An experimental mouse model of AIDS-related progressive outer retinal necrosis (PORN) shows evidence for subclinical herpesvirus encephalitis

Abstract

Purpose : Progressive outer retinal necrosis (PORN) in AIDS patients is a variant of acute retinal necrosis (ARN) in immunocompetent patients. ARN caused by herpes simplex virus type 1 (HSV1) has been associated with subclinical herpes simplex encephalitis (HSE). We therefore sought to develop a new animal model of HSV1 retinal necrosis in mice with retrovirus-induced immunosuppression (MAIDS) that mimics AIDS-related PORN and investigate the possible development and pathogenesis of subclinical HSE during HSV1 PORN as seen during HSV1 ARN.

Methods : Following anterior chamber inoculation of right eyes of groups of C57BL/6 mice with MAIDS with 10⁴ PFU of either HSV1 [KOS] or HSV1 [H299] (ARN-associated clinical isolate), the inoculated right eyes, right brain halves, left brain halves, and uninoculated left eyes were collected at 3, 5, 7, or 10 days postinfection (pi) and subjected to standard plaque assay or histopathologic analysis.

Results : Histopathologic analysis of HSV1 [KOS]- or HSV1 [H299]-infected right eyes of mice with MAIDS at 10 days pi revealed retinal disease reminiscent of AIDS-related PORN in ~80% of inoculated animals whereas all uninoculated left eyes showed normal retinal architecture. Although HSV1 [KOS]- or HSV1 [H299]-infected right eyes of MAIDS mice showed consistently high amounts of infectious virus ranging from 10³ to 10⁵ PFU, right brain halves in comparison showed little (<10² PFU) to no detectable infectious virus. Significantly, none (0%) of the HSV1 [KOS] or HSV1 [H299] uniocular-infected animals showed evidence for acute HSE.

Conclusions : We have successfully developed a clinically relevant mouse model for AIDS-related HSV1 PORN using mice with MAIDS that also shows evidence for subclinical HSE. The mouse model is not virus strain dependent. Studies are ongoing to define with greater clarity the development of subclinical HSE during MAIDS-related HSV1 PORN and identify those factors of innate immunity that prevent or minimize virus spread from retina to brain and protect against acute HSE development with focus on macrophages and related cytokines/chemokines as well as programmed cell death pathways.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.