Infectious Triggers of Cytokine Storm Syndromes: Herpes Virus Family (Non-EBV).

The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein-Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations.

Nanopore guided annotation of transcriptome architectures.

Nanopore direct RNA sequencing (DRS) enables the capture and full-length sequencing of native RNAs, without recoding or amplification bias. Resulting data sets may be interrogated to define the identity and location of chemically modified ribonucleotides, as well as the length of poly(A) tails, on individual RNA molecules. The success of these analyses is highly dependent on the provision of high-resolution transcriptome annotations in combination with workflows that minimize misalignments and other analysis artifacts. Existing software solutions for generating high-resolution transcriptome annotations are poorly suited to small gene-dense genomes of viruses due to the challenge of identifying distinct transcript isoforms where alternative splicing and overlapping RNAs are prevalent. To resolve this, we identified key characteristics of DRS data sets that inform resulting read alignments and developed the nanopore guided annotation of transcriptome architectures (NAGATA) software package (https://github.com/DepledgeLab/NAGATA). We demonstrate, using a combination of synthetic and original DRS data sets derived from adenoviruses, herpesviruses, coronaviruses, and human cells, that NAGATA outperforms existing transcriptome annotation software and yields a consistently high level of precision and recall when reconstructing both gene sparse and gene-dense transcriptomes. Finally, we apply NAGATA to generate the first high-resolution transcriptome annotation of the neglected pathogen human adenovirus type F41 (HAdV-41) for which we identify 77 distinct transcripts encoding at least 23 different proteins. IMPORTANCE: The transcriptome of an organism denotes the full repertoire of encoded RNAs that may be expressed. This is critical to understanding the biology of an organism and for accurate transcriptomic and epitranscriptomic-based analyses. Annotating transcriptomes remains a complex task, particularly in small gene-dense organisms such as viruses which maximize their coding capacity through overlapping RNAs. To resolve this, we have developed a new software nanopore guided annotation of transcriptome architectures (NAGATA) which utilizes nanopore direct RNA sequencing (DRS) datasets to rapidly produce high-resolution transcriptome annotations for diverse viruses and other organisms.

Characterization of Herpesviridae Family Members, BK Virus, and Adenovirus in Children and Adolescents with Nephrotic Syndrome.

Since the significance of viral infections in children and adolescents with nephrotic syndrome (NS) is yet to be defined, this study intended to estimate the occurrence, pattern, and outcomes of some DNA viral infections in children with NS. METHODS: A prospective study was conducted to determine the genome identification of the viruses Epstein-Barr (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6 type A and type B) and 7 (HHV-7), polyomavirus (BKV), and human adenovirus (HAdV) in plasma and urine samples of pediatric patients with NS. RESULTS: A total of 35 patients aged 1 to 18 years with NS and under immunosuppressant drugs participated in the study. Plasma and urine samples were collected at regular intervals during a median follow-up of 266 days (range 133-595), and DNA was analyzed to detect the selected DNA viruses. Eleven patients (31.4%) had active virus infections, and patterns were classified as coinfection, recurrent, and consecutive. Of these, six patients (54.5%) presented viral coinfection, six (54.5%) viral recurrence, and seven patients (63.3%) had viral consecutive infection. Ten of the eleven patients with active infection had a proteinuria relapse (91%) and eight (72.7%) were hospitalized (p = 0.0022). Active HCMV infection was the most frequent infection and was observed in six patients (54.5%), three of the eleven patients (27.2%) had suspected HCMV disease in the gastrointestinal tract, and one had HHV-7 coinfection. The frequency of other infections was: 9% for HHV-6, 45.5% for BKV, 27.3% for HHV-7, 18.2% for EBV, and 18.2% for HAdV. CONCLUSION: viral infections, especially HCMV, can be an important cause of morbidity and nephrotic syndrome relapse in children.

Assessing the Efficacy of Three Hatchery Disinfectants for the Inactivation of a Lake Sturgeon Herpesvirus (Family: Alloherpesviridae).

Infectious diseases are a leading cause of losses in the aquaculture industry and conservation programs globally. Simultaneously, infectious diseases pose a substantial risk to fish being hatchery-reared and released into natural habitats for conservation purposes, including the Great Lakes lake sturgeon (Acipenser fulvescens, i.e., GL-LST). Recently, an alloherpesvirus (lake sturgeon herpesvirus 2, i.e., LSHV-2) capable of inducing disease and/or mortality in adult and juvenile GL-LSTs was detected in two adult GL-LST populations. To begin developing disease prevention and/or control methods, in vitro experiments were designed to determine the susceptibility of LSHV-2 to disinfectants commonly used in hatchery and aquaculture facilities (Virkon®-Aquatic: potassium peroxymonosulfate; Ovadine®: polyvinylpyrrolidone iodine complex; and Perox-Aid®: hydrogen peroxide). Cultured LSHV-2 was exposed to each disinfectant at two concentrations (Virkon®-Aquatic: 0.5% and 1%; Ovadine®: 50 and 100 ppm; and Perox-Aid®: 500 and 1000 ppm) in duplicate for durations of 1, 10, and 30 min. Following exposure, the disinfectant was neutralized, and after a 14-day incubation period on a white sturgeon × lake sturgeon hybrid cell line (WSxLS), percent reduction was calculated by comparing the 50% tissue culture infectious doses (TCID50/mL) of the virus with and without disinfectant exposure. When exposed to Perox-Aid®, LSHV-2 percent reduction ranged from 58.7% to 99.5%. When exposed to Ovadine®, the percent reduction ranged from 99.4% to 100%. Lastly, the percent reduction when exposed to Virkon®-Aquatic was 100% for both concentrations and all timepoints. The results herein provide evidence that both Virkon®-Aquatic and Ovadine® are virucidal to LSHV-2 and may represent a means to reduce virus transmission risk under field settings.

Cytokine Dynamics and Herpesvirus Interactions in Pediatric Liver and Kidney Transplant Recipients: The Distinct Behavior of HCMV, HHV6, HHV7 and EBV.

Pediatric solid organ transplant (SOT) recipients face a challenging balance between immunosuppression and graft rejection. While Epstein-Barr Virus (EBV) and cytomegalovirus (HCMV) are known contributors to post-transplant lymphoproliferative