Human Cytomegalovirus Biology and Pathogenesis

Human cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus with a large double-stranded DNA genome encoding over 160 proteins and multiple non-coding RNAs. After primary infection, usually asymptomatic in healthy individuals, the virus enters a lifelong cycle of latency and reactivation. Latency is established predominantly in CD34+ haematopoietic progenitor cells and their CD14+ derivatives, where the viral genome is maintained in a transcriptionally repressed state through epigenetic mechanisms. Reactivation can be triggered by inflammation, cell differentiation or immunosuppression, leading to lytic replication in fibroblasts, endothelial and epithelial cells. This process follows an ordered cascade of immediate-early, early and late gene expression that drives DNA replication, virion assembly and release. HCMV employs multiple immune evasion strategies, including downregulation of antigen presentation, modulation of cytokine networks and interference with interferon signalling. The virus’s broad cell tropism and ability to manipulate host chromatin and innate sensors underlie its pathogenesis, contributing to severe outcomes in transplant recipients and congenital infection. Current therapies target the viral polymerase or terminase complex but are limited by toxicity and resistance, underscoring the need for new interventions that disrupt key host–virus interactions.

Research from Nature Portfolio

Recent work has revealed how HCMV subverts innate immune sensing in monocyte-derived dendritic cells. Single-cell RNA sequencing has shown that viral entry activates the STING pathway and induces a transient interferon-stimulated gene response, yet HCMV rapidly inhibits interferon-beta transcription and downstream antiviral effectors to facilitate productive infection. A distinct subset of dendritic cells displays heightened permissiveness, linked to differential regulation of both pro- and antiviral host genes. These findings illuminate the dynamic interplay between viral gene expression and host immune signalling and point to novel targets for enhancing antiviral defences.

Human Cytomegalovirus Biology and Pathogenesis publication trend

The graph below shows the total number of articles in human cytomegalovirus biology and pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Latency: A reversible state in which the viral genome persists in host cells with minimal gene expression.

Lytic cycle: The phase of infection characterised by active viral gene expression, genome replication and production of infectious virions.

STING (stimulator of interferon genes): A host adaptor protein that senses cytosolic DNA and activates interferon responses.

Epigenetic repression: Silencing of gene expression through chemical modifications of DNA or histones without altering the genetic code.

Monocyte-derived dendritic cells: Immune cells differentiated from monocytes that present antigens and initiate antiviral responses.

Reactivation: The process by which latent virus resumes active replication, often triggered by cellular stress or differentiation.

References

1. Human cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells. Nature Communications (2024).
2. Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response. Frontiers in Cellular and Infection Microbiology (2020).
3. Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing. mBio (2018).
4. Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation. Viruses (2018).
5. Cis and Trans Acting Factors Involved in Human Cytomegalovirus Experimental and Natural Latent Infection of CD14 (+) Monocytes and CD34 (+) Cells. PLOS Pathogens (2013).
6. Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch. eLife (2015).
7. A Novel Human Cytomegalovirus Locus Modulates Cell Type-Specific Outcomes of Infection. PLOS Pathogens (2011).
8. High-Definition Analysis of Host Protein Stability during Human Cytomegalovirus Infection Reveals Antiviral Factors and Viral Evasion Mechanisms. Cell Host & Microbe (2018).