Cytomegalovirus-induced immunopathology and its clinical consequences

Human cytomegalovirus (CMV) is a widespread agent that belongs to the Herpesviridae family [1]. Viral proteins are expressed in the immediate early (IE), early (E), and late (L) phases of CMV infection. Its genome contains more than 200 potential reading frames from which effector proteins can be generated, but merely one-quarter is committed to replication [2,3]. Thus, the majority of viral proteins potentially modulates cellular responses in the host; of all herpesviruses, CMV expresses the most genes that alter innate and adaptive host immune responses [4].During the acute phase of CMV infection, many cell types in an organ system can be infected, including endothelial cells, epithelial cells, smooth muscle cells, fibroblasts, neuronal cells, hepatocytes, trophoblasts, monocytes/macrophages (M？s), and dendritic cells (DCs) [5]. The virus typically is acquired early in life and can be transmitted by direct or indirect contact with infected body fluids. There are 3 forms of active CMV infection: a) primary infection, which occurs when the virus infects a CMV-naive host; b) endogenous infection in CMV-seropositive individuals who experience reactivation from latency, and c) exogenous reinfection in previously infected individuals who experience infection by a different strain [6].Recent evidence shows that active and latent CMV infection induces sustained systemic inflammatory responses that are accompanied by a type 1 cytokine signature [7]. Viral persistence is established in all infected individuals and is chronically productive or occurs as a latent infection in which viral gene expression is limited [8].Initiation of viral replication from latency not only is caused by immunosuppression but, like other viruses, such as HIV [9], also appears to be linked to activation of the immune system. For example, the virus can be reactivated by tumor necrosis factor (TNF)- α, which is released during inflammation. TNF-α binds to the TNF receptor on latently infected cells,