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2001 Fiscal Year Final Research Report Summary

Basic Research for AIDS control A03 ; Prevention and control of AIDS

Research Project

Project/Area Number 10180104
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

MATSUSHITA Shuzo  Kumamoto University, Center for AIDS Research, Professor, エイズ学研究センター, 教授 (00199788)

Co-Investigator(Kenkyū-buntansha) IWAKURA Yoichiro  University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (10089120)
BABA Masanori  Kagoshima University, Faculty of Medicine, Professor, 医学部, 教授 (70181039)
MITSUYA Hiroaki  Kumamoto University, Faculty of Medicine, Professor, 医学部, 教授 (20136724)
TANAKA Yuetsu  University of the Ryukyus, Faculty of Medicine, Professor, 医学部, 教授 (30163588)
FUJII Nobutaka  Kyoto University, Graduate School of Medicine, Professor, 薬学研究科, 教授 (60109014)
Project Period (FY) 1998 – 2001
KeywordsProtease inhibitor / CCR5 inhibitor / Drug resistance / CXCR4 inhibitor / Membrane fusion inhibitor / Vpr transgenic mouse / Neutralizing antibody / Reverse transcriptase inhibitor
Research Abstract

Mitsuya had developed a novel CCR5 inhibitor, E913, and shown that the combination of this drug with AMD3100 suppressed the replication of dual tropic virus synergistically. Mitsuya also analyzed the structural biology of LD78β and reported that the replacement of certain amino acid facilitated the anti-viral activity of this chemokine. Baba isolated a virus clone resistant to CCR5 antagonist, TAK-779, analyzed mutations in the gp120 gene of this clone, and found that mutations in V3 region facilitated the affinity of gp120 to CCR5, resulting in the resistance to TAK-779. Fujii developed a potent and selective inhibitor for CXCR4, T140, and a membrane fusion inhibitor, SC34, and analyzed the drug resistance using SC34 as a molecular probe. Iwakura established a Vpr transgenic mouse and showed that peripheral T cells decreased in number by 1/20 in this mouse, suggesting that Vpr might be involved in the depletion of peripheral T cells. Tanaka reported that immunized SCID-PBL mice with dendritic cells from the same donor pulsed with inactivated HIV-1 showed the resistance to R5 HIV-1 challenge, Matsushita analyzed the activity of neutralizing antibodies in infected patients, and found that 4 cases among 19 patients showed the upregulation of neutralizing activities more than 1 year after introduction of HAART. He also reported that virus escape from neutralizing antibody in vivo was associated with the mutations in the C3 region as well as the variable regions of gp120.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Kimura T.: "Reconstitution of spontaneous neutralizing antibody response against autologous human immunodeficiency virus during highly active antiretroviral therapy"J.Infect.Dis.. 185(1). 53-60 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Gatanada H.: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J.Biol.Chem.. 277. 5952-5961 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yasuda J.: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka R.: "A unique monoclonal antibody recognizing the third extracellular loop of the human CXCR4 induces lymphocytes agglutination and enhances HIV-1-mediated syncytium formation and productive infection"J.Virol.. 75. 11534-11543 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Baba M.: "A small-molecule nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity"Proc.Natl.Acad.Sci. USA. 96. 5698-5703 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhang WB: "A point mutation that confers constitutive activity to CXCR4 reveals T140 is an inverse gonist and AMD3100 and ALX4O-4C are weak partial agonists"J.Biol.Chem.. 277(27). 24515-24521 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mitsuya H.: "The emergence of drug resistant HIV-1 variants and its impact on antiretroviral therapy of HIV-1 infection. In The Art of Antiretrovitral Therapy"American Society for Microbiology, Washington, D.C.. 33 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kimura T. et al: "Reconstitution of spontaneous neutralizing antibody response against autologous human immunodeficiency virus during highly active antiretroviral therapy"J. Infect. Dis.. 185(1). 53-60 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Wang FX. et al: "Emergence of autologous neutralization-resistant variants from preexisting human immunodeficiency virus (HIV) quasi species during virus rebound in HIV type 1-infected patients undergoing highly active antiretroviral therapy"J. Infect. Dis.. 185(5). 608-617 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Gatanada H. et al: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J. Biol. Chem.. 277. 5952-5961 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miyakawa T. et al: "Identification of amino acid residues critical for LD78β (a variant of human macrophage inflammatory protein-1 α) binding to CCR5 and inhibition of R5 HIV-1 replication"J. Biol. Chem.. 277. 4649-4655 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yasuda J. et al: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka R. et al: "A unique monoclonal antibody recognizing the third extracellular loop of the human CXCR4 induces lymphocytes agglutination and enhances HIV-1-mediated syncytium formation and productive infection"J. Virol.. 75. 11534-11543 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zhang WB. et al: "A point mutation that confers constitutive activity to CXCR4 reveals T140 is an inverse gonist and AMDS3100 and ALX40-4C are weak partial agonists"J. Biol. Chem.. 277. 24515-24521 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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