Molecular Mechanisms of Herpesvirus Latency and Reactivation: From Host-Virus Interactions to Therapeutic Targets

Herpesviruses establish lifelong infection by entering latency, a state of restricted viral gene expression that supports persistence despite immune pressure. Periodic reactivation drives recurrent disease, transmission, and in immunocompromised settings, severe morbidity. While many correlates of latency and reactivation have been described, causal mechanisms and regulatory hierarchies remain incompletely defined. A sharper mechanistic understanding is needed to connect host virus interactions to clinically meaningful intervention, including strategies that prevent reactivation, reduce reservoir stability, or limit disease severity.

This Research Topic focuses on mechanistic studies of latency and reactivation in clinically relevant human herpesviruses, with emphasis on HSV 1, HSV 2, EBV, CMV, and HHV 8 (or KSHV), given its importance in immunocompromised settings including HIV infection. Other herpesviruses may be considered when they are used as a strong model system for human herpesvirus infection and when the work delivers clear mechanistic insight into latency, reactivation competence, or host virus control.

We welcome contributions that define causal regulators and regulatory hierarchies, map host virus interactions that shape latent and reactivation competent states, and identify actionable pathways for therapeutic targeting. Studies may use experimental virology, functional genomics, single cell and spatial profiling, and integrative modelling, provided they are anchored in clear biological questions and support mechanistic conclusions.

We encourage submissions on:
1. Epigenetic and chromatin control of latent viral genomes, histone marks, chromatin remodelers, nuclear organization.
2. Viral and host non coding RNAs, miRNAs, and RNA based regulatory circuits.
3. Transcriptional and post transcriptional switches that gate entry into latency and reactivation competence.
4. Host stress, inflammatory, metabolic, and differentiation pathways that trigger reactivation, with causal evidence.
5. Immune surveillance, immune evasion, and persistence mechanisms that shape latent reservoirs.
6. Single cell, spatial, and longitudinal profiling linked to functional validation of regulators and transitions.
7. Mechanistic modelling and network inference that generates testable predictions, ideally supported by experimental validation.
8. Therapeutic targets and strategies supported by mechanistic rationale, including small molecules, biologics, and genome targeting approaches.

Scope note
This Topic prioritizes Original Research and Reviews that advance mechanistic understanding and propose testable models. Meta analyses, and submissions that are primarily descriptive without mechanistic advancement, are out of scope for this collection.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Editorial
• FAIR² Data
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Editorial
• FAIR² Data
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Herpesvirus latency, Reactivation, Host–virus interactions, Epigenetic regulation, Viral reservoirs, Immune evasion

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.