title: 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.
abstract: 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 microM). 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 10(2) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml] versus median of 9.9 x 10(4) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml]; P < 0.001), the p24 level in plasma (2.5 x 10(3) pg/ml [range, 8.2 x 10(2) to 5.6 x 10(3) pg/ml] versus 2.8 x 10(2) pg/ml [range, 8.2 x 10(1) to 6.3 x 10(2) 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.
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto, Japan.
authors: Shinichiro
authors: S
authors: Hattori
authors: Kazuhiko
authors: K
authors: Ide
authors: Hirotomo
authors: H
authors: Nakata
authors: Hideki
authors: H
authors: Harada
authors: Shinya
authors: S
authors: Suzu
authors: Noriyuki
authors: N
authors: Ashida
authors: Satoru
authors: S
authors: Kohgo
authors: Hiroyuki
authors: H
authors: Hayakawa
authors: Hiroaki
authors: H
authors: Mitsuya
authors: Seiji
authors: S
authors: Okada
mesh_terms: D000818:Animals; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003839:Deoxyadenosines; D018894:Reverse Transcriptase Inhibitors; D053616:Janus Kinase 3; C058118:2'-deoxyadenosine