MURINE RETROVIRAL MODEL FOR HIV DRUG EVALUATION

用于 HIV 药物评估的小鼠逆转录病毒模型

• 批准号: 3143247
• 负责人: THOMAS C MERIGAN
• 金额: $ 21.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-11-01 至 1992-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3143247
• 关键词: AIDS; AIDS therapy; Betaherpesvirinae; CD4 molecule; CD8 molecule; T lymphocyte; acyclovir; antiAIDS agent; antiviral agents; biological response modifiers; combination chemotherapy; disease /disorder model; dosage forms; drug adverse effect; drug delivery systems; human immunodeficiency virus 1; immunoglobulins; laboratory mouse; latent virus infection; liposomes; nonhuman therapy evaluation; nucleoside analog; phosphorylation; sign /symptom; splenomegaly; virus replication; zidovudine

We have preliminary data in the mouse LP-BM5 model of AIDS infection (MAIDS) showing that AZT, the only FDA approved treatment of AIDS at this point, reduced virus titer in spleen and lymph nodes by 100-1000 fold, as well as serum immunoglobulin levels, B, CD4+, and Macl+ cell proliferation, and splenomegaly and lymphadenopathy. After six weeks of AZT therapy both the number of CD8+ cells were increased and survival time was extended by 5-6 weeks as compared to untreated virus infected control mice. This model has proven to be very reproducible, inexpensive, and lends itself to specific and sophisticated immunoanalysis. We propose to investigate several means of improving current in vivo anti-retroviral therapy using the LP-BM5 MAIDS pre-clinical model. We will test additional treatment schedules and doses of AZT for maximum effectiveness. Other antiviral drugs will be used both alternately and concomitantly with, AZT in an effort to improve efficacy. Selected BMR will be studied for their ability to enhance AZT action. We will extend our Stanford group's (Blaschke and Robinson) in vitro observation that lithium enhanced AZT activity against HIV in molt4 cells by testing a combination in AZT and LiCl in the MAIDS model. In addition, new drugs including nucleotide analogs, specific protease and glycosidase inhibitors from industrial sources will be assessed by pre-clinical testing in vitro and in vivo as they are available. We will also attempt to improve drug delivery and effectiveness via drug encapsulation in liposomes. The impact of murine CMV both as a latent and acute infection will be explored in the MAIDS model. This is particularly relevant because of the potential lethal sequelae of CMV infections in human AIDS patients. Information on optimum dose, route scheduling, the effectiveness of combination therapy and the impact of at least one other infectious agent in the model will be useful in designing more rational future clinical protocols.

我们有艾滋病感染小鼠 LP-BM5 模型的初步数据 (MAIDS) 表明 AZT 是 FDA 目前唯一批准的治疗艾滋病的药物 点，脾脏和淋巴结中的病毒滴度降低100-1000倍，如 以及血清免疫球蛋白水平、B、CD4+ 和 Macl+ 细胞增殖， 以及脾肿大和淋巴结肿大。 经过六周的 AZT 治疗后， CD8+细胞数量增加，存活时间延长 与未治疗的病毒感染对照小鼠相比，需要 5-6 周。 这个型号 已被证明是非常可重复的，廉价的，并且适合 特异性和复杂的免疫分析。 我们建议调查 改善当前体内抗逆转录病毒治疗的几种方法 LP-BM5 MAIDS 临床前模型。 我们将测试额外的治疗 AZT 的时间表和剂量以获得最大效果。 其他抗病毒药 药物将与 AZT 交替或同时使用 努力提高效能。 将研究选定的 BMR 的能力 增强AZT作用。 我们将扩展我们的斯坦福小组（Blschke 和 Robinson）体外观察到锂增强了 AZT 的活性 通过在 MAIDS 中测试 AZT 和 LiCl 的组合来检测 molt4 细胞中的 HIV 模型。 此外，新药包括核苷酸类似物、特异性 来自工业来源的蛋白酶和糖苷酶抑制剂将 通过临床前体外和体内测试进行评估 可用的。 我们还将尝试改善药物输送和有效性 通过将药物封装在脂质体中。 小鼠 CMV 的影响 将在 MAIDS 模型中探索潜伏性和急性感染。 这是 由于 CMV 潜在的致命后遗症而特别相关 人类艾滋病患者的感染。 有关最佳剂量、途径的信息 时间安排、联合治疗的有效性以及 at 的影响 模型中至少一种其他感染因子将有助于设计 未来更加合理的临床方案。