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Antimicrobial Agents and Chemotherapy, September 2009, p. 3887-3893, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00270-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Potent Activity of a Nucleoside Reverse Transcriptase Inhibitor, 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine, against Human Immunodeficiency Virus Type 1 Infection in a Model Using Human Peripheral Blood Mononuclear Cell-Transplanted NOD/SCID Janus Kinase 3 Knockout Mice

Shinichiro Hattori,¹ Kazuhiko Ide,² Hirotomo Nakata,⁴ Hideki Harada,¹ Shinya Suzu,¹ Noriyuki Ashida,³ Satoru Kohgo,³ Hiroyuki Hayakawa,³ Hiroaki Mitsuya,^2,4 and Seiji Okada^1*

Division of Hematopoiesis, Center for AIDS Research,¹ Department of Infectious Diseases and Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto, Japan,² Biochemicals Division, Yamasa Corporation, Chiba, Japan,³ Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland⁴

Received 26 February 2009/ Returned for modification 9 April 2009/ Accepted 16 June 2009

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a recently discovered nucleoside reverse transcriptase inhibitor, exhibits activity against a wide spectrum of wild-type and multidrug-resistant clinical human immunodeficiency virus type 1 (HIV-1) isolates (50% effective concentration, 0.0001 to 0.001 µM). In the present study, we used human peripheral blood mononuclear cell-transplanted, HIV-1-infected NOD/SCID/Janus kinase 3 knockout mice for in vivo evaluation of the anti-HIV activity of EFdA. Administration of EFdA decreased the replication and cytopathic effects of HIV-1 without identifiable adverse effects. In phosphate-buffered saline (PBS)-treated mice, the CD4⁺/CD8⁺ cell ratio in the spleen was low (median, 0.04; range, 0.02 to 0.49), while that in mice receiving EFdA was increased (median, 0.65; range, 0.57 to 1.43). EFdA treatment significantly suppressed the amount of HIV-1 RNA (median of 9.0 x 10² copies/ml [range, 8.1 x 10² to 1.1 x 10³ copies/ml] versus median of 9.9 x 10⁴ copies/ml [range, 8.1 x 10² to 1.1 x 10³ copies/ml]; P < 0.001), the p24 level in plasma (2.5 x 10³ pg/ml [range, 8.2 x 10² to 5.6 x 10³ pg/ml] versus 2.8 x 10² pg/ml [range, 8.2 x 10¹ to 6.3 x 10² pg/ml]; P < 0.001), and the percentage of p24-expressing cells in the spleen (median of 1.90% [range, 0.33% to 3.68%] versus median of 0.11% [range, 0.00% to 1.00%]; P = 0.003) in comparison with PBS-treated mice. These data suggest that EFdA is a promising candidate for a new age of HIV-1 chemotherapy and should be developed further as a potential therapy for individuals with multidrug-resistant HIV-1 variants.

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* Corresponding author. Mailing address: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Phone: 81-96-373-6522. Fax: 81-96-373-6523. E-mail: okadas{at}kumamoto-u.ac.jp

Published ahead of print on 22 June 2009.

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Antimicrobial Agents and Chemotherapy, September 2009, p. 3887-3893, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00270-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.