Human cytomegalovirus (HCMV) persists as a subclinical, lifelong infection in the normal human host, maintained at least in part by its carriage in the absence of detectable infectious virus – the hallmark of latent infection. Reactivation from latency in immunocompromised individuals, in contrast, often results in serious disease. Latency and reactivation are defining characteristics of the herpesviruses and key to understanding their biology. However, the precise cellular sites in which HCMV is carried and the mechanisms regulating its latency and reactivation during natural infection remain poorly understood. This review will detail our current knowledge of where HCMV is carried in healthy individuals, which viral genes are expressed upon carriage of the virus and what effect this has on cellular gene expression. It will also address the accumulating evidence suggesting that reactivation of HCMV from latency appears to be linked intrinsically to the differentiation status of the myeloid cell, and how the cellular mechanisms that normally control host gene expression play a critical role in the differential regulation of viral gene expression during latency and reactivation.

Human cytomegalovirus (HCMV) persists as a subclinical, lifelong infection in the normal human host, but reactivation from latency in immunocompromised subjects results in serious disease. Latency and reactivation are defining characteristics of the herpesviruses and are key to understanding their biology; however, the precise cellular sites in which HCMV is carried and the mechanisms regulating its latency and reactivation during natural infection remain poorly understood. Here we present evidence, based entirely on direct analysis of material isolated from healthy virus carriers, to show that myeloid dendritic cell (DC) progenitors are sites of HCMV latency and that their ex vivo differentiation to a mature DC phenotype is linked with reactivation of infectious virus resulting from differentiation-dependent chromatin remodeling of the viral major immediate-early promoter. Thus, myeloid DC progenitors are a site of HCMV latency during natural persistence, and there is a critical linkage between their differentiation to DC and transcriptional reactivation of latent virus, which is likely to play an important role in the pathogenesis of HCMV infection.

Human cytomegalovirus (HCMV) is a frequent cause of major disease following primary infection or reactivation from latency in immunocompromised patients. Infection of non-permissive mononuclear cells is used for analyses of HCMV latency in vitro. Using this approach, it is shown here that repression of lytic gene expression following experimental infection of CD34⁺ cells, a site of HCMV latency in vivo, correlates with recruitment of repressive chromatin around the major immediate-early promoter (MIEP). Furthermore, long-term culture of CD34⁺ cells results in carriage of viral genomes in which the MIEP remains associated with transcriptionally repressive chromatin. Finally, specific differentiation of long-term cultures of infected CD34⁺ cells to mature dendritic cells results in acetylation of histones bound to the MIEP, concomitant loss of heterochromatin protein 1 and the reactivation of HCMV. These data are consistent with ex vivo analyses of latency and may provide a model for further analyses of the mechanisms involved during latency and reactivation.

Human cytomegalovirus (HCMV) is an opportunistic human pathogen that establishes a lifelong latent infection, which can reactivate periodically. If unchecked by a robust immune response, this reactivation can result in severe disease in immunocompromised patients. Reactivation of latent virus in myeloid progenitor cells is concomitant with cellular differentiation through regulation of the major immediate-early promoter (MIEP) by chromatin remodelling. In this study, we analysed the expression of the latent gene transcript UL81–82as (LUNA). LUNA is expressed in latently infected CD34+ cells and its expression decreases as CD34+ cells differentiate to immature dendritic cells. Upon maturation (and HCMV reactivation), a second wave of transcription occurs, consistent with expression during lytic infection. Furthermore, we show that the LUNA promoter is associated with acetylated histones during HCMV latency in experimentally and naturally infected CD34+ cells, thus suggesting that latent gene promoters are, like the MIEP, regulated by post-translational modifications of their associated histone proteins.