Cytomegalovirus replication

Human cytomegalovirus (HCMV), the prototypic member of the β-Herpesviruses, is responsible for both acute and latent infections, is one of the major infectious causes leading to birth defects and is an important opportunistic pathogen in immunocompromised individuals. The mature viral particle consists of a nucleocapsid containing a linear ds-DNA of about 235 kb surrounded by a protein layer, the so-called tegument, which, in turn, is enclosed in a lipid bilayer containing numerous viral glycoproteins. The HCMV genome is expressed through a cascade of transcriptional events leading to the synthesis of three categories of viral proteins designated as immediate-early (IE or α), early (E or β) and late (L or γ) proteins. Using advanced technologies that can manipulate large Herpesviruses genomes, functional analysis studies of all HCMV ORFs performed in the context of the viral genome have identified the virus’s requirements for productive replication in cell culture. About 40% of the HCMV genes essential for replication were found clustered in the central region of the genome. They encode functions related to viral DNA metabolism and replication, structural organization and maturation of virions. Since these core genes are highly conserved across all Herpesviruses, they may correspond to a minimal Herpesvirus genome required for replication and assembly. DNA microarray-based technology has provided a systematic comprehensive view of the changes in host gene activity profiles following HCMV infection. These analyses revealed that HCMV profoundly modifies cellular gene expression, leading to morphological changes and stress response of the infected cell. HCMV infection also alters several biochemical pathways, including activation of receptor tyrosine kinase and mitogen-activated protein kinase signaling, stimulation of transcription factor activity, expansion of deoxyribonucleotide pools, induction of prostaglandins synthesis, induction of cytokines and stimulation of interferon-responsive gene expression, and activation of the innate immune response. HCMV exploits this plethora of changes to facilitate the progression of its replication cycle and to provide an intracellular environment favorable for its DNA replication.