Protection of hu-PBL-SCID/beige mice from HIV-1 infection by a 6-mer modified oligonucleotide, R-95288.
We analyzed the anti-HIV-1 activity of an oligonucleotide derivative, R-95288, in severe combined immunodeficient (SCID/beige) mice transplanted with normal human peripheral blood leukocytes (PBLs), designated hu-PBL-SCID/beige mice. The human chimeric mice were inoculated with HIV-1(CC1) 3 weeks after the transplantation and sacrificed 2 weeks later. Virus infection was determined by coculture of splenocytes with fresh human PBLs and also by detection of HIV- specific DNA sequences using the polymerase chain reaction. No evidence of infection was observed in mice treated with R-95288 (100 mg/kg/day) using intraperitoneal delivery by osmotic minipumps starting 1 day before virus challenge. In contrast, virus infection was observed in over 80% of the saline-treated control mice. In addition, partial inhibition of HIV-1 infection was obtained in mice treated subcutaneously with R-95288 (100 mg/kg/day). Toxicity towards the engrafted human cells was not observed by flow cytometric analysis. Moreover, R-95288 failed to inhibit lymphocyte proliferation (CC50 > 400 microg/ml), while 90% inhibition of HIV-1 replication was achieved at 3.1 microg/ml in vitro. These results suggest the ability of R-95288 to protect the human chimeric mice against HIV-1 infection.
Agatsuma
T
T
Biological Research Laboratories, Sankyo Company Ltd., Shinagawa-ku, Tokyo, Japan. HQM10004@Niftyserve.or.jp
Abe
K
K
Furukawa
H
H
Koga
R
R
Koizumi
M
M
Hotoda
H
H
Kaneko
M
M
D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002678:Chimera; D004279:DNA, Viral / Q000302:isolation & purification; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017708:Leukocyte Transfusion; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009841:Oligonucleotides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D013154:Spleen / Q000821:virology; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004279:DNA, Viral; D009841:Oligonucleotides; C107381:R 95288