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 艾滋病病毒感染后期的常见疾病。有许多问题没有得到解答 关于其发病机制的问题，即，临床关系 HADC的表达与脑炎的病理表现有关， 特别是CNS病毒载量与HADC的相关性。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CNS病毒载量，但它 尚不清楚CNS病毒载量的降低是否会导致 痴呆高效抗逆转录病毒治疗（HAART）的临床试验 表明它可以延迟HADC的发作并可以逆转HADC。然而，由于其他 研究表明抗逆转录病毒药物的CNS渗透性差， 改善认知和减轻神经病理学特征尚不清楚。 HIV脑炎的严重联合免疫缺陷（SCID）小鼠模型， 在我们的实验室中开发，并概括了许多行为和 人类HIV脑炎的病理学方面。因此，它是一个系统的研究 HAART对异常行为和神经病理学的影响。这种模式的 确定HAART是否降低病毒载量并改善行为和 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HADC的基本发病机制， 其他更具体的治疗。实验设计采用了2 （HAART vs.溶媒）× 2（HIV感染vs.未感染）析因设计进行检验 这两个假设： I. AZT +拉米夫定+茚地那韦三联抗逆转录病毒疗法（HAART）将（1） 降低脑组织中的病毒载量和（2）减轻神经病理学 感染HIV的SCID小鼠中常见。具体目标1：确定后， 腹膜内注射，无论：（A）小鼠耐受在建议的剂量下的HAART。 通过一般外观、重量和活性测量的剂量，（B）病毒 用HAART治疗的HIV感染小鼠的脑中滴度降低， 通过半定量RT-PCR测量的对照，（C）HIV的测量 脑炎（神经病理学-如HIV感染的巨噬细胞的数量， 神经胶质增生等）与接受HAART治疗的HIV感染小鼠相比， 对照 二. HAART的长期治疗将改善神经病理学， 与HIV脑炎相关的行为异常艾滋病毒感染和 将评价未感染的SCID小鼠的：特异性目标2：运动减慢和 认知功能障碍，以运动活动测试期间的表现为指标， 空间学习/记忆任务;具体目标3：病毒载量， 半定量PCR检测感染巨噬细胞的mRNA和免疫细胞化学; 具体目标4：以胶质增生和神经元凋亡为指标的神经病理学研究; 具体目标5：脑组织中的细胞因子活性。