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Pathogens
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Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations
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Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations

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

Deadline for manuscript submissions: 31 August 2026 | Viewed by 4314

Special Issue Editors

Dr. Gaëtan Ligat

E-Mail Website
Guest Editor
Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM UMR1291, CNRS UMR5051, Toulouse University, CEDEX 3, 31024 Toulouse, France
Interests: human cytomegalovirus; glioblastoma; targets; biomarkers; biotherapies
Special Issues, Collections and Topics in MDPI journals
Dr. Alexia Damour

E-Mail Website
Guest Editor
UMR 1092 RESINFIT, Limoges University, BP 23204, 87032 Limoges, France
Interests: human cytomegalovirus; antiviral targets; helicase–primase complex

Special Issue Information

Dear Colleagues,

Human cytomegalovirus (HCMV) or human herpesvirus 5 is a ubiquitous herpesvirus that infects a large proportion of the global population. It remains asymptomatic in most healthy individuals, but it is one of the most important causes of complications in immunocompromised patients (patients with AIDS and solid organ transplant or hematopoietic stem cell transplant recipients) and those with congenital infections. HCMV could also represent an interesting target for treatment to limit the progression of glioblastoma, a highly aggressive tumor.

HCMV encodes a variety of gene products that regulate a wide array of cellular and immune pathways. However, there are still significant gaps in our understanding of how these gene products contribute to viral persistence and pathogenesis. Furthermore, the currently used antivirals, for which efficacy has been demonstrated, exhibit significant toxicity, and, most importantly, numerous resistances to these treatments have emerged. Therefore, it is essential to identify new therapeutic targets.

This Special Issue will focus on recent advances in understanding the pathogenesis of HCMV, its interactions with the host cells and new developments in therapeutic strategies.

Dr. Gaëtan Ligat
Dr. Alexia Damour
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • human cytomegalovirus
  • therapeutic strategies and vaccines
  • glioblastoma
  • congenital infection
  • immunocompromised

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Related Special Issue

Published Papers (5 papers)

