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What have we learned from scid mouse4/18/2024 The original HCMV humanized mouse models involved SCID (severe combined immunodeficient) mice engrafted with either human peripheral blood leukocytes (SCID-hu-PBL model) or with human fetal thymic and liver tissues (SCID-huThy/Liv model) 23, 24, 25. The strict species specificity of HCMV and the lack of surrogate CMV animal models have driven the development of humanized mouse models in which mice are engrafted with human cells or tissues capable of supporting local HCMV infection (reviewed in ref. Development of humanized mouse models in which mice are engrafted with human cells or tissues have been shown to be capable of supporting human-tropic viral infections and modeling the human immune response for a number of viruses in the relevant cellular contexts 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. Generation of huBLT mice has been instrumental for the direct in vivo investigation of viruses with growth restricted to human cells. The development of CMV-specific T-cell responses in rhesus macaques is slightly different as both CD4+ and CD8+ CMV-specific T-cells appear at high frequency during primary infection and then persist indefinitely at high levels 7. Similarly, during maturation of the immune response in murine cytomegalovirus (MCMV)-infected mice, CMV-specific CD8+ T-cells assume a steadily increasing percentage of the overall T-cell pool in a process termed “memory inflation” 5 (reviewed by ref. Interestingly, these responses expand over time thus overcoming normal T-cell exhaustion. These anti-CMV T-cell responses are phenotypically unique, characterized by their mature effector memory phenotype. In CMV infected individuals, both the CD4 and CD8 memory T-cell compartments including blood and tissues contain approximately 10% CMV-specific CD8 T-cells 4. Following primary CMV infection, the virus establishes a large CD4+ and CD8+ T-cell response that is maintained for the life of the host 3. However, CD8+ and CD4+ T-cell responses, antiviral antibodies, and natural cytotoxicity have all been shown to have a potential role in controlling HCMV replication 2. Specific immunological determinants that predispose individuals to infection and disease remain incompletely characterized. Populations susceptible to severe HCMV infections include transplant recipients undergoing immunosuppressive therapy, HIV-infected individuals, and the developing fetus 1. Human cytomegalovirus (HCMV) is a prototypical betaherpesvirus and a ubiquitous opportunistic pathogen. These results indicate that the HCMV huBLT mouse model may provide a valuable tool to study viral latency and reactivation as well as evaluate HCMV vaccines and immune responses in the context of a functional human immune system. Additionally, both HCMV specific IgM and IgG B-cell responses with the ability to neutralize virus were detected. Following infection, huBLT mice generate human effector and central memory CD4+ and CD8+ T-cell responses reactive to peptides corresponding to both IE and pp65 proteins. In this study, we characterized the functional human adaptive immune responses in HCMV latently-infected huBLT (humanized Bone marrow-Liver-Thymus) mice. We have previously shown that HCMV infection of human hematopoietic progenitor cells engrafted in immune deficient mice (huNSG) results in viral latency that can be reactivated following G-CSF treatment. The strict species specificity of Human Cytomegalovirus (HCMV) has impeded our understanding of antiviral adaptive immune responses in the context of a human immune system.
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