SOCS and Herpesviruses, With Emphasis on Cytomegalovirus Retinitis.

Suppressor of cytokine signaling (SOCS) proteins provide selective negative feedback to prevent pathogeneses caused by overstimulation of the immune system. Of the eight known SOCS proteins, SOCS1 and SOCS3 are the best studied, and systemic deletion of either gene causes early lethality in mice. Many viruses, including herpesviruses such as herpes simplex virus and cytomegalovirus, can manipulate expression of these host proteins, with overstimulation of SOCS1 and/or SOCS3 putatively facilitating viral evasion of immune surveillance, and SOCS suppression generally exacerbating immunopathogenesis. This is particularly poignant within the eye, which contains a diverse assortment of specialized cell types working together in a tightly controlled microenvironment of immune privilege. When the immune privilege of the ocular compartment fails, inflammation causing severe immunopathogenesis and permanent, sight-threatening damage may occur, as in the case of AIDS-related human cytomegalovirus (HCMV) retinitis. Herein we review how SOCS1 and SOCS3 impact the virologic, immunologic, and/or pathologic outcomes of herpesvirus infection with particular emphasis on retinitis caused by HCMV or its mouse model experimental counterpart, murine cytomegalovirus (MCMV). The accumulated data suggests that SOCS1 and/or SOCS3 can differentially affect the severity of viral diseases in a highly cell-type-specific manner, reflecting the diversity and complexity of herpesvirus infection and the ocular compartment.

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression.

AIDS-related human cytomegalovirus retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. To study mechanisms of this disease, we used a clinically relevant animal model of murine cytomegalovirus (MCMV) retinitis with retrovirus-induced murine AIDS (MAIDS) that mimics the progression of AIDS in humans. We found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling 1 (SOCS1) and SOCS3, host proteins which hinder immune-related signaling by cytokines, including antiviral type I and type II interferons. The present study demonstrates that in the absence of retinal disease, systemic MCMV infection of mice without MAIDS, but not in mice with MAIDS, leads to mild stimulation of splenic SOCS1 mRNA. In sharp contrast, when MCMV is directly inoculated into the eyes of retinitis-susceptible MAIDS mice, high levels of intraocular SOCS1 and SOCS3 mRNA and protein are produced which are associated with significant intraocular upregulation of gamma interferon (IFN-γ) and interleukin-6 (IL-6) mRNA expression. We also show that infiltrating macrophages, granulocytes, and resident retinal cells are sources of intraocular SOCS1 and SOCS3 protein production during development of MAIDS-related MCMV retinitis, and SOCS1 and SOCS3 mRNA transcripts are detected in retinal areas histologically characteristic of MCMV retinitis. Furthermore, SOCS1 and SOCS3 are found in both MCMV-infected cells and uninfected cells, suggesting that these SOCS proteins are stimulated via a bystander mechanism during MCMV retinitis. Taken together, our findings suggest a role for MCMV-related stimulation of SOCS1 and SOCS3 in the progression of retinal disease during ocular, but not systemic, MCMV infection.IMPORTANCE Cytomegalovirus infection frequently causes blindness in untreated HIV/AIDS patients. This virus manipulates host cells to dysregulate immune functions and drive disease. Here, we use an animal model of this disease to demonstrate that cytomegalovirus infection within eyes during retinitis causes massive upregulation of immunosuppressive host proteins called SOCS. As viral overexpression of SOCS proteins exacerbates infection with other viruses, they may also enhance cytomegalovirus infection. Alternatively, the immunosuppressive effect of SOCS proteins may be protective against immunopathology during cytomegalovirus retinitis, and in such a case SOCS mimetics or overexpression treatment strategies might be used to combat this disease. The results of this work therefore provide crucial basic knowledge that contributes to our understanding of the mechanisms of AIDS-related cytomegalovirus retinitis and, together with future studies, may contribute to the development of novel therapeutic targets that could improve the treatment or management of this sight-threatening disease.

Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression.

AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models.

Murine cytomegalovirus infection of mouse macrophages stimulates early expression of suppressor of cytokine signaling (SOCS)1 and SOCS3.

Human cytomegalovirus (HCMV) is a species-specific ß-herpesvirus that infects for life up to 80% of the world's population and causes severe morbidity in at-risk immunocompromised populations. Suppressors of cytokine signaling (SOCS)1 and SOCS3 are host proteins that act as inducible negative feedback regulators of cytokine signaling and have been implicated in several ocular diseases and viral infections. We recently found in our mouse model of experimental cytomegalovirus retinitis that subretinally-injected murine cytomegalovirus (MCMV) stimulates ocular SOCS1 and SOCS3 during retrovirus-induced immune suppression of murine AIDS (MAIDS), and that infiltrating macrophages are prominent cellular sources of retinal SOCS1 and SOCS3 expression. Herein we investigate possible virologic mechanisms whereby MCMV infection may stimulate SOCS1 and/or SOCS3 expression in cell culture. We report that infection of IC-21 mouse macrophages with MCMV propagated through the salivary glands of BALB/c mice, but not from tissue culture in C57BL/6 fibroblasts, transiently stimulates SOCS1 and SOCS3 mRNA transcripts, but not SOCS5 mRNA. Viral tegument proteins are insufficient for this stimulation, as replication-deficient UV-inactivated MCMV fails to stimulate SOCS1 or SOCS3 in IC-21 macrophages. By contrast, infection of murine embryonic fibroblasts (MEFs) with either productive MCMV or UV-inactivated MCMV significantly stimulates SOCS1 and SOCS3 mRNA expression early after infection. Treatment of MCMV-infected IC-21 mouse macrophages with the antiviral drug ganciclovir significantly decreases MCMV-stimulated SOCS3 expression at 3 days post-infection. These data suggest cell type-specific, different roles for viral immediate early or early gene expression and/or viral tegument proteins in the early stimulation of SOCS1 and SOCS3 during MCMV infection. Furthermore, putative biphasic stimulation of SOCS3 during late MCMV infection of IC-21 mouse macrophages may occur by divergent virologic mechanisms.