Date of Award

Fall 12-12-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Dr. Richard Dix

Second Advisor

Dr. Julia Hilliard

Third Advisor

Dr. John Houghton

Fourth Advisor

Dr. Homayon Ghiasi

Abstract

AIDS is associated with a number of unique sight-threatening retinal diseases that include AIDS-related human cytomegalovirus (HCMV) retinitis and AIDS-related herpes simplex virus type 1 (HSV-1) progressive outer retinal necrosis (PORN). Herein, we summarize investigations of the pathogenesis of these herpesvirus retinal diseases using mice with murine acquired immunodeficiency syndrome (MAIDS).

AIDS-related HCMV retinitis pathogenesis may involve cell death pathways. Studies were performed to test the hypothesis that parthanatos, a cell death pathway distinct from apoptosis, necroptosis, and pyroptosis, is stimulated within the ocular compartment of MAIDS mice following intraocular infection with murine cytomegalovirus (MCMV). Significant intraocular stimulation of all parthanatos-associated proteins was observed during development of MAIDS-related MCMV retinitis, but MCMV-infected eyes of corticosteroid immunosuppressed mice exhibited markedly reduced stimulation. Additional studies revealed cell-type specific parthanotos stimulation following MCMV infection. These findings suggest that ocular MCMV infection stimulates parthanatos in immunosuppressed animals during retinitis development, but stimulation is dependent on the immunosuppression method and is cell-type specific.

AIDS-related PORN is a variant of acute retinal necrosis (ARN) in immunocompetent persons. Using a laboratory HSV-1 strain (KOS-63) and a clinical HSV-1 ARN isolate (H299), we sought to develop a new animal model to investigate the pathogenesis of PORN. Intraocular HSV-1 inoculation of MAIDS mice with both HSV-1 strains produced a retinal necrosis reminiscent of AIDS-related PORN. Surprisingly, virus did not spread from retina to brain to cause acute encephalitis; all animals survived. Brains recovered from these animals showed no detectable or exceedingly small amounts of infectious virus. Macrophage deficiency did not alter this pathogenic outcome. In comparison, studies using a clinical HSV-1 isolate (H129) from a patient with herpes simplex encephalitis produced retinal disease in MAIDS mice that also progressed to acute encephalitis and death. Unlike KOS-63 and H299-infected MAIDS mice, the brains of H129-infected MAIDS mice exhibited significantly higher amounts of infectious virus. Thus, development of subclinical HSV-1 encephalitis during MAIDS appears to be virus strain-specific. These studies have led to development of a new mouse model for future studies of AIDS-related PORN pathogenesis as well as subclinical HSV-1 encephalitis pathogenesis during retrovirus-induced immunosuppression.

DOI

https://doi.org/10.57709/32638968

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