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

艾滋病相关的 HSV-1 视网膜坏死：先天免疫和病毒传播

基本信息

批准号：
10328549
负责人：
Richard D Dix
金额：
$ 23.4万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328549
关键词：
AIDS dementia Acquired Immunodeficiency Syndrome Acute Acute Retinal Necrosis Syndrome Address Animal Model Biological Assay Brain Clinical DNA Development Diagnostic tests Encephalitis Evolution Eye Goals HIV Herpes encephalitis Herpesvirus 1 Immunocompromised Host Immunosuppression Incidence Infection Investigation JC Virus Lead Mediating Messenger RNA Methods Mission Modeling Mus Natural Immunity Necrosis Neural Pathways Optic Nerve Patients Pattern Performance Peripheral Plaque Assay Principal Investigator Progressive Multifocal Leukoencephalopathy Public Health RIPK3 gene Retina Retinal Diseases Retroviridae Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Site Testing Time Tissues Transactivation Travel United States National Institutes of Health Variant Virus Virus Diseases Virus Replication Western Blotting acute symptom antiretroviral therapy brain parenchyma brain tissue chemokine clinically relevant cytokine macrophage mouse development nano-string nervous system disorder novel novel therapeutic intervention prevent programs seropositive virus-induced neurologic disease

项目摘要

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

计划主任/首席研究员（最后，第一，中间）：DIX，理查德·D 项目摘要艾滋病患者可以开发出急性视网膜坏死（ARN）设计的变体。由单纯疱疹病毒1型（HSV-1）引起的坏死（色情）。尽管传染病中存在于色情期间的视网膜组织，艾滋病患者无法发展出急性疱疹单纯脑炎（HSE）病毒要么包含在视网膜时机内，要么确实传播到大脑，但包含在神经内引起亚临床HSV-1脑炎的途径。进步前进的关键障碍在艾滋病期间对HSE HSE的HSV-1视网膜坏死的理解是缺乏临床相关的与AIDS相关的HSV-1视网膜坏死的动物模型。拟议的项目将解决这个关键障碍通过使用新开发和临床相关的HSV-1诱导的残留疾病的动物模型来进步带有逆转录病毒引起的免疫抑制（女仆）的小鼠组织病理学模仿艾滋病中的色情患者。该项目的目的是解决与艾滋病有关的HSV-1色情和HSE的问题以及通过获得理解先天免疫作用所需的信息来实现进步的关键障碍停止病毒从视网膜传播到大脑或最小化病毒在大脑内传播以引起亚临床脑炎使用我们的新型女仆HSV-1色情片。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期间起作用的先天免疫的成分通过阻止HSV-1扩散到大脑的急性HSE，或在大脑内包含HSV-1复制到产生亚临床脑炎。我们的目标是将我们的新颖女仆模型用于（1）确定视网膜时间内HSV-1感染的命运以及病毒的程度（如果有）扩散到脑组织，（2）开始了解含有先天免疫的关键组成部分的贡献视网膜和/或大脑内的HSV-1感染，产生亚临床脑炎。这些目标将是通过成功完成两个具体目标，以满足：（1）确定小鼠病毒扩散的程度与女仆有关的HSV-1色情和（2）确定先天免疫关键组成部分的相对角色包含与女仆相关的HSV-1色情片中传播的病毒。对艾滋病领域的影响将包括（1）迄今为止，先天免疫的作用含有从视网膜到大脑和/或在逆转录病毒诱导的免疫抑制期间，在脑实质中，（2）也许是迄今在HIV免疫抑制患者中，亚临床HSE的潜在发展无法识别。 PHS 398/2590（修订版06/09）页面延续格式页面