2001 Fiscal Year Final Research Report Summary
AN ANALYSIS OF THE INHIBITION OF HIV-1 INFECTION BY CHEMOKINE-FC CHIMERA
| Project/Area Number |
12670287
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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 |
Virology
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| Research Institution | KINKI UNIVERSITY |
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Principal Investigator |
HIESHIMA Kunio KINKI UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF MICROBIOLOGY, ASSISTANT PROFESSOR, 医学部, 講師 (10322570)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIE Osamu KINKI UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF MICROBIOLOGY, PROFESSOR, 医学部, 教授 (10166910)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Chemokine / Fc chimera / HIV-1 / SDF-1 / RANTES / RANTES / CCR5 / CXCR4 |
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| Research Abstract |
Chemokine receptors CCR5 and CXCR4 are the major co-receptors for macrophage tropic and T-cell line tropic HTV-1 viral isolates, respectively. Therefore, these chemokine receptors are potential targets for anti-HIV drugs. However, the adverse effect as well as the inhibitory effect of HIV-l replication in vivo remains unknown. To understand the effects of blocking these chemokine receptors in vivo, we generated chemokine-Fc chimeras with antagonistic activity against their wild-type chemokines (i.e. met-RANTES-Fc and P2G-SDF-l-Fc) as well as wild-type chemokine-Fc chimeras (i.e. RANTES-Fc and SDF-l-Fc). Although significant antagonistic activity was observed for P2G-SDF-l-Fc against SDF-1 in vitro, met-RANTES-Fc had no antagonistic effect against RANTES. Therefore, we focused on SDF-l-Fc chimeras, and found that both SDF-1-Fc and P2G-SDF-l-Fc had inhibitory effect of X4 virus replication in vitro. The apparent half-lives of SDF-1, SDF-l-Fc, and P2G-SDF-l-Fc in the blood circulation of BALB/c mice were about <lh, 4h and 9h, respectively. Intraperitoneal injection of P2G-SDF-l-Fc into mice caused significant reduction of B220+CD43; pre-B cells and B220^IeM4 Immature B cells in the bone marrow, which is in agreement with the previous reports of CXCR4 deficient mice. However, when these chimeras were injected into the human-PBL-SCID mice after infection of X4 virus, there was a dramatic enhancement of virus replication by both agonistic SDF-l-Fc and antagonistic P2G-SDF-1-Fc, more strongly in the latter, in contrast to the control PBS treatment. The mechanism of promotion of HIV-1 growth in vivo by these chimeras is not known at present, but these data implicated that blocking CXCR4 in vivo should be considered carefully.
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