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: 6650331
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650331
• 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（申请人的摘要）：与HIV相关的痴呆症综合体（HADC）是 在艾滋病毒感染的后期，常见疾病。有很多未回答的 有关其发病机理的问题，即临床的关系 HADC表达脑炎的病理发现和 特别是中枢神经系统病毒载荷与HADC的关联。最近的研究表明 该单一抗逆转录病毒药物（Abacavir）可以减少中枢神经系统病毒载量，但 尚不清楚CNS病毒负荷是否会导致改善 失智。高度活性抗逆转录病毒疗法（HAART）的临床试验 建议它延迟HADC的发作，并且可以逆转HADC。但是，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不良， 尚不清楚认知和衰减神经病理学特征的改善。 HIV脑炎的严重组合免疫缺陷（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脑炎的病理方面。因此，这是一个学习的系统 HAART对异常行为和神经病理学的影响。这个模型将 确定Haart是否减少病毒载荷并改善行为和 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的基本发病机理，这可能导致 其他更具体的治疗方法。实验设计结合了2 （Haart vs.车辆）X 2（艾滋病毒感染与未感染的）阶乘设计 这两个假设： I. AZT + Lamivudine + Indinavir三重抗逆转录病毒疗法（HAART）将（1） 降低脑组织中的病毒负荷，（2）衰减神经病理学 与HIV感染的SCID小鼠共同。特定目标1：确定，之后 腹膜内注射，是否：（a）小鼠在提议的 通过一般外观，重量和活动测量的剂量，（b）病毒 用Haart与Haart治疗的HIV感染小鼠的大脑减少了滴度 通过半定量RT-PCR测量的控制，（c）HIV测量 脑炎（神经病理学，例如HIV感染的巨噬细胞数量， 在用HAART治疗的HIV感染小鼠中，神经胶质病等得到改善 控件。 ii。 HAART长期治疗将改善神经病理学和 与HIV脑炎有关的行为异常。艾滋病毒感染和 将评估未感染的SCID小鼠：特定目标2：电动机放慢和 在运动活动测试期间的性能索引的认知功能障碍和 在空间学习/记忆任务上；特定目标3：由 用于mRNA和免疫细胞化学的半定量PCR用于感染巨噬细胞； 特定目的4：神经病理学通过神经胶质和神经元细胞凋亡确定； 特定目标5：脑组织中的细胞因子活性。