Abstract
Human cytomegalovirus (HCMV) is an opportunistic human herpesvirus that causes a sight-threatening retinitis in immunosuppressed patients, especially those with AIDS. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS), we have been attempting to define with greater clarity the immunologic mechanisms that contribute to the progression of AIDS-related HCMV retinitis in the unique immunosuppressive setting of HIV infection. Toward this end, we provide herein a comprehensive assessment of immune response gene expression during the onset and development of MAIDS-related MCMV retinitis employing NanoString nCounter. In so doing, we analyzed and compared the intraocular expressions of 561 immune response genes within MCMV-infected eyes of groups of healthy mice, MCMV-infected mice with MAIDS of 4 weeks’ (MAIDS-4) duration, and MCMV-infected eyes of mice with MAIDS of 10 weeks’ (MAIDS-10) duration. These animal groups show a progression of retinal disease from absolute resistance to retinitis development in healthy mice to the development of classic full-thickness retinal necrosis in MAIDS-10 mice but through an intermediate stage of retinal disease development in MAIDS-4 mice. Our findings showed that increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation or downregulation of a surprisingly large number of immune response genes that operate within several immune response pathways often unique to each animal group. Analysis of 14 additional immune response genes associated with programmed cell death pathways suggested involvement of necroptosis and pyroptosis during MAIDS-related MCMV retinitis pathogenesis. Use of the NanoString nCounter technology provided new and unexpected information on the immunopathogenesis of retinitis within MCMV-infected eyes of mice with retrovirus-induced immunosuppression. Our findings may provide new insights into the immunologic events that operate during the pathogenesis of AIDS-related HCMV retinitis.
Highlights
The unique immunosuppressive environment created by HIV infection during the development of AIDS resulted in the emergence of a significant number of diseases caused by opportunistic viruses that prior to AIDS were no more than rare medical curiosities
While the clinical and histopathologic features of AIDSrelated human cytomegalovirus (HCMV) retinitis have been well documented, the immunologic mechanisms that continue to operate during HIV-induced immunosuppression and contribute to the onset and development of retinal tissue destruction caused by ocular HCMV infection in patients with AIDS remain unexplored
We report the first comprehensive analysis of a total of 571 immune response genes that are expressed during the pathogenesis of experimental murine cytomegalovirus (MCMV) retinitis in mice at different stages of retrovirus-induced immunosuppression (MAIDS) who exhibit different susceptibilities to retinal disease development
Summary
The unique immunosuppressive environment created by HIV infection during the development of AIDS resulted in the emergence of a significant number of diseases caused by opportunistic viruses that prior to AIDS were no more than rare medical curiosities. MAIDS-related MCMV retinitis mimics AIDS-related HCMV retinitis in many ways These include the appearance of generalized lymphadenopathy, polyclonal B cell activation, hypergammaglobulinemia, and a Th1 to Th2 shift in cytokine profile accompanied by progressive dysfunction of cellular immunity that takes place over weeks following systemic infection with an immunosuppressive murine retrovirus mixture [14]. These events culminate in the development of MAIDS by 8 to 10 weeks after retrovirus infection that allows susceptibility to a retinitis in eyes inoculated with MCMV [15].
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