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Research

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11 pages, 724 KB  
Article
An Evaluation of IL-10 Encoded by Cytomegalovirus in the Prediction of Coronary Artery Disease in People Living with HIV
by Shelley Waters, Luna-Faye Veld, Silvia Lee, Anna C. Hearps, Janine Trevillyan, Jennifer F. Hoy and Patricia Price
Pathogens 2026, 15(2), 192; https://doi.org/10.3390/pathogens15020192 - 9 Feb 2026
Viewed by 576
Abstract
Cytomegalovirus (CMV) seropositivity associates with cardiovascular disease in healthy adults, but associations are unclear in people living with HIV (PLWH) despite their high CMV burden. However, CMV antibody levels correlated with inflammatory biomarkers only in PLWH who subsequently developed coronary artery disease (CAD), [...] Read more.
Cytomegalovirus (CMV) seropositivity associates with cardiovascular disease in healthy adults, but associations are unclear in people living with HIV (PLWH) despite their high CMV burden. However, CMV antibody levels correlated with inflammatory biomarkers only in PLWH who subsequently developed coronary artery disease (CAD), so the effects of CMV in an individual may vary. Here we investigate the role of CMV-encoded interleukin-10 (cmvIL-10) in PLWH on anti-retroviral therapy. Plasma levels of cmvIL-10 and antibodies reactive with a cmvIL-10 peptide or a lysate of CMV-infected fibroblasts were assessed in PLWH with or without CAD. cmvIL-10 was assessed at diagnosis/selection (T0) and 12 months earlier (T-12), with anti-cmvIL-10 also assessed at −24 and −36 months (n = 36–58/group). Plasma cmvIL-10 was recorded as positive in 5–10 PLWH per group, irrespective of CAD status. Of 21 PLWH with detectable cmvIL-10, only six were positive at both timepoints. Anti-cmvIL-10 was measurable in all samples, at levels independent of cmvIL-10, CAD or time of sampling. Amongst PLWH without CAD, the detection of cmvIL-10 associated with higher levels of CXCL10 (T0 and T-12) and lower levels of the IL-1 receptor antagonist (IL-1Ra; T0 only). At T-12, anti-cmvIL-10 correlated with IL-1Ra in PLWH without CAD (p = 0.01), and sCD14 in PLWH with CAD (p = 0.01). Anti-cmvIL-10 correlated with VCAM-1 at several timepoints in both groups. Hence, cmvIL-10 may be produced episodically, inducing anti-cmvIL-10 peptide antibody, which may represent levels of the cytokine averaged over time. Plasma levels of cmvIL-10 and anti-cmvIL-10 antibody associated differently with inflammatory biomarkers in PLWH with and without CAD, suggesting mechanisms by which host responses to CMV may have different clinical consequences. Full article
(This article belongs to the Special Issue Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations)
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15 pages, 1084 KB  
Article
Antigenic-Specificity and Cytokine Profile of the T-Cell Response to Human Cytomegalovirus in Transplant Recipients
by Federica Zavaglio, Paola Zelini, Asja Cera, Piera d’Angelo, Marilena Gregorini, Teresa Rampino, Lucia Del Frate, Federica Meloni, Oscar Borsani, Carlo Pellegrini, Fausto Baldanti and Daniele Lilleri
Pathogens 2026, 15(1), 53; https://doi.org/10.3390/pathogens15010053 - 5 Jan 2026
Viewed by 573
Abstract
Human cytomegalovirus (HCMV) infection is a significant complication in transplant recipients. Following HCMV reactivation, the recovery of T-cell responses serves as a key indicator of protection from HCMV disease. This study aimed to assess the HCMV-specific CD4+ and CD8+ T-cell responses [...] Read more.
Human cytomegalovirus (HCMV) infection is a significant complication in transplant recipients. Following HCMV reactivation, the recovery of T-cell responses serves as a key indicator of protection from HCMV disease. This study aimed to assess the HCMV-specific CD4+ and CD8+ T-cell responses and their cytokine production (IFNγ, TNFα, IL2) against various HCMV proteins (IE-1, pp65, gB, gH/gL/pUL128L) in solid organ transplant recipients (SOTRs) and hematopoietic stem cell transplant recipients (HSCTRs) with active HCMV infection. The cohort consisted of 16 SOTR and 16 HSCTR categorized into two groups: (i) Controllers, who spontaneously controlled the infection, and (ii) Non-Controllers, who required antiviral treatment. T-cell responses were analyzed following stimulation with peptide pools and intracellular cytokine staining. Prior to transplantation, all patients exhibited a significantly higher frequency of CD4+ T cells specific to pp65 compared to gH and gL/pUL128L. During the peak of infection, T-cell frequencies across all peptides were similar, but at infection resolution, the frequency of pp65 and gB-specific CD4+IFNγ+ T cells was significantly higher than gL/pUL128L. Additionally, pp65 and IE-1-specific CD8+IFNγ+ T-cell responses were significantly greater than those against gH and gL/pUL128L at the resolution of infection. Notably, Controllers exhibited significantly higher frequencies of monofunctional pp65-specific T cells, particularly in CD8+ T cells producing IFNγ and TNFα. The response to pp65, especially IFNγ production, may serve as a key marker for identifying patients capable of controlling HCMV infection. Full article
(This article belongs to the Special Issue Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations)
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Review

