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--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
Dix, Richard D Project Narrative HIV-immunosuppressed patients suffer from a number of virus-induced neurologic diseases but rarely develop herpes simplex encephalitis (HSE) caused by herpes simplex virus type 1(HSV-1) even when HSV-1-induced retinal disease occurs and virus should easily spread from retina to brain through the optic nerve. The proposed project is relevant to public health because its performance will demonstrate for the first time that one or more components of innate immunity that operate during AIDS either prevents virus spread from a peripheral site of infection (e.g., retina) to the brain or decreases the amount of virus within the brain to allow brain infection without development of acute encephalitis. The project is relevant to the NIH mission because its performance could lead to better diagnostic tests and new therapeutic approaches to lessen HSV-1 spread to the brain during AIDS and thereby reduce the clinical impact of HSV-1 neurological disease on other AIDS- related neurologic diseases of virus origin including HIV-associated dementia. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
