Perturbation of amyloid processing in HAND

描述（由申请人提供）：抗逆转录病毒治疗（ART）在对抗HIV感染方面的成功导致HIV感染患者的预期寿命大幅增加。感染艾滋病毒的老龄化人口引起了人们的关注，即病毒或病毒相关因素可能与年龄相关的神经病理学相互作用。事实上，越来越多的证据表明，阿尔茨海默病（AD）样病理可能存在于一些感染艾滋病毒的个体中。特别是，已经反复观察到致病形式的淀粉样蛋白（A）在感染HIV的患者的脑中积累的频率比在HIV血清阴性患者中观察到的频率高得多。这些观察结果表明，可能有一些病毒或病毒相关的因素，促进异常淀粉样蛋白的加工。在初步研究中，我们发现病毒外壳蛋白gp 120可以诱导淀粉样蛋白致病过程中所涉及的分泌酶的活性。本申请中概述的实验旨在阐明gp 120可能干扰淀粉样蛋白加工以促进致病性β-淀粉样蛋白肽产生的潜在机制。 公共卫生相关性：用于对抗艾滋病毒（获得性免疫缺陷综合征的致病病毒;艾滋病）感染的药物疗法的成功极大地延长了艾滋病毒感染者的预期寿命。虽然与艾滋病毒感染相关的神经系统并发症也随着药物治疗的出现而下降，但感染艾滋病毒的人口老龄化引起了人们的担忧，即病毒或病毒相关因素可能导致该人群中阿尔茨海默氏症的增加。事实上，几项研究已经发现了艾滋病毒感染者大脑中阿尔茨海默病样病理学的证据。本申请中概述的研究旨在确定HIV感染可能促进阿尔茨海默病样神经病理学的机制。

DESCRIPTION (provided by applicant): The success of antiretroviral therapy (ART) in combating HIV infection has resulted in a dramatic increase in the expected lifespan of HIV-infected patients. An aging population infected with HIV has raised the concern that viral- or viral-associated factors could interact with age-related neuropathologies. Indeed, there is increasing evidence that Alzheimer's disease (AD)-like pathology may be present in some individuals infected with HIV. In particular, there have been repeated observations that pathogenic forms of amyloid (A) accumulate in brains of patients infected with HIV at much higher frequency than is seen in HIV seronegative patients. These observations suggest that there may be some viral- or viral-associated factors that promote abnormal amyloid processing. In preliminary studies we have found that the viral coat protein gp120 can induce activity of secretases involved in the pathogenic processing of amyloid. The experiments outlined in this application are designed to eludicate potential mechanisms by which gp120 may perturb amyloid processing to promote the generation of pathogenic ¿-amyloid peptides. PUBLIC HEALTH RELEVANCE: The success of drug therapies used to combat infection with HIV (the causative virus of Acquired Immunodeficiency Syndrome; AIDS) has dramatically increased the expected lifespan of people infected with HIV. Although neurological complications associated with HIV infection also declined with the advent of drug therapies, an aging population of people infected with HIV has raised the concern that virus- or virus-associated factors could contribute to an increase of Alzheimer's in this population. Indeed, several studies have found evidence for Alzheimer's-like pathology in the brains of people infected with HIV. The studies outlined in this application are designed to determine the mechanisms by which infection with HIV could promotes Alzheimer's-like neuropathology.