Ruxrungtham K, Boone E, Ford H, Driscoll J S, Davey R T, Lane H C
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
Antimicrob Agents Chemother. 1996 Oct;40(10):2369-74. doi: 10.1128/AAC.40.10.2369.
A new antiretroviral agent, 2'-beta-fluoro-2',3'-dideoxyadenosine (FddA), is an acid-stable compound whose triphosphate form is a potent reverse transcriptase inhibitor with in vitro anti-human immunodeficiency virus (HIV) activity and a favorable pharmacokinetic profile. Severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) provide a useful small-animal model for HIV research. In the present study we utilized this experimental system for the in vivo evaluation of the anti-HIV activity of this new compound when administered prior to infection. Initial studies revealed that, following a challenge with 50 100% tissue culture infective doses of HIV type 1 lymphadenopathy-associated virus, 39 of 42 (93%) control mice developed HIV infection, as evidenced by positive coculture or positive PCR. Administration of zidovudine decreased the infection rate to 5 of 16 (31%), while administration of FddA decreased the infection rate to 0 of 44 (0%). In follow-up controlled studies, the anti-HIV activity of FddA was confirmed, with 18 of 20 control mice showing evidence of HIV infection, compared with 4 of 20 FddA-treated mice. In addition to having direct anti-HIV effects, FddA was found to have a protective effect on human CD4+ T cells in the face of HIV infection. Mice treated with FddA were found to have a significantly higher percentage of CD4+ T cells than controls (10.3% +/- 3.4% versus 0.27% +/- 0.21%; P = 0.01). Thus, FddA, with its potent anti-HIV activity in vivo, high oral bioavailability, long intracellular half-life, and ability to preserve CD4+ cells in the presence of HIV, appears to be a promising agent for clinical investigation.
一种新型抗逆转录病毒药物，2'-β-氟-2'，3'-双脱氧腺苷（FddA），是一种酸稳定化合物，其三磷酸形式是一种有效的逆转录酶抑制剂，具有体外抗人免疫缺陷病毒（HIV）活性和良好的药代动力学特征。用人外周血白细胞重建的严重联合免疫缺陷（SCID）小鼠（hu-PBL-SCID小鼠）为HIV研究提供了一个有用的小动物模型。在本研究中，我们利用这个实验系统对该新化合物在感染前给药时的体内抗HIV活性进行评估。初步研究表明，在用50或100%组织培养感染剂量的1型HIV淋巴结病相关病毒攻击后，42只对照小鼠中有39只（93%）发生了HIV感染，通过阳性共培养或阳性PCR证实。给予齐多夫定可将感染率降至16只中的5只（31%），而给予FddA可将感染率降至44只中的0只（0%）。在后续的对照研究中，FddA的抗HIV活性得到证实，20只对照小鼠中有18只显示出HIV感染的证据，而FddA治疗的20只小鼠中有4只。除了具有直接的抗HIV作用外，还发现FddA在面对HIV感染时对人CD4+T细胞有保护作用。发现用FddA治疗的小鼠的CD4+T细胞百分比明显高于对照小鼠（10.3%±3.4%对0.27%±0.21%；P = 0.01）。因此，FddA在体内具有强大的抗HIV活性、高口服生物利用度、长细胞内半衰期以及在HIV存在下保护CD4+细胞的能力，似乎是一种有前途的临床研究药物。
