Pre- and postexposure chemoprophylaxis: evidence that 3'-azido-3'-dideoxythymidine inhibits feline leukemia virus disease by a drug-induced vaccine response.
Pre- and postexposure chemoprophylaxis: evidence that 3'-azido-3'-dideoxythymidine inhibits feline leukemia virus disease by a drug-induced vaccine response.
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暴露前和暴露后化学预防：3-叠氮基-3-二脱氧胸苷通过药物诱导的疫苗反应抑制猫白血病病毒病的证据。
DOI：
10.1128/aac.36.12.2715
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发表时间：
1992
影响因子：
4.9
通讯作者：
Kociba,GJ
中科院分区：
文献类型：
--
作者：
Mathes,LE;Polas,PJ;Hayes,KA;Swenson,CL;Johnson,S;Kociba,GJ
人类免疫缺陷病毒暴露后，暴露后 3'-叠氮基-3'-二脱氧胸苷 (AZT) 预防的益处尚不清楚。我们描述了在艾滋病猫白血病病毒（FeLV）猫模型中暴露前和暴露后 AZT 治疗的综合评估，包括体外测试、体内剂量反应滴定、暴露后治疗研究、血浆药物浓度测定以及对 FeLV 的免疫反应评估。在体外研究中，AZT 可以预防猫 T 淋巴细胞系的 FeLV 感染，50% 和 90% 抑制浓度分别为 4.6 和 11.1 mM。在所有体内功效研究中，AZT 均通过连续皮下输注 28 天进行给药。每天120毫克/公斤体重的剂量时AZT毒性过量，导致急性贫血，但每天60毫克/公斤体重时AZT是可以耐受的。在暴露前研究中，AZT 在剂量 > 或 = 15 mg/kg/天时可有效预防慢性抗原血症，此时血浆 AZT 浓度平均在 0.51 至 0.81 微克/毫升（2.13 至 3.03 微摩尔）之间。作为暴露后治疗，60 mg/kg/天的 AZT 在病毒接种后 96 小时（接种后 96 小时）开始治疗时可预防慢性 FeLV 抗原血症，但在接种后 192 小时开始治疗时则不能预防慢性 FeLV 抗原血症。下午 96 点至 192 点之间的 4 天时间段。似乎对于建立慢性病毒血症至关重要。据推测，感染后 4 至 8 天之间病毒载量的增加。尽管 AZT 疗法在治疗期间有效控制了病毒血症，但能够压倒负责遏制 FeLV 感染的免疫功能。 FeLV 的抗体反应根据相对于病毒攻击的 AZT 治疗开始时间而变化。当在 FeLV 攻击前 48 小时或后 8 小时开始 AZT 治疗时，直到注射后 28 天停止 AZT 治疗后才检测到 FeLV 抗体。然而，AZT 治疗后，抗体滴度迅速增加，其速度表明出现了二次免疫反应。当 AZT 治疗在相对于病毒攻击较晚的时间点（注射后 24、48 和 96 小时）开始时，在治疗期间可检测到 FeLV 抗体。这些结果表明，即使在病毒攻击之前开始治疗，AZT 治疗也不能完全预防 FeLV 感染，并且在预防性药物治疗期间，对 FeLV 的免疫敏化仍在进行。
The benefits of postexposure 3'-azido-3'-dideoxythymidine (AZT) prophylaxis following human immunodeficiency virus exposure are unknown. We describe a comprehensive assessment of pre- and postexposure AZT therapy in the feline leukemia virus (FeLV)-cat model for AIDS which included in vitro testing, an in vivo dose-response titration, a postexposure treatment study, plasma drug concentration determinations, and evaluation of the immune response to FeLV. In in vitro studies, AZT prevented FeLV infection of a feline T-lymphoid cell line, giving 50 and 90% inhibition concentrations of 4.6 and 11.1 mM, respectively. In all of the in vivo efficacy studies, AZT was administered by continuous subcutaneous infusion for 28 days. AZT toxicity was excessive at a dosage of 120 mg/kg of body weight per day, causing acute anemia, but AZT was tolerable at 60 mg/kg/day. In preexposure studies, AZT was efficacious in preventing chronic antigenemia at a dosage of > or = 15 mg/kg/day, at which plasma AZT concentrations averaged between 0.51 and 0.81 micrograms/ml (2.13 and 3.03 microM). As a postexposure treatment, at 60 mg/kg/day, AZT prevented chronic FeLV antigenemia when treatment was started up to 96 h post-virus inoculation (p.i.), but not when treatment was started at 192 h p.i. The 4-day period between 96 and 192 h p.i. appears to be critical for establishing chronic viremia. It is presumed that the increase in virus load between 4 and 8 days p.i. was able to overwhelm the immunologic functions responsible for containment of FeLV infection, even though AZT therapy effectively controlled viremia during the treatment period. The antibody response to FeLV varied depending on the time of AZT treatment initiation relative to virus challenge.When AZT treatment was started 48 h before or 8 h after FeLV challenge, antibodies to FeLV were not detected until after AZT treatment was discontinued at 28 days p.i. Following AZT treatment, however, antibody titers rapidly increased at a rate suggestive of a secondary immune response. When AZT treatment was initiate at later time points relative to virus challenge (24, 48, and 96 h p.i.), antibodies to FeLV became detectable during the treatment period. These results indicate that AZT treatment does not completely prevent FeLV infection, even when treatment begins before virus challenge, and that immune sensitization to FeLV proceeds during the prophylactic drug treatment period.