Herpesvirus Latency and Reactivation

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 4631

Special Issue Editors


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Guest Editor
School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China
Interests: human herpesviruses; virus–host interactions; latency; reactivation; pathogenesis
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL, USA
Interests: cGAS-STING; herpesviruses; KSHV; oncogenesis
Department of Biopharmaceutical Sciences, College of Pharmacy, Jinan University No. 601, West Huangpu Avenue, Guangzhou 510632, China
Interests: human cytomegalovirus; herpesvirus; molecular virology; virus–host interaction

Special Issue Information

Dear Colleagues,

Herpesviridae is a large family of DNA viruses that infect a wide variety of hosts. Herpesviruses can cause various diseases including skin lesions, respiratory syndrome, reproductive diseases, neurological disorders, and cancers. A hallmark of all known herpesviruses is their ability to establish a lifelong latency in hosts. During latency, the viral genome is maintained in infected cells without causing cell death, but the expression of viral genes contributes to herpesvirus-associated diseases. Additionally, reactivation from latency periodically occurs, resulting in the production and transmission of infectious virus particles, which usually causes severe clinical symptoms.
This Special Issue aims to present the latest research on herpesvirus latency and reactivation. Developing a better understanding of herpesvirus–cell interactions will be crucial for the prevention and control of herpesvirus-associated diseases. Manuscripts of all types are welcome, including reviews, research articles, and short communications. We look forward to your valuable contributions.

Dr. Yonggang Pei
Dr. Zhe Ma
Dr. Jun Chen
Guest Editors

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Keywords

  • herpesviruses
  • latency
  • reactivation
  • virus–cell interactions
  • EBV
  • cytomegalovirus
  • HHV-6/7
  • KSHV
  • pathogenesis
  • antiviral therapies

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Published Papers (4 papers)

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Research

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12 pages, 2254 KiB  
Article
Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2
by Yuejia Cao, Shihan Shao, Yingying Zhang, Dandan Song, Fei Gui, Xinyi Chen, Yu Hong, Rong Chen, Yang Song, Dongmei Li, Xiaohua Tan and Chunhong Di
Pathogens 2025, 14(6), 590; https://doi.org/10.3390/pathogens14060590 - 15 Jun 2025
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Abstract
Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. [...] Read more.
Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. Although studies reported that KSHV infection enhanced cellular resistance to ferroptosis, the specific role of LANA in this process remains unexplored. Here, we demonstrate that LANA unexpectedly promotes ferroptosis. In KSHV-positive iSLK.219 cells, LANA knockdown significantly attenuated RSL-3-induced ferroptosis, whereas LANA overexpression sensitized HeLa cells to ferroptotic death. Quantitative analysis revealed that LANA-depleted cells exhibited significantly elevated ROS accumulation (p < 0.01), whereas LANA-overexpressing cells maintained reduced ROS levels during challenge with the ferroptosis inducer RSl-3. Mechanistically, LANA suppressed glutathione peroxidase 4 (GPX4) expression, reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and impaired its nuclear translocation, and upregulated mouse double minute 2 homolog (MDM2) expression. Pharmacological inhibition of Nrf2 (ML385) or MDM2 (nutlin3a) reversed the ferroptotic effects of LANA knockdown or overexpression, respectively. These findings reveal a pro-ferroptotic role of LANA via Nrf2/GPX4 suppression and MDM2 activation. Full article
(This article belongs to the Special Issue Herpesvirus Latency and Reactivation)
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Review

