| Project/Area Number |
13226027
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | National Institute of Infectious Diseases (2004-2006)
Tokyo Medical and Dental University (2001-2003) |
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Principal Investigator |
YAMAMOTO Naoki National Institute of Infectious Diseases, AIDS Research Center, Director, エイズ研究センター, センター長 (00094053)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAOKA Shoji Tokyo Medical and Dental University, Graduate School of Medicine, Associate Professor, 大学院・医歯学総合研究科, 助教授 (90263160)
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥62,800,000 (Direct Cost: ¥62,800,000)
Fiscal Year 2005: ¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2004: ¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2003: ¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2002: ¥19,000,000 (Direct Cost: ¥19,000,000)
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| Keywords | AIDS / anti-HIV drugs / host factors / chemokine / CXCR4 / HEXIM1 / chemotherapy / HIV-1 / pseudotype / マウス白血病ウィルス / Integration / KRH / HIV / AIDS / 変異原 / pesudotype / マウス白血病ウイルス / CDCR4 / KRH-1636 / 経口吸収性 / 増殖 / レセプター / コレセプター / CXCR-4 |
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| Research Abstract |
Replication of human immunodeficiency virus type 1 (HIV-1) depends on host cell factors, but only a limited number of such proteins have been reported. Through the use of expression cloning method, we established and analyzed two mutant human cell clones derived from 293T cells, C611 and YD4, which are resistant to HIV-1 infection, but permissive to murine leukemia virus (MLV) infection. Quantitative polymerase chain reaction (qPCR) studies revealed that C611 cells had a post-entry block prior to the completion of reverse transcription, whereas in YD4 cells viral DNA entered the nucleus, but failed to be integrated in the cellular genome. The genetic phenotype of these blocks appeared to be recessive, because hybridization between the mutant and parental cells restored the susceptibility to HIV-1 infection. Of note, the defects were not complemented by known cofactors, and hence these mutant cells are expected to be useful for identifying new cellular cofactors of HIV-1 infection.
Beside this, we made different types of experiments and found 3 additional host factors, acting either positively or negatively for HIV-1 infection. They include the Arp2/3 complex which appears to be important for early step of primate lentivirus and vaccinia IMV infection, and two negative regulators,NAF-1 and HEXIM1.
As to CXCR4 antagonists, we have completed the screening and selection of the candidates through in vitro studies and they have been subjected to animal studies using mice model. Amongst them, KRH-3955 is considered best at this moment and the whole story will be reported.
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