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: 3143248
• 负责人: THOMAS C MERIGAN
• 金额: $ 20.17万
• 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/3143248
• 关键词: AIDS; AIDS therapy; CD4 molecule; CD8 molecule; T lymphocyte; acyclovir; antiAIDS agent; biological response modifiers; combination chemotherapy; cytomegalovirus; disease /disorder model; dosage forms; drug adverse effect; drug delivery systems; foscarnet; 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.

我们在艾滋病感染的小鼠LP-BM5模型中有初步数据 （女佣）表明AZT是FDA唯一批准的艾滋病治疗 点，脾脏中的病毒滴度降低，淋巴结减少100-1000倍，AS 以及血清免疫球蛋白水平B，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 CD8+细胞的数量增加，生存时间延长了 与未经治疗的病毒感染对照小鼠相比，5-6周。 这个模型 被证明是非常可重复的，便宜的，并借给自己 特定而复杂的免疫分析。 我们建议调查 使用的几种方法改善了使用体内抗逆转录病毒疗法的手段 LP-BM5女仆前临床模型。 我们将测试其他治疗 AZT的时间表和剂量可提高最大有效性。 其他抗病毒 药物将交替和同时使用，AZT 努力提高功效。 选定的BMR的能力将被研究 增强AZT动作。 我们将扩展我们的斯坦福集团（Blaschke和 罗宾逊）体外观察，锂增强了AZT活性 通过在女仆中测试AZT和LICL的组合，Molt4细胞中的HIV 模型。 此外，包括核苷酸类似物在内的新药，特定的 来自工业来源的蛋白酶和糖苷酶抑制剂将是 通过体外和体内进行临床前测试评估 可用的。 我们还将尝试提高药物输送和有效性 通过脂质体中的药物封装。 鼠CMV的影响既是 在女仆模型中将探索潜在和急性感染。 这是 由于CMV的潜在致命后遗症特别相关 人类艾滋病患者的感染。 有关最佳剂量的信息，路线 调度，组合疗法的有效性和AT的影响 该模型中至少有一个其他传染剂将在设计中有用 更多理性的未来临床方案。