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34 pages, 981 KiB  
Review
Applying CRISPR Technologies for the Treatment of Human Herpesvirus Infections: A Scoping Review
by Chloë Hanssens and Jolien Van Cleemput
Pathogens 2025, 14(7), 654; https://doi.org/10.3390/pathogens14070654 - 1 Jul 2025
Abstract
Background: Human herpesviruses are double-stranded DNA viruses of which eight types have been identified at present. Herpesvirus infection comprises an active lytic phase and a lifelong latency phase with the possibility of reactivation. These infections are highly prevalent worldwide and can lead to [...] Read more.
Background: Human herpesviruses are double-stranded DNA viruses of which eight types have been identified at present. Herpesvirus infection comprises an active lytic phase and a lifelong latency phase with the possibility of reactivation. These infections are highly prevalent worldwide and can lead to a broad spectrum of clinical manifestations, ranging from mild symptoms to severe disease, particularly in immunocompromised individuals. Clustered regularly interspaced palindromic repeats (CRISPR)-based therapy is an interesting alternative to current antiviral drugs, which fail to cure latent infections and are increasingly challenged by viral resistance. Objective: This scoping review aimed to summarize the current state of CRISPR-based antiviral strategies against herpesvirus infections, highlighting the underlying mechanisms, study design and outcomes, and challenges for clinical implementation. Design: A literature search was conducted in the databases PubMed and Web of Science, using both a general and an individual approach for each herpesvirus. Results: This scoping review identified five main mechanisms of CRISPR-based antiviral therapy against herpesvirus infections in vitro and/or in vivo. First, CRISPR systems can inhibit the active lytic replication cycle upon targeting viral lytic genes or host genes. Second, CRISPR technologies can remove latent viral genomes from infected cells by targeting viral genes essential for latency maintenance or destabilizing the viral genome. Third, reactivation of multiple latent herpesvirus infections can be inhibited by CRISPR-Cas-mediated editing of lytic viral genes, preventing a flare-up of clinical symptoms and reducing the risk of viral transmission. Fourth, CRISPR systems can purposefully induce viral reactivation to enhance recognition by the host immune system or improve the efficacy of existing antiviral therapies. Fifth, CRISPR technology can be applied to develop or enhance the efficiency of cellular immunotherapy. Conclusions: Multiple studies demonstrate the potential of CRISPR-based antiviral strategies to target herpesvirus infections through various mechanisms in vitro and in vivo. However, aspects regarding the delivery and biosafety of CRISPR systems, along with the time window for treatment, require further investigation before broad clinical implementation can be realized. Full article
(This article belongs to the Special Issue Herpesvirus Latency and Reactivation)
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12 pages, 517 KiB  
Review
Recent Advances in the Study of Alphaherpesvirus Latency and Reactivation: Novel Guidance for the Design of Herpesvirus Live Vector Vaccines
by Shinuo Cao, Mo Zhou, Shengwei Ji, Dongxue Ma and Shanyuan Zhu
Pathogens 2024, 13(9), 779; https://doi.org/10.3390/pathogens13090779 - 10 Sep 2024
Cited by 2 | Viewed by 2596
Abstract
Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV), infect a diverse array of hosts, spanning both humans and animals. Alphaherpesviruses have developed a well-adapted relationship with their hosts through long-term evolution. Some alphaherpesviruses [...] Read more.
Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV), infect a diverse array of hosts, spanning both humans and animals. Alphaherpesviruses have developed a well-adapted relationship with their hosts through long-term evolution. Some alphaherpesviruses exhibit a typical neurotropic characteristic, which has garnered widespread attention and in-depth research. Virus latency involves the retention of viral genomes without producing infectious viruses. However, under stress, this can be reversed, resulting in lytic infection. Such reactivation events can lead to recurrent infections, manifesting as diseases like herpes labialis, genital herpes, and herpes zoster. Reactivation is a complex process influenced by both viral and host factors, and identifying how latency and reactivation work is vital to developing new antiviral therapies. Recent research highlights a complex interaction among the virus, neurons, and the immune system in regulating alphaherpesvirus latency and reactivation. Neurotropic alphaherpesviruses can breach host barriers to infect neurons, proliferate extensively within their cell bodies, and establish latent infections or spread further. Whether infecting neurons or spreading further, the virus undergoes transmission along axons or dendrites, making this process an indispensable part of the viral life cycle and a critical factor influencing the virus’s invasion of the nervous system. Research on the transmission process of neurotropic alphaherpesviruses within neurons can not only deepen our understanding of the virus but can also facilitate the targeted development of corresponding vaccines. This review concentrates on the relationship between the transmission, latency, and activation of alphaherpesviruses within neurons, summarizes recent advancements in the field, and discusses how these findings can inform the design of live virus vaccines for alphaherpesviruses. Full article
(This article belongs to the Special Issue Herpesvirus Latency and Reactivation)
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Other

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13 pages, 2372 KiB  
Case Report
Reactivation of Latent Tuberculosis Following COVID-19 and Epstein-Barr Virus Coinfection: A Case Report
by Iryna Halabitska, Pavlo Petakh, Valentyn Oksenych and Oleksandr Kamyshnyi
Pathogens 2025, 14(5), 488; https://doi.org/10.3390/pathogens14050488 - 16 May 2025
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Abstract
Background: This case is unique in demonstrating the reactivation of latent tuberculosis (TB) following co-infection with SARS-CoV-2 and Epstein–Barr virus (EBV) in an otherwise healthy young adult. It highlights a rare clinical scenario in which viral immune dysregulation likely facilitated TB progression. To [...] Read more.
Background: This case is unique in demonstrating the reactivation of latent tuberculosis (TB) following co-infection with SARS-CoV-2 and Epstein–Barr virus (EBV) in an otherwise healthy young adult. It highlights a rare clinical scenario in which viral immune dysregulation likely facilitated TB progression. To date, few reports have explored the complex interplay between COVID-19, EBV reactivation, and TB in a single patient, particularly with isolated extrapulmonary involvement. Case Presentation: A 24-year-old woman presented with persistent low-grade fever, fatigue, night sweats, unintentional weight loss, and progressive cervical and supraclavicular lymphadenopathy. These symptoms emerged shortly after a moderate COVID-19 infection. Laboratory studies revealed elevated inflammatory markers and pronounced lymphopenia. EBV reactivation was confirmed via serology and PCR. Despite antiviral therapy, symptoms persisted, and imaging revealed necrotic lymphadenopathy. Tuberculous lymphadenitis was diagnosed through fine-needle aspiration cytology and PCR detection of Mycobacterium tuberculosis. The patient was treated with a standard anti-tuberculosis regimen, resulting in clinical, radiological, and immunological improvement. Conclusions: This case underscores the importance of considering latent TB reactivation in patients with persistent lymphadenopathy and recent viral infections, particularly in regions with high TB prevalence. It also emphasizes the need for thorough immunological and microbiological assessment in complex post-viral syndromes. The main clinical takeaway is that COVID-19 and EBV co-infection may create a permissive environment for TB reactivation through immune system compromise. Full article
(This article belongs to the Special Issue Herpesvirus Latency and Reactivation)
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