from Christof K. Seckert, Marion Grieβl, Julia K. Büttner, Kirsten Freitag and Niels A.W. Lemmermann and Mary A. Hummel, Xue-Feng Liu and Michael I. Abecassis and Ana Angulo and Martin Messerle and Charles H. Cook and Matthias J. Reddehase writing in Cytomegaloviruses: From Molecular Pathogenesis to Intervention:
Cytomegalovirus (CMV) disease with cytopathogenic viral replication and multiple organ involvement is typically confined to the immunocompromised or immunologically immature host. In the immunocompetent host, productive primary CMV infection is efficiently controlled, and is eventually resolved at all tissue sites, by well-orchestrated mechanisms of the innate and adaptive branches of the immune system in due time to prevent overt disease manifestations. At the earliest stages of an acute infection, NK cells rapidly followed by virus epitope-specific CD8+ T cells play major antiviral roles, and recent findings indicate that these two effector systems are cross-talking for keeping the virus in check despite the fact that during co-speciation with their specific host species all CMVs have evolved strategies to reduce the infected cells' susceptibility to both NK cell-mediated and CD8+ T cell-mediated antiviral immune functions. The outcome of this virus-host struggle for survival is a ceasefire in which the viral genome is not cleared but is maintained for the lifetime of the individual host in the presence of a fully developed, protective antiviral 'immune memory' without producing infectious viral progeny but retaining the functional capacity to complete the productive replication cycle under conditions of waning immune surveillance and transcription factor-mediated viral gene desilencing as a result of inflammatory cytokine signaling. These phenomena, known as 'latency' and 'reactivation' are biological hallmarks that CMVs share with all other members of the herpesvirus family. Notably, while immune surveillance appears to play a central role in maintaining latency, that is in preventing the virus from completing the productive replication cycle and, if it nevertheless should happen locally, preventing recurrent virus from further rounds of infection and spreading, increasing evidence suggests that the establishment of latency on the molecular level may not be immune-driven. Rather, molecular latency results from the cells' intrinsic antiviral defense by epigenetic silencing of viral gene expression associated with rapid circularization and chromatinization of incoming linear viral genomes within repressive nuclear domains. In this view, 'latency' is the default state, whereas productive infection, from the hosts' perspective, is the accident when viral genomes evade epigenetic silencing, with the chance for this being dependent on cell type, cell differentiation stage, cell cycle stage, and an overall nuclear environment that favors open chromatin structures, collectively defining what we describe as 'permissively' for productive infection. It is proposed that during latency stochastic episodes of promiscuous desilencing of single or combinatorial sets of viral genes can lead to the expression of transcripts (transcript expressed in latency, TEL), which, when translated into proteins, can result in the presentation of antigenic peptides sensed by tissue-patrolling effector-memory T cells. Importantly, promiscuous gene desilencing, unlike reactivation, does not usually initiate the productive viral replication cycle and can affect any viral gene regardless of its temporal expression in the kinetic classes immediate-early (IE), early (E) and late (L), and regardless of the function it takes during lytic infection. It is our current understanding that these limited desilencing episodes are the molecular motor that drives the CMV-typic expansion of T cells, of CD8+ T cells in particular, a phenomenon commonly known under the catchphrase 'memory inflation'. The 'classical era' of research in diverse murine models of CMV latency and reactivation has been reviewed by Jordan (1983) and authors of this review have provided updates (Hummel and Abecassis, 2002; Reddehase et al., 2002; 2008). Here, independent research groups have joined to review their more recent results and current views on CMV latency and reactivation based on murine CMV models with focus on neonatal infection, hematopoietic (stem) cell transplantation (HCT), solid organ transplantation (SOT), and sepsis.
Further reading: Cytomegaloviruses: From Molecular Pathogenesis to Intervention