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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 10470

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Dr. Sherif T.S. Hassan

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Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic
Interests: gene; infectious diseases; herpesviruses; pharmacology and toxicology; molecular medicine; oncology and hematology; cardiovascular diseases; natural products; drug discovery; analytical and bioanalytical techniques
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Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to delving into the complex world of herpesviruses and their associated diseases. Herpesviruses represent a diverse family of DNA viruses known for their ability to establish lifelong infections in their hosts, posing significant challenges to public health worldwide. These viruses are ubiquitous pathogens that infect a wide range of hosts, including humans and other animals. The family Herpesviridae comprises three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae, each with distinct biological properties and associated diseases. The clinical spectrum of diseases caused by herpesviruses is broad, ranging from mild, self-limiting conditions to severe, life-threatening illnesses. Herpesvirus infections can affect various organ systems, including the skin, mucous membranes, central nervous system, and visceral organs, resulting in manifestations such as oral and genital ulcers, encephalitis, pneumonia, hepatitis, and certain types of cancer. Despite advances in molecular virology and immunology, many aspects of herpesvirus biology and pathogenesis remain not fully understood. Factors contributing to the complexity of herpesvirus infections include viral latency and reactivation, immune evasion strategies, host genetics, and environmental influences. Furthermore, the development of effective vaccines and antiviral therapies against herpesviruses remains a significant challenge, underscoring the need for continued research efforts in this field.

In this Special Issue, we aim to assemble a collection of original research articles, reviews, and perspectives from leading experts in the field of virology and infectious diseases. These contributions aim to deepen our understanding of herpesvirus–host interactions, identify novel therapeutic targets, and explore innovative approaches for the prevention and control of herpesvirus-associated diseases.

Dr. Sherif T. S. Hassan
Guest Editor

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Keywords

human herpesviruses
animal herpesviruses
viral latency and reactivation
immune evasion strategies
herpesvirus–host interactions
herpesvirus biology and pathogenesis
herpesvirus diagnosis
environmental factors
herpesvirus-associated diseases
prevention and treatment strategies
antiviral therapies
vaccine development

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Published Papers (9 papers)

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Research

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13 pages, 2156 KiB

Open AccessArticle

Analysis of the Interaction Between the Attenuated HSV-1 Strain M6 and Macrophages Indicates Its Potential as an Effective Vaccine Immunogen

by Zhenxiao Zhang, Xiaohong Ren, Ying Zhang, Jingjing Zhang, Xinghang Li, Fengyuan Zeng, Rong Yue, Qi Li, Haobo Zhang, Danjing Ma, Yuansheng Liao, Yun Liao, Dandan Li, Li Yu, Guorun Jiang, Heng Zhao, Huiwen Zheng, Heng Li, Xin Zhao, Longding Liu and Qihan Li Show full author list Hide full author list

Viruses 2025, 17(3), 392; https://doi.org/10.3390/v17030392 - 10 Mar 2025

Viewed by 532

Abstract

Herpes simplex virus type 1 (HSV-1) is a very concerning pathogen due to its ability to persist in the host’s nervous system and continuously interfere with the immune system, which complicates treatment. Therefore, the development of an effective HSV-1 vaccine is crucial. In this study, we focused on an HSV-1 mutant strain, M6, which includes several deleted genes associated with viral infection virulence and latent infection function, and explored its infection of macrophages and immunological characteristics. The study found that both the attenuated strain M6 and the wild-type strain infect macrophages through the binding of the gD protein to the HVEM receptor on the macrophage surface. Compared to the wild-type strain, the attenuated M6 strain induced a milder immune response, characterized by the lower expression of immune signaling molecules and inflammatory cytokine levels. Upon reintroducing macrophages infected with the two strains into mice, the M6 strain induced lower levels of inflammatory cytokines and higher levels of chemokines in spleen cells and also slightly lower humoral and cellular immune responses than the wild-type strain. Further histopathological analysis revealed that mice in the attenuated M6 group showed more stable body weight changes and milder pathological damage in immune organs such as the liver, spleen, and lymph nodes. In conclusion, the attenuated M6 strain exhibits good immunogenicity and mild pathological side effects, suggesting its potential as an effective immunogen. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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26 pages, 5072 KiB

