる抗ウイルス機能の分子機序を活用した新しい治療基盤の構築につながると期待される。
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