1999 Fiscal Year Final Research Report Summary
Gene therapy of AIDS using the HIV-1 vector carrying the mutated chemokine
| Project/Area Number |
09671126
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kumamoto University |
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Principal Investigator |
OBARU Kenshi Kumamoto University School of Medicine, Department of Internal Medicine II, Assistant Professor, 医学部・附属病院, 講師 (90281211)
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| Project Period (FY) |
1997 – 1999
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| Keywords | LD78 / chemokines / HIV-1 / CCR5 / gene therapy / CD26 / MIP-1α |
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| Research Abstract |
We found that the human LD78 (MIP-1α) gene family has a wide spectrum of variations including multiplication, deletions, and mutations, and that the LD78 gene family is consisted of at least 10 different subtypes which can be divided into two subfamilies, LD78A and LD78B, based on their N terminal structures. A striking correlation was found between HIV-1 disease progression and the ratio of LD78B and LD78A gene counts: HIV-1 -infected long-term nonprogressors had lower LD78B/LD78A ratios than progressors. An LD78B protein (LD78β) had a greater activity to inhibit the replication of macrophage-tropic HIV-1 in vitro compared to an LD78A protein (LD78α). Mutational analyses of these proteins suggest that the major determinant of functional difference is located at the second amino acid residue of the N terminus. When the effects of CD26 on LD78β, which is cleaved twice by CD26, were examined, single cleavage of LD78β did not affect its CCR5 down-regulation property, while a twice-cleaved LD78b had lesser activity compared to uncleaved LD78b. These results demonstrate the divergence of the LD78 gene family and an importance of the N-terminus of LD78β for its potent anti-HIV-1 function, and may have a relevance in considering human LD78β and its analogs as potential therapeutic agents.
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[Publications] S.Fujii, K.Obaru, S., Matusita, T.Morikita, H., Higuchi, K., Fujimoto and K., Takatsuki: "Characterization of Proviral DNA From an Individual With Long-Term, Nonprogressive Infection With HIV- 1 and Nonrecoverable Virus."Journal of Acquired Immune Deficiency Syndrome and Human Retrovirology. 15. 247-256 (1997)
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