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

• 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
• 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

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

项目主管/首席研究员（最后、第一、中）：Dix, Richard D