The cytomegaloviruses (CMVs), a genus of members of a beta herpesvirus family, adapted perfectly to their mammalian hosts during millions of years of coevolution. Human cytomegalovirus (HCMV; officially Human betaherpesvirus 5) became a ubiquitous human pathogen with seroprevalence ranging from 56% to 94% [1]. The virus developed multiple immune-modulatory strategies to escape mechanisms the immune system employs to fight HCMV infection 2, 3, 4. Upon penetration into the organism predominantly through mucosal surfaces, HCMV manages to disseminate, infect various organs, and eventually establish a latency, hiding from the virus-specific T cells and antibodies (Figure 1a). The virus thus remains within the organism for the host’s lifetime, requiring constant immunosurveillance to remain in the latent state [2]. HCMV is, therefore, a major cause of disease in immunosuppressed adults and vulnerable groups such as low birth-weight infants and congenitally infected unborn fetuses [5].

Understanding the mechanisms by which the immune system successfully controls, or fails to clear, a given viral pathogen benefits greatly from the visualization of infection location. The use of tailor-made, reporter CMV mutants enabled numerous new insights into mechanisms of viral penetration into the cells, immune system-mediated protection, viral immune evasion, and latency. Especially potent proved to be in vivo models using reporter mutants of murine cytomegaloviru (MCMV; Figure 1b), a natural mouse pathogen that serves as a reliable model for HCMV disease 6, 7. As discussed in this review, the combination of reporter CMV strains, various genetically modified mice, and advanced microscopy techniques, such as two-photon microscopy, proved to be essential for the understanding of all stages of CMV infection and protective immune response at the single-cell level.