Open AccessArticle

Targeting Herpes Simplex Virus Glycoprotein D with Bispecific Antibodies: Expanding Therapeutic Horizons by Searching for Synergy

by Doina Atanasiu, Wan Ting Saw, Harvey M. Friedman and Gary H. Cohen

Viruses 2025, 17(2), 249; https://doi.org/10.3390/v17020249 - 12 Feb 2025

Viewed by 1005

Abstract

Herpes simplex viruses (HSV-1 and HSV-2), which can be transmitted both orally and sexually, cause lifelong morbidity and in some cases, meningitis and encephalitis. While both the passive transfer of neutralizing antibodies and placental transfer of anti-HSV monoclonal antibodies (Mabs) have shown therapeutic promise in animal models, clinical trials have yet to identify approved immunotherapeutics for herpes infection. Here, we present strategies for the generation of recombinant bispecific antibodies (BsAbs) that target different domains of glycoprotein D (gD), crucial for HSV entry, that have the potential to outperform the effect of individual Mabs to curb herpes infection. Specifically, we selected three pairs of Mabs from our extensive panel for BsAb design and production based on their binding site and ability to block virus entry. Actual binding of BsAbs to gD and epitope availability on gD after BsAb binding were characterized using surface plasmon resonance (SPR) and inhibition by IgG Fab fragments generated from selected Mabs. While one BsAb exhibited an additive effect similar to that observed using a combination of the Mabs utilized for its generation, two showed antagonistic effects, suggesting that the simultaneous engagement of two epitopes or selective binding to one affected their activity against HSV. One BsAb (DL11/1D3) targeting the binding site for both nectin-1 and HVEM receptors demonstrated synergistic inhibitory activity against HSV, outperforming the effect of the individual antibodies. Recombinant DL11/1D3 antibody variants, in which the size of one or both paratopes was decreased to single chains (scFv-Fc), highlighted differences in potency depending on antibody size and format. We propose that BsAbs to individual glycoproteins offer a potential avenue for herpes therapeutics, but their design, mechanism of action, antibody format, and epitope engagement require careful consideration of structure for optimal efficacy. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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17 pages, 6691 KiB

Open AccessArticle

Decoding Critical Targets and Signaling Pathways in EBV-Mediated Diseases Using Large Language Models

by Jingwen Yu, Yaohao Wang, Haidong Wang, Zhi Wei and Yonggang Pei

Viruses 2024, 16(11), 1660; https://doi.org/10.3390/v16111660 - 24 Oct 2024

Cited by 1 | Viewed by 1941

Abstract

Epstein–Barr virus (EBV), a member of the gamma herpesvirus, is the first identified human oncovirus and is associated with various malignancies. Understanding the intricate interactions between EBV antigens and cellular pathways is crucial to unraveling the molecular mechanisms in EBV-mediated diseases. However, fully elucidating EBV–host interactions and the associated pathogenesis remains a significant challenge. In this study, we employed large language models (LLMs) to screen 36,105 EBV-relevant scientific publications and summarize the current literature landscape on various EBV-associated diseases like Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and so on. LLM-generated data indicate that the most-studied EBV-associated pathways are enriched in immune response, apoptosis, cell growth, and replication. The analyses of protein–protein interactions (PPIs) reveal three principal EBV-related protein clusters: TP53-centered apoptotic factors, EBV-associated transcription factors, and immune response elements. Utilizing our dataset and public databases, we demonstrated that BLLF3-targeted TLR2-associated factors are effective diagnostic markers for DLBCL. Next, we confirmed the co-expression of LMP1-targeted calcium pathway factors in BL. Finally, we demonstrated the correlation and co-expression of LMP1-induced PARP1, HIF1A, HK2, and key glycolysis-related factors, further suggesting that LMP1 actively regulates the glycolysis pathway. Therefore, our study presents a comprehensive functional encyclopedia of the interactions between EBV antigens and host signaling pathways across various EBV-associated diseases, providing valuable insights for the development of therapeutic strategies. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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9 pages, 1518 KiB

Open AccessArticle

Herpesvirus Antibody Response and Occurrence of Symptoms in Acute and Post-Acute COVID-19 Disease

by Julia Butt, Julia Simon, Tim Waterboer and Uta Merle

Viruses 2024, 16(10), 1577; https://doi.org/10.3390/v16101577 - 7 Oct 2024

Viewed by 1185

Abstract

Knowledge about the underlying causes of the individual occurrence of symptoms during acute COVID-19 disease and during the post-acute sequelae of COVID-19 is limited. In a German COVID-19 follow-up study, we assessed whether elevated antibody responses to herpesviruses were associated with symptom occurrence in acute COVID-19 disease (n = 96 participants) and during 20 months of follow-up (n = 62 participants). Serum samples were analyzed for their antibodies to herpes simplex virus (HSV)-1 and -2, Epstein–Barr virus (EBV), and Cytomegalovirus (CMV) using fluorescent bead-based multiplex serology. The association of herpesvirus antibodies with symptom occurrence (fatigue, fever, dyspnea, decrease in taste, concentration problems) was assessed using multivariate logistic regression models. High EBV antibody levels were significantly associated with a more than fourfold increased odds of experiencing fatigue during acute COVID-19 disease and during follow-up. High CMV antibody levels were significantly associated with a more than threefold increased odds of experiencing concentration problems and a decrease in taste during the follow-up. The HSV-1 and -2 antibody levels were not elevated in the individuals that experienced symptoms. In conclusion, our findings indicate that herpesvirus infections, specifically EBV and CMV infections, might play a role in symptom development during acute and post-acute COVID-19 disease. It remains to be elucidated whether the elevated EBV and CMV antibodies determined in our study are indicators of herpesvirus reactivation. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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10 pages, 538 KiB

