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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.

Human cytomegalovirus (HCMV) is a species-specific β-herpesvirus that establishes a lifelong latent infection in ~80% of the world’s population and can cause severe opportunistic diseases in immunosuppressed patients including those with AIDS. Of these, AIDS-related HCMV retinitis is a significant ophthalmological problem worldwide. Although the clinical features of AIDS-related HCMV retinitis are well established, the virologic and immunologic events that take place during onset and development of this sight-threatening retinal disease remain poorly understood. Toward this end, an established animal model of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS) that mimics AIDS-related HCMV retinitis was used in the present investigation to test the central hypothesis that pyroptosis, as a programmed cell death pathway of innate immunity, and associated inflammasomes contribute to the onset and development of full-thickness retinal necrosis during MAIDS-related MCMV retinitis. Our findings show (i) intraocular MCMV infection stimulates key pyroptosis-associated transcripts and proteins within the eyes of retinitis-susceptible MAIDS mice but not within the eyes of retinitis-resistant mice; (ii) a deficiency in key pyroptosis-associated molecules and inflammasomes in MAIDS mice results in an atypical histopathologic pattern of retinal disease within MCMV-infected eyes characterized by preservation of the neurosensory retina without full-thickness retinal necrosis but with proliferation of the retinal pigmented epithelium; (iii) MCMV-infected eyes of corticosteroid-immunosuppressed mice display stimulation of key pyroptosis-associated molecules and inflammasomes similar to that observed for MCMV-infected eyes of mice with MAIDS; (iv) MCMV infection of IC-21 macrophages and mouse embryo fibroblasts grown in culture stimulates key pyroptosis-associated transcripts in a cell-type specific manner; and (v) increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation of a surprisingly large number of immune response genes that operate within several immune response pathways. Taken together, these results suggest that pyroptosis and associated inflammasomes play a significant role during the pathogenesis of full-thickness retinal necrosis within MCMV-infected eyes during MAIDS. These findings add new knowledge to our understanding of the contributions of programmed cell death pathways of innate immunity towards the pathogenesis of AIDS-related HCMV retinitis and may extend to other AIDS-related opportunistic virus infections.

Sight threatening human cytomegalovirus (HCMV) retinitis still remains a cause for concern among AIDS patients who do not respond to or do not have access to current antiretroviral (ART) therapy [1]. However, little is currently known about the degenerative mechanisms behind HHCMV retinal destruction during retroviral immunosuppression. The well-established murine AIDS (MAIDS) related murine cytomegalovirus (MCMV) retinitis model closely mimics disease progression seen in AIDS patients [4]. Previous work using this model has shown that while the cell death pathway apoptosis is involved in disease progression, it is not fully responsible [1]. It has been found that the mRNA of molecules associated with two other cell death pathways, necroptosis and pyroptosis, are also correlated with the pathophysiology of MAIDS-related MCMV retinitis [1]. We propose that retinal degeneration seen during CMV retinitis involves necroptosis/pyroptosis programmed cell death correlating with the increased mRNA/protein expression of associated molecules observed in this study.

AIDS-related human cytomegalovirus (HCMV) retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. Understanding the pathogenesis of this disease is essential for developing new, safe, and effective treatments for its prevention or management, yet much remains unknown about the virologic and immunologic mechanisms contributing to its pathology. To study such mechanisms, we use a well-established, reproducible, and clinically relevant animal model with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) that mimics in mice the symptoms and progression of AIDS in humans. Over 8 to 12 weeks, MAIDS mice become susceptible to experimental murine cytomegalovirus (MCMV) retinitis. We have found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling (SOCS)1 and SOCS3, host proteins which dampen immune-related signaling by cytokines, including antiviral interferons. Herein we investigated virologic and/or immunologic mechanisms involved in this stimulation and how virally-modulated SOCS1 and/or SOCS3 proteins may contribute to MCMV infection or experimental MAIDS-related MCMV retinitis. Through pursuit of two specific aims, we tested the central hypothesis that MCMV stimulates and employs SOCS1 and/or SOCS3 to induce the onset and development of MCMV retinal disease. MCMV-related SOCS1 and SOCS3 stimulation in vivo occurred with intraocular infection, was dependent on method and stage of immune suppression and severity of ocular pathology, was associated with stimulation of SOCS-inducing cytokines, and SOCS1 and SOCS3 were differentially sensitive to antiviral treatment. In vitro studies further demonstrated that SOCS1 and SOCS3 stimulation during MCMV infection occurred with expected immediate early kinetics, required viral gene expression in cell-type-dependent and virus origin-dependent patterns of expression, and displayed differential sensitivity to antiviral treatment. These data suggest that SOCS1 and SOCS3 are stimulated by divergent virologic, immunologic, and/or pathologic mechanisms during MCMV infection, and that they contribute to the pathogenesis of retinal disease, revealing new insights into the pathophysiology of AIDS-related HCMV retinitis.

Background: Cytomegalovirus retinitis (CMVR) is one of the most common opportunistic infection in immunocompromised individuals. Intravitreal ganciclovir injection has been used successfully but no standard regimen was established. Risks of drug toxicity, endophthalmitis, and injection-related complications increased with number and frequency of injection. The aim of this study is to evaluate the outcomes of reduced-dose intravitreal ganciclovir (2 mg/0.04 mL) for the treatment of CMVR. Methods: A prospective observational cohort study involving 67 eyes of 49 patients with CMVR was performed. Induction therapy involved intravenous ganciclovir (10 mg/kg/day) for 2 weeks unless contraindicated or patients refused. Patients were then treated with reduced-dose intravitreal ganciclovir every week for 4 weeks, and then every other week until the lesion healed. The patients’ demographic data were recorded, and vision parameters were examined every visit. Results: Twenty eyes (29.9 %) presented with initial visual acuities less than 6/60. The majority of patients were diagnosed with CMVR in zones 1 or 2 (63 eyes, 94 %), and, at least, one quadrant of the retina was involved (56 eyes, 83.6 %). Forty-one eyes (61.2 %) completely resolved after treatment within the 6-month follow-up. There was no significant difference in healing time, whether or not patients received induction treatment with intravenous ganciclovir (111.00 ± 12.96 vs 105.00 ± 28.32 days, p = 0.8). Five eyes (12.2 %) of patients with healed CMVR had visual acuities less than 6/60. Conclusions: Reduced-dose intravitreal ganciclovir is a safe and effective treatment option. It provides comparable results to other weekly regimens. Induction with intravenous ganciclovir is not crucial in a resolution of retinitis, although it may be necessary to reduce systemic cytomegalovirus loads and mortality rates. Trial registration: The trial was registered with Thai Clinical Trials Registry (TCTR) on 16 March 2016 – TCTR20160316001.