AIDS-related HSV-1 retinal necrosis: Innate immunity and virus spread

项目主任/首席调查员(最后、第一、中间)：DIX，Richard D 项目摘要 艾滋病患者可发展为急性视网膜坏死(ARN)的变种，称为进行性视网膜外 由单纯疱疹病毒1型(HSV-1)引起的坏死(色情)。尽管体内存在传染性病毒 色情期间视网膜组织，艾滋病患者未发生急性单纯疱疹病毒性脑炎(HSE)提示 病毒要么包含在视网膜组织中，要么确实传播到大脑，但包含在神经中 引起亚临床HSV-1脑炎的途径。推进我们的经济发展的关键障碍 艾滋病期间HSV-1视网膜坏死与HSE的认识一直缺乏临床相关性 艾滋病相关性单纯疱疹病毒1型视网膜坏死动物模型。拟议的项目将解决这一关键障碍，以 一种新发展的与临床相关的单纯疱疹病毒1型视网膜疾病动物模型的研究进展 具有逆转录病毒诱导的免疫抑制的小鼠(MAIDs)，在组织病理学上模仿艾滋病中的色情 病人。该项目的目标是解决与艾滋病相关的HSV-1色情和HSE问题，以及 获得了解先天免疫在人类免疫系统中的作用所需的信息，从而阻碍进展 阻止病毒从视网膜传播到大脑，或将病毒在大脑内的传播降至最低，从而导致亚临床 脑炎使用我们的新女佣-HSV-1色情模型。我们的中心假设是一个或多个 在逆转录病毒诱导的免疫抑制过程中起作用的先天免疫成分可预防 通过阻止HSV-1传播到大脑或在大脑中包含HSV-1复制来实现急性HSE 产生亚临床脑炎。我们的目标是使用我们的HSV-1色情的新女佣模型来(1) 确定HSV-1在视网膜组织中感染的命运以及病毒传播到 脑组织，以及(2)开始了解先天免疫的关键成分在包含 单纯疱疹病毒1型在视网膜和/或脑内感染，导致亚临床脑炎。这些目标将是 MET通过成功完成两个特定目标：(1)确定病毒在小鼠体内的传播程度 与女佣相关的HSV-1色情和(2)确定先天免疫关键成分在 含有与女佣有关的HSV-1色情的小鼠传播的病毒。对艾滋病领域的影响将包括 (1)迄今未被认识到的先天免疫抑制HSV-1从视网膜传播到大脑和/或的作用 在逆转录病毒诱导的免疫抑制期间的脑实质内，以及(2)可能到目前为止 HIV免疫抑制患者的亚临床HSE的潜在发展未被认识到。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Dix, Richard D Project Summary AIDS patients can develop a variant of acute retinal necrosis (ARN) designated progressive outer retinal necrosis (PORN) caused by herpes simplex virus type 1 (HSV-1). Although infectious virus is present within retinal tissues during PORN, AIDS patients fail to develop acute herpes simplex encephalitis (HSE) suggesting virus is either contained within retinal tissues or indeed spreads to the brain but is contained within neural pathways to cause subclinical HSV-1 encephalitis. A critical barrier to progress in advancing our understanding of HSV-1 retinal necrosis vis-à-vis HSE during AIDS has been the lack of a clinically relevant animal model for AIDS-related HSV-1 retinal necrosis. The proposed project will address this critical barrier to progress by using a newly developed and clinically relevant animal model of HSV-1-induced retinal disease in mice with retrovirus-induced immunosuppression (MAIDS) that histopathologically mimics PORN in AIDS patients. The goal of this project is to address the problem of AIDS-related HSV-1 PORN and HSE and the critical barrier to progress by obtaining the information needed to understand the role of innate immunity in halting virus spread from retina to brain or minimizing virus spread within the brain to cause subclinical encephalitis using our novel MAIDS-model of HSV-1 PORN. Our central hypothesis is that one or more components of innate immunity that operate during retrovirus-induced immunosuppression prevent onset of acute HSE by either blocking HSV-1 spread to the brain or containing HSV-1 replication within the brain to produce subclinical encephalitis. Our objectives are to use our novel MAIDS model of HSV-1 PORN to (1) define with certainty the fate of HSV-1 infection within retinal tissues and the extent (if any) of virus spread to brain tissues, and (2) begin to understand the contributions of key components of innate immunity in containing HSV-1 infection at the retina and/or within the brain to yield a subclinical encephalitis. These objectives will be met through successful completion of two Specific Aims: (1) determine the extent of virus spread in mice with MAIDS-related HSV-1 PORN and (2) determine the relative roles of key components of innate immunity in containing virus spread in mice with MAIDS-related HSV-1 PORN. The impact on the field of AIDS will include (1) the heretofore unrecognized role of innate immunity to contain HSV-1 spread from retina to brain and/or within the brain parenchyma during retrovirus-induced immunosuppression and (2) perhaps the heretofore unrecognized potential development of subclinical HSE in HIV-immunosuppressed patients. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page