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

项目主任/主要研究者（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膜坏死。 1型单纯疱疹病毒（HSV-1）引起的坏死（PORN）。虽然感染性病毒存在于 PORN期间的视网膜组织，艾滋病患者没有发展为急性单纯疱疹病毒性脑炎（HSE），这表明 病毒要么包含在视网膜组织中，要么确实传播到大脑，但包含在神经系统中。 导致亚临床HSV-1脑炎的途径。在推进我们的社会发展方面， 对艾滋病期间HSV-1视网膜坏死维斯HSE的理解一直缺乏临床相关性， AIDS相关HSV-1视网膜坏死的动物模型。拟议项目将解决这一关键障碍， 通过使用新开发的HSV-1诱导的视网膜疾病的临床相关动物模型， 逆转录病毒诱导的免疫抑制（MAIDS）小鼠，其组织病理学模拟AIDS中的PORN 患者该项目的目标是解决与艾滋病有关的HSV-1 PORN和HSE问题， 通过获得了解先天免疫在疾病中的作用所需的信息， 阻止病毒从视网膜传播到大脑或最小化病毒在大脑内的传播以引起亚临床 使用我们的HSV-1 PORN的新型MAIDS模型，我们的核心假设是，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防止 通过阻断HSV-1传播到大脑或抑制HSV-1在大脑内复制， 产生亚临床脑炎。我们的目标是使用我们新的HSV-1 PORN MAIDS模型来（1） 确定性地确定HSV-1感染在视网膜组织内的命运和病毒传播到视网膜的程度（如果有的话）。 脑组织，（2）开始了解先天免疫的关键组成部分在包含 视网膜和/或脑内HSV-1感染，产生亚临床脑炎。这些目标将 通过成功完成两个特定目的来满足：（1）确定病毒在小鼠中传播的程度， MAIDS相关的HSV-1 PORN和（2）确定先天免疫的关键成分在MAIDS中的相对作用。 含有在患有MAIDS相关HSV-1 PORN的小鼠中传播的病毒。对艾滋病领域的影响将包括 (1)迄今未认识到先天免疫对包含HSV-1的作用从视网膜扩散到脑和/或 在逆转录病毒诱导的免疫抑制过程中脑实质内，以及（2）可能迄今为止 HIV免疫抑制患者中未被认识到的亚临床HSE的潜在发展。 PHS 398/2590（Rev.06/09）

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