HAART IN SCID MICE WITH HIV ENCEPHALITIS

描述(申请人摘要)：HIV相关痴呆症(HADC)是一种 艾滋病病毒感染晚期的常见病。有很多问题没有得到回答 关于其发病机制的问题，即与临床的关系 HADC在脑炎和脑炎病理表现中的表达 尤其是中枢神经系统病毒载量与HADC的相关性。最近的研究表明 单一的抗逆转录病毒药物(阿巴卡韦)可以降低中枢神经系统的病毒载量，但它 目前尚不清楚降低中枢神经系统病毒载量是否会改善 痴呆症。高效抗逆转录病毒疗法(HAART)的临床试验 提示它可延缓HADC的发病，并能逆转HADC。然而，由于其他人 研究表明，抗逆转录病毒药物的中枢神经系统渗透率很低， 改善认知和减轻神经病理特征的作用尚不清楚。 目的建立重症联合免疫缺陷(SCID)小鼠HIV脑炎模型。 在我们的实验室开发的，并概括了许多行为和 人类艾滋病毒脑炎的病理方面。因此，它是一个需要研究的系统。 HAART对行为异常和神经病理的影响这款车型将 确定HAART是否降低了病毒载量并改善了行为和 HIV脑炎的病理特点。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，可能导致 其他更具体的治疗方法。实验设计包含了2个 (HAART与Vehicle)x 2(感染HIV与未感染)析因设计进行测试 这两个假设： 一、AZT+拉米夫定+吲哚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 常见于感染艾滋病毒的SCID小鼠。具体目标1：确定后 腹腔注射：(A)小鼠是否耐受建议的HAART 通过一般外观、体重和活动测量的剂量，(B)病毒 HAART与HAART相比，HIV感染小鼠脑内滴度降低 通过半定量RT-PCR测量的对照，(C)艾滋病毒测量 脑炎(神经病理学--如感染艾滋病毒的巨噬细胞数量， 神经胶质增多症等。)与HAART相比，HAART对HIV感染小鼠的改善 控制。 HAART的长期治疗将改善神经病理和 与艾滋病毒脑炎相关的行为异常。感染艾滋病毒和 未感染的SCID小鼠将被评估：特定目标2：运动减慢和 以运动活动测试中的表现为指标的认知功能障碍 空间学习/记忆任务；具体目标3：病毒载量由 感染巨噬细胞的半定量聚合酶链式反应和免疫细胞化学； 具体目标4：神经病理由胶质细胞增生症和神经元凋亡决定； 具体目标5：脑组织中的细胞因子活性。

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.