Perturbation of amyloid processing in HAND

描述（由申请人提供）：抗逆转录病毒疗法（ART）在防治艾滋病毒感染方面的成功使艾滋病毒感染者的预期寿命大大延长。艾滋病毒感染人口的老龄化引起了人们的关注，即病毒或病毒相关因素可能与年龄相关的神经病变相互作用。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，有反复的观察表明，致病性淀粉样蛋白(A)在艾滋病毒感染患者的大脑中积累的频率远高于在艾滋病毒血清阴性患者中所见的频率。这些观察结果表明，可能有一些病毒或病毒相关因素促进异常淀粉样蛋白加工。在初步研究中，我们发现病毒外壳蛋白gp120可以诱导参与淀粉样蛋白致病过程的分泌酶活性。本应用程序中概述的实验旨在阐明gp120可能干扰淀粉样蛋白加工以促进致病性淀粉样肽产生的潜在机制。

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.