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25 pages, 713 KB  
Review
Cytomegalovirus Infection of the Anterior Segment: Corneal Endotheliitis and Secondary Glaucoma
by Fan Liu, Yaru Zou, Mingming Yang, Jing Zhang, Kyoko Ohno-Matsui and Koju Kamoi
Pathogens 2026, 15(4), 371; https://doi.org/10.3390/pathogens15040371 - 31 Mar 2026
Viewed by 619
Abstract
Cytomegalovirus (CMV) infection of the anterior segment is increasingly recognized as an important cause of corneal endotheliitis and secondary glaucoma, even in immunocompetent individuals. CMV corneal endotheliitis typically presents with coin-shaped or linear keratic precipitates (KPs), corneal edema, mild anterior chamber inflammation, and [...] Read more.
Cytomegalovirus (CMV) infection of the anterior segment is increasingly recognized as an important cause of corneal endotheliitis and secondary glaucoma, even in immunocompetent individuals. CMV corneal endotheliitis typically presents with coin-shaped or linear keratic precipitates (KPs), corneal edema, mild anterior chamber inflammation, and recurrent intraocular pressure (IOP) elevation; persistent or episodic ocular hypertension may progress to glaucomatous optic neuropathy if inadequately treated. Definitive diagnosis relies on aqueous humor polymerase chain reaction (PCR) testing for CMV DNA, supported by adjunctive imaging including specular microscopy, anterior segment optical coherence tomography (AS-OCT), and in vivo confocal microscopy (IVCM). Management requires a comprehensive strategy integrating antiviral therapy, anti-inflammatory treatment, and appropriate IOP control. Topical or systemic ganciclovir remains the cornerstone, while refractory disease may necessitate surgical intervention. Older age and male sex, host immune status, prolonged or recurrent CMV infection, and pre-existing ocular conditions are major risk factors for progression and poor outcomes. The pathogenesis of secondary glaucoma is thought to involve both direct viral cytopathic effects and inflammation-mediated damage to the trabecular meshwork (TM), resulting in impaired aqueous outflow. Therefore, early recognition, accurate diagnosis, and effective treatment are essential to prevent corneal decompensation and permanent vision loss. Full article
(This article belongs to the Special Issue Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations)
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9 pages, 339 KB  
Review
Exploring pUS27: Insights into Its Role in HCMV Pathogenesis and Potential for Antiviral Strategies
by Gage M. Connors and Juliet V. Spencer
Pathogens 2025, 14(10), 993; https://doi.org/10.3390/pathogens14100993 - 1 Oct 2025
Viewed by 981
Abstract
Human cytomegalovirus (HCMV) is a complex pathogen that encodes a diverse array of proteins essential for its survival and replication within host organisms. Among these proteins, a noteworthy group comprises four chemokine-like G protein-coupled receptors (cellular GPCRs), which play pivotal roles in the [...] Read more.
Human cytomegalovirus (HCMV) is a complex pathogen that encodes a diverse array of proteins essential for its survival and replication within host organisms. Among these proteins, a noteworthy group comprises four chemokine-like G protein-coupled receptors (cellular GPCRs), which play pivotal roles in the virus’s evasion of the host immune response and the establishment of persistent infections. Of particular interest is pUS28, recognized as one of the most extensively studied viral GPCRs (vGPCRs). This receptor has attracted significant attention for its potential as a target for innovative antiviral therapies aimed at addressing HCMV-related diseases. In contrast, pUS27 has not been as thoroughly characterized, presenting a potentially promising avenue for antiviral intervention. The relative scarcity of research surrounding pUS27 underscores an exciting opportunity for further exploration, as a deeper understanding of its functions and mechanisms may reveal novel strategies for combating HCMV infections. This review seeks to synthesize recent advancements in our understanding of pUS27, elucidating its biological roles, interactions, and potential implications for therapeutic development. We will also highlight critical gaps in the existing literature that warrant further investigation, underscoring the need for a more comprehensive understanding of this understudied receptor. By delving into the complexities of pUS27, we aim to inspire future research initiatives that could lead to the development of novel antiviral treatments, thereby enhancing our overall understanding of HCMV pathogenesis. Importance: The study of vGPCRs is essential for understanding how viruses like HCMV manipulate host cell signaling and evade immune responses. While pUS28 has been extensively studied due to its broad chemokine binding and signaling activity, its lesser-known homolog, pUS27, warrants closer attention. Likely arising from a gene duplication event, pUS27 shares approximately 31% sequence identity with pUS28 and is conserved across HCMV strains, suggesting an important functional role. By focusing on pUS27, we may uncover shared mechanisms that allow therapies to effectively target both pUS28 and pUS27, potentially leading to more potent antiviral treatments. The implications of studying pUS27 are profound, as it could play a pivotal role in improving our approaches to combating HCMV and enhancing our overall understanding of immune evasion strategies. Full article
(This article belongs to the Special Issue Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations)
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Other

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10 pages, 524 KB  
Opinion
Targeting Human Cytomegalovirus as a Novel Approach for Glioblastoma Treatment
by Thelma Flores, Eloïse Delpierre, Ghislain Male, Claire Gourin, Sébastien Hantz, Alexia Damour and Gaëtan Ligat
Pathogens 2025, 14(12), 1291; https://doi.org/10.3390/pathogens14121291 - 16 Dec 2025
Viewed by 933
Abstract
Glioblastoma (GB) is a highly aggressive brain tumor with a very poor prognosis. Treatment usually consists of surgery, followed by radiotherapy and chemotherapy, but the prognosis remains poor due to its resistance to therapies and a high recurrence rate. Multiple studies have reported [...] Read more.
Glioblastoma (GB) is a highly aggressive brain tumor with a very poor prognosis. Treatment usually consists of surgery, followed by radiotherapy and chemotherapy, but the prognosis remains poor due to its resistance to therapies and a high recurrence rate. Multiple studies have reported the presence of human cytomegalovirus (HCMV) proteins and/or nucleic acids in GB tissues, suggesting its possible implication. These findings have led to the hypothesis that HCMV may contribute to tumor progression, immune evasion, angiogenesis, and resistance to therapy. Clinical trials using anti-HCMV therapies have shown promising preliminary results, indicating a potential therapeutic benefit. This review aims to provide a comprehensive overview of the current evidence linking HCMV to GB and the therapeutic implications. A deeper understanding of this complex interaction could unveil novel strategies for GB treatment. Full article
(This article belongs to the Special Issue Human Cytomegalovirus: From Molecular Pathogenesis to Therapeutic Innovations)
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