HAART IN SCID MICE WITH HIV ENCEPHALITIS

HAART 在患有 HIV 脑炎的 SCID 小鼠中的应用

• 批准号: 6392909
• 负责人: WILLIAM R TYOR
• 金额: $ 17.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392909
• 关键词: AIDS dementia complex; AIDS therapy; SCID mouse; combination chemotherapy; cytokine; gliosis; indinavir; lamivudine; longitudinal animal study; neuropathology; nonhuman therapy evaluation; psychomotor function; virus load; zidovudine

DESCRIPTION (Applicant's abstract): HIV-associated dementia complex (HADC) is a common disease in the late stages of HIV infection. There are many unanswered questions regarding its pathogenesis, i.e., the relationship of the clinical expression of HADC to the pathological findings of encephalitis and particularly the association of CNS viral load to HADC. Recent studies suggest that single antiretroviral agents (abacavir) can reduce CNS viral load, but it is unknown if reduction of CNS viral load results in the amelioration of dementia. Clinical trials of highly active antiretroviral therapy (HAART) suggest it delays the onset of HADC and can reverse HADC. However, since other studies suggest that there is poor CNS penetration of antiretroviral agents, the improving cognition and attenuating neuropathological features is unclear. The severe combined immunodeficient (SCID) mouse model of HIV encephalitis was developed in our laboratory and recapitulates many of the behavioral and pathological aspects of human HIV encephalitis. Thus, it is a system to study the effects of HAART on abnormal behavior and neuropathology. This model will establish whether HAART reduces viral load and improves the behavioral and pathological features of HIV encephalitis. More importantly, these studies will enable us to begin to elucidate the basic pathogenesis of HADC that may lead to other, more specific treatments. The experimental design incorporates a 2 (HAART vs. vehicle) x 2 (HIV infected vs. uninfected) factorial design to test these two hypotheses: I. AZT + lamivudine + indinavir triple antiretroviral therapy (HAART) will (1) lower the viral load in brain tissue and (2) attenuate the neuropathology common to HIV-infected SCID mice. Specific Aim 1: Determine, after intraperitoneal injections, whether: (A) Mice tolerate HAART at the proposed dosages as measured by general appearance, weight, and activity, (B) Viral titer is reduced in brains of HIV-infected mice treated with HAART versus controls as measured by semiquantitative RT-PCR, (C) Measures of HIV encephalitis (neuropathology-such as numbers of HIV-infected macrophages, gliosis, etc.) are improved in HIV-infected mice treated with HAART versus controls. II. Long-term treatment with HAART will improve the neuropathology and behavioral abnormalities associated with HIV encephalitis. HIV-infected and uninfected SCID mice will be evaluated for: Specific Aim 2: Motor slowing and cognitive dysfunction as indexed by performance during motor activity tests and on a spatial learning/memory task; Specific Aim 3: Viral load determined by semiquantitative PCR for mRNA and immunocytochemistry for infected macrophages; Specific Aim 4: Neuropathology determine by gliosis and neuronal apoptosis; Specific Aim 5: Cytokine activity in brain tissue.

描述（申请人摘要）：HIV 相关痴呆综合征 (HADC) 是一种 HIV感染后期的常见病。还有很多没有答案 关于其发病机制的问题，即与临床的关系 HADC表达与脑炎病理结果的关系 特别是 CNS 病毒载量与 HADC 的关联。最近的研究表明 单一抗逆转录病毒药物（阿巴卡韦）可以降低中枢神经系统病毒载量，但它 尚不清楚中枢神经系统病毒载量的减少是否会导致症状的改善 失智。高效抗逆转录病毒疗法（HAART）的临床试验 表明它可以延迟 HADC 的发生并可以逆转 HADC。然而，由于其他 研究表明抗逆转录病毒药物的中枢神经系统渗透性较差， 改善认知和减弱神经病理学特征尚不清楚。 严重联合免疫缺陷（SCID）小鼠 HIV 脑炎模型 在我们的实验室中开发并概括了许多行为和 人类艾滋病毒脑炎的病理学方面。因此，它是一个系统研究 HAART 对异常行为和神经病理学的影响。该模型将 确定 HAART 是否可以降低病毒载量并改善行为和行为 HIV脑炎的病理特征。更重要的是，这些研究将 使我们能够开始阐明可能导致 HADC 的基本发病机制 其他更具体的治疗方法。实验设计包含 2 （HAART 与载体）x 2（HIV 感染与未感染）析因设计进行测试 这两个假设： 一、AZT+拉米夫定+茚地那韦三联抗逆转录病毒治疗（HAART）会（1） 降低脑组织中的病毒载量并（2）减弱神经病理学 常见于感染 HIV 的 SCID 小鼠。具体目标 1：确定之后 腹膜内注射，是否： (A) 小鼠在建议的剂量下耐受 HAART 通过一般外观、重量和活性来衡量的剂量，(B) 病毒 与接受HAART治疗的HIV感染小鼠相比，其大脑中滴度降低 通过半定量 RT-PCR 测量的对照，(C) HIV 测量 脑炎（神经病理学——例如感染艾滋病毒的巨噬细胞的数量， 与接受HAART治疗的HIV感染小鼠相比，神经胶质增生等）得到改善 控制。 二.长期HAART治疗将改善神经病理学和 与艾滋病毒脑炎相关的行为异常。艾滋病毒感染者和 未感染的 SCID 小鼠将接受以下评估： 具体目标 2：运动减慢和 以运动活动测试期间的表现为指标的认知功能障碍和 空间学习/记忆任务；具体目标 3：病毒载量由以下因素确定 半定量 PCR 检测受感染的巨噬细胞的 mRNA 和免疫细胞化学； 具体目标4：通过神经胶质增生和神经元凋亡确定神经病理学； 具体目标 5：脑组织中的细胞因子活性。