Open AccessArticle

Unveiling the Impact of Human Herpesviruses-Associated on CNS Infections: An Observational Study

by Caio Cesar L. B. Barrionuevo, Pedro P. A. Baptista, Ewerton F. da Silva, Bernardo M. da Silva, Cássia da L. Goulart, Sabrina A. de Melo, Valderjane A. da Silva, Lara Laycia A. de Souza, Rossicleia L. Monte, Fernando F. Almeida-Val, Pablo Vinícius S. Feitoza and Michele de S. Bastos

Viruses 2024, 16(9), 1437; https://doi.org/10.3390/v16091437 - 9 Sep 2024

Viewed by 1071

Abstract

Human Herpesviruses (HHVs) play a significant role in neurological diseases such as encephalitis and meningitis, adding significant morbidity. This study aims to retrospectively analyze the effect of HHVs on patients with neurological symptoms, focusing on the Herpesviridae family’s contributions to central nervous system (CNS) infections. Methods: This retrospective cohort study included 895 patients suspected of viral CNS infections, utilizing molecular diagnosis via qPCR to identify HHVs in cerebrospinal fluid (CSF) samples. This was conducted at a reference tertiary care hospital for infectious diseases in the western Brazilian Amazon from January 2015 to December 2022, focusing on the Herpesviridae family’s clinical repercussions and of Cytomegalovirus in CNS infections. Results: The findings revealed that 7.5% of the analyzed samples tested positive for HHVs, with Human Cytomegalovirus (HCMV) and Epstein–Barr Virus (EBV) being the most prevalent. A significant association was found between HHVs and neurological diseases such as encephalitis and meningitis, especially among people living with HIV/AIDS (PLWHA), highlighting the opportunistic nature of these viruses. The study underscores the critical role of CSF analysis in diagnosing CNS infections and the complexity of managing these infections in HIV patients due to their immunocompromised status. Conclusions: The results emphasize the need for comprehensive diagnostic approaches and tailored treatment strategies for CNS infections in immunocompromised individuals. The study calls for ongoing research and advancements in clinical practice to improve patient outcomes facing CNS infections, particularly those caused by HHVs. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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8 pages, 463 KiB

Open AccessArticle

Analysis of HSV1/2 Infection Reveals an Association between HSV-2 Reactivation and Pregnancy

by Sara Dovrat, Adar Shabat, Anat Yahav-Dovrat, Zvia Soufiev, Ella Mendelson, Ela Kashi-Zagdoun and Galia Rahav

Viruses 2024, 16(9), 1370; https://doi.org/10.3390/v16091370 - 28 Aug 2024

Cited by 1 | Viewed by 1144

Abstract

The herpes simplex viruses consist of the strains, HSV-1 and HSV-2, which are prevalent worldwide and lack a definitive cure. We aimed to explore the specific characteristics of HSV 1 and 2 infections, such as differences between gender assigned at birth, age at infection, site of infection, comorbidities, and effect of pregnancy, through a data analysis. Between 2011 and 2018, the Israeli Central Virology Laboratory diagnosed 9189 samples using multiplexed real-time PCR. In addition, we extracted all of the medical data for 287 females hospitalized at the Sheba Medical Center with HSV-1 (161) or HSV-2 (126) genital infections. HSV-2 was almost absent in the orofacial samples from both genders, while in other lesion sites, HSV-2 was significantly more abundant in females than in males (p < 0.05,). HSV-2 was initially detected at puberty. In the hospitalized females’ malignancies, both HSV-1 and HSV-2 were found with a non-significant difference. Simultaneously, pregnancies were more common in females who were HSV-2-positive compared with those who were HSV-1-positive (27.8% vs. 12.4%, respectively, p < 0.01). Primary infections occur more with HSV-1 than with HSV-2 (15.6% vs. 3.2%, respectively). Our findings demonstrate that genital HSV-2 infection episodes are more frequent during pregnancy, suggesting that pregnancy may serve as a risk factor for HSV-2 reactivation or infection. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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Review

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33 pages, 1847 KiB

Open AccessReview

Immunological Control of Herpes Simplex Virus Type 1 Infection: A Non-Thermal Plasma-Based Approach

by Julia Sutter, Jennifer L. Hope, Brian Wigdahl, Vandana Miller and Fred C. Krebs

Viruses 2025, 17(5), 600; https://doi.org/10.3390/v17050600 - 23 Apr 2025

Viewed by 356

Abstract

Herpes simplex virus type 1 (HSV-1) causes a lifelong infection due to latency established in the trigeminal ganglia, which is the source of recurrent outbreaks of cold sores. The lifelong persistence of HSV-1 is further facilitated by the lack of cure strategies, unsuccessful vaccine development, and the inability of the host immune system to clear HSV-1. Despite the inefficiencies of the immune system, the course of HSV-1 infection remains under strict immunological control. Specifically, HSV-1 is controlled by a CD8⁺ T cell response that is cytotoxic to HSV-1-infected cells, restricts acute infection, and uses noncytolytic mechanisms to suppress reactivation in the TG. When this CD8⁺ T cell response is disrupted, reactivation of latent HSV-1 occurs. With antiviral therapies unable to cure HSV-1 and prophylactic vaccine strategies failing to stimulate a protective response, we propose non-thermal plasma (NTP) as a potential therapy effective against recurrent HSV-1 infection. We have demonstrated that NTP, when applied directly to HSV-1-infected cells, has antiviral effects and stimulates cellular stress and immunomodulatory responses. We further propose that the direct effects of NTP will lead to long-lasting indirect effects such as reduced viral seeding into the TG and enhanced HSV-1-specific CD8⁺ T cell responses that exert greater immune control over HSV-1 infection. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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18 pages, 1219 KiB

Open AccessReview

REST Is Restless in Neuronal and Non-Neuronal Virus Infections: An In Silico Analysis-Based Perspective

by Vinod Soman Pillai, Shilpa Ravindran, Gayathri Krishna, Chandran S. Abhinand, Shijulal Nelson-Sathi and Mohanan Valiya Veettil

Viruses 2025, 17(2), 234; https://doi.org/10.3390/v17020234 - 8 Feb 2025

Viewed by 1104

Abstract

Repressor element-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) is an extensively studied neuronal gene regulator both in neuronal cells and non-neuronal cells. Even though the role of REST in host cellular gene regulation is well established, its role in the establishment of viral infections and its capability to stabilize and destabilize such viral infections are scarcely studied. Co-repressor and DNA modifiers are involved in REST-mediated repressive action of its target genes. The role of REST and co-repressors together or individually in the regulation of viral as well as host genes has been unraveled in a few viruses such as HIV and influenza as well as two of the herpesvirus family members, namely herpes simplex virus type 1 (HSV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we summarize all such virus studies involved with REST to gain a better insight into REST biology in virus infections. We also focus on unraveling the possible RE-1 binding sites in the Epstein–Barr virus (EBV) genome, a well-known human oncogenic herpesvirus that is associated with infectious mononucleosis and neoplasms such as B-cell lymphomas, nasopharyngeal carcinoma, gastric carcinoma, etc. An in silico-based approach was employed towards the prediction of such possible RE-1 binding elements in the EBV genome. This review advances the present knowledge of REST in virus infection which will aid in future efforts towards a better understanding of how REST acts in herpesviruses and other viruses for their infections and pathogenesis. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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11 pages, 1138 KiB

Open AccessSystematic Review

The Role of Viruses in Pulpal and Apical Disease: A Systematic Review

by Katia Hermosilla Hermosilla, Paula Soto Cárdenas, Manuel Donoso Zuñiga, Cecilia Pérez Ñanco and Scarlette Hernández-Vigueras

Viruses 2024, 16(10), 1537; https://doi.org/10.3390/v16101537 - 28 Sep 2024

Cited by 1 | Viewed by 1293

Abstract

Apical lesions are diseases of infectious origin that can cause destruction of the surrounding periapical tissue, including bone tissue and periodontal ligaments, resulting in the loss of the affected teeth. Currently, the microorganisms present in pulp and apical disease are mostly studied as bacteria. However, in recent years, interest has been aroused in the study of viruses that could be present in apical lesions, and how these could affect the progression of disease. In the present study, we conducted a systematic review of the literature to evaluate and synthesize the scientific evidence on the presence of viruses and their possible role in pulpal and apical disease. This systematic review was performed according to the PRISMA reporting guidelines. The search for studies was performed in the PubMed and Web of Science databases. A total of seven studies published in the last 10 years were included. The types of samples used for virus analysis varied from one study to another. In all the included studies, the presence of any of the types of viruses studied was found, either in pulp or apical tissue. Herpesviridae family, Epstein–Barr virus (EBV) and Human cytomegalovirus (HCMV) stood out as the most commonly present in apical lesions. Further studies are required to clarify and understand the pathogenic role of viruses in pulpal and periapical disease. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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