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
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
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DOI：
10.1128/aac.00270-09
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发表时间：
2009-09-01
影响因子：
4.9
通讯作者：
Okada, Seiji
中科院分区：
文献类型：
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作者：
Hattori, Shinichiro;Ide, Kazuhiko;Okada, Seiji
4′-乙基-2-氟-2′-脱氧腺苷（EFdA）是一种最近发现的核苷类逆转录酶抑制剂，对广泛的野生型和多药耐药临床人类免疫缺陷病毒1型（HIV-1）分离株（50%有效浓度，0.0001至0.001 μ M）具有活性。在本研究中，我们使用人外周血单个核细胞移植，hiv -1感染NOD/SCID/Janus激酶3敲除小鼠进行体内评价EFdA的抗hiv活性。EFdA的施用减少了HIV-1的复制和细胞病变效应，但没有明显的不良反应。PBS处理小鼠脾脏CD4(+)/CD8（+）细胞比值较低（中位数为0.04，范围为0.02 ~ 0.49），EFdA处理小鼠脾脏CD4(+)/CD8（+）细胞比值升高（中位数为0.65，范围为0.57 ~ 1.43）。EFdA治疗显著抑制HIV-1 RNA的数量(中位数为9.0 × 10(2)拷贝/ml[范围，8.1 × 10(2)至1.1 × 10(3)拷贝/ml]，中位数为9.9 × 10(4)拷贝/ml[范围，8.1 × 10(2)至1.1 × 10(3)拷贝/ml]；P < 0.001)，血浆中p24水平(2.5 × 10(3) pg/ml[范围，8.2 × 10(2)至5.6 × 10(3) pg/ml]对2.8 × 10(2) pg/ml[范围，8.2 × 10(1)至6.3 × 10(2) pg/ml]；P < 0.001)，脾脏中表达p24细胞的百分比（中位数为1.90%[范围，0.33%至3.68%]，中位数为0.11%[范围，0.00%至1.00%],P = 0.003）与pbs处理小鼠相比。这些数据表明，EFdA是HIV-1化疗新时代的一个有希望的候选者，应该进一步开发作为多药耐药HIV-1变异个体的潜在治疗方法。
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 mu M). 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.