Developing an anti-HIV drugs that inhibit uncoating for overcomingdrug resistance
| Project/Area Number |
23659066
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Environmental pharmacy
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| Research Institution | Kumamoto University |
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Principal Investigator |
MISUMI Shogo 熊本大学, 大学院・生命科学研究部, 准教授 (40264311)
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| Project Period (FY) |
2011 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | ウイルス / 感染症 / 微生物 / HIV / 薬剤耐性 / Pin1 / 脱殻 / キナーゼ |
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| Research Abstract |
We previously reported that Pin1 facilitates the humanimmunodeficiency virus type 1 (HIV -1) uncoating by interacting with the capsid (CA) corethrough the phosphorylated Ser16-Pro17motif. However , the specific kinase responsible forSer16phosphorylation has remained unknown. Here, we show that virion-associatedextracellular signal-regulated kinase 2 (ERK2) phosphorylates Ser16. The characterization ofimmature virions produced by exposing of CEM/LA V -1 cells to 10 μM saquinavir and a D25Ninactive mutant of HIV -1 protease indicated that Ser16is phosphorylated after the initiationof Pr55gagprocessing. Furthermore, a mass spectrometry-based in vitro kinase assaydemonstrated that ERK2 specifically phosphorylated the Ser16residue in theSer16-Pro17-motif-containing substrate. The treatment of CEM/LA V -1 cells with the ERK2inhibitor sc-222229 decreased the Ser16phosphorylation level inside virions, and the viruspartially defective in Ser16phosphorylation showed an impaired reverse transcription and anattenuated replication owing to an attenuated Pin1-dependent uncoating. Furthermore, thesuppression of ERK2 expression by RNA interference in CEM/LA V -1 cells resulted insuppressed ERK2 packaging inside virions and decreased the Ser16phosphorylation levelinside virions. Interestingly , the ERK2-packaging-defective virus showed an impaired reversetranscription and an attenuated HIV -1 replication. Taken together , these findings provideinsights into the as yet obscure processes in Pin1-dependent HIV -1 uncoating.
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Report
(3 results)
Research Products
(16 results)
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[Journal Article] Induction of extremely low proteinexpression level by fusion ofC-terminal region of Nef2012
Author(s)
Takamune, N.*, Irisaka, Y., Yamamoto,M., Harada, K., Shoji, S., Misumi, S
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Journal Title
Biotechnology and AppliedBiochemistry
Volume: 59
Pages: 245-253
Related Report
Peer Reviewed
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[Journal Article] Glyceraldehyde 3-phosphatedehydrogenase negatively regulateshuman immunodeficiency virus type 1infection2012
Author(s)
Kishimoto, N., Onitsuka, A., Kido, K.,Takamune, N., Shoji, S., Misumi, S
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Journal Title
Retrovirology
Volume: 9
Pages: 107-107
Related Report
Peer Reviewed
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[Journal Article] Induction of extremely low protein expression level by fusion of C-terminal region of Nef.2012
Author(s)
Takamune, N. *, Irisaka, Y., Yamamoto, M., Harada, K., Shoji, S., Misumi, S.
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Journal Title
Biotechnology and Applied Biochemistry
Volume: 59
Issue: 3
Pages: 245-253
DOI
Related Report
Peer Reviewed
-
[Journal Article] Glyceraldehyde 3-phosphate dehydrogenase negatively regulates human immunodeficiency virus type 1 infection.2012
Author(s)
Kishimoto, N., Onitsuka, A., Kido, K., Takamune, N., Shoji, S., Misumi, S.
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Journal Title
Retrovirology
Volume: 9
Issue: 1
Pages: 107-107
DOI
Related Report
Peer Reviewed
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