alexa 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
Microbiology

Microbiology

Journal of Antivirals & Antiretrovirals

Author(s): Shinichiro Hattori

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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 × 102 copies/ml [range, 8.1 × 102 to 1.1 × 103 copies/ml] versus median of 9.9 × 104 copies/ml [range, 8.1 × 102 to 1.1 × 103 copies/ml]; P < 0.001), the p24 level in plasma (2.5 × 103 pg/ml [range, 8.2 × 102 to 5.6 × 103 pg/ml] versus 2.8 × 102 pg/ml [range, 8.2 × 101 to 6.3 × 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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This article was published in Antimicrob Agents Chemother and referenced in Journal of Antivirals & Antiretrovirals

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