Lytic or Latent Phase in Human Cytomegalovirus Infection: An Epigenetic Trigger

Human cytomegalovirus (HCMV) is a herpesvirus (family) belonging to the beta herpesvirus subfamily that causes significant morbidity both in immunocompromised hosts (horizontal transmission) and during vertical transmission from mother to child. HCMV has the ability to establish a permanent latent infection with its host (even for decades), in which the DNA remains as a silent nuclear episome (latent phase) until reactivation after the appropriate conditions have occurred (lytic phase). The transition between the two phases (latent/lytic) is largely determined by the type of infected cell and the health status of the host, which ultimately corresponds to the epigenetic state of the infected cells. Lytic infection of the virus normally occurs in epithelial cells, endothelial cells, fibroblasts or macrophages, whereas the latent phase occurs when undifferentiated cells of the myeloid lineage, such as CD34+ hematopoietic progenitor cells, are infected. Epigenetic regulation of the viral genome begins with the formation of chromatin in the viral DNA just 30 min after infection and then evolves towards the latent or lytic phase. DNA viruses, including members of the herpesvirus family, are currently the subject of intense study regarding the role that epigenetics plays in controlling the viral life cycle, focusing primarily on the role of post-translational modifications (PTMs) of histones, as well as DNA methylation. Within the viral genome, nucleosomes are organized for the spatial/temporal expression of appropriate genes due to epigenetic modifications. Therefore, during the infection cycle, DNA chromatinization and chromatin modifications influence the expression of genes in the HCMV genome. This process is mediated by (i) enzymes called "writers", which catalyze PTMs by adding chemical groups to proteins (acetylation, methylation, etc.); (ii) recruitment of specific transcription factors called "readers", that bind to modified amino acid residues of proteins and act as interpreters of the PTM code; and (iii) "erasers", enzymes that remove these modifications (e.g., HDACs). Indeed, recent advances in understanding the chromatin-based mechanisms of viral infections offer some promising strategies for therapeutic intervention that could be particularly useful in immunosuppressed recipients of transplants to avoid allograft rejection and infection by other opportunistic pathogens. In this review, we comprehensively examine the epigenetic regulation of the HCMV genome across distinct phases of viral infection, with particular attention to recent studies that significantly enriched the current knowledge about molecular mechanisms and future therapeutic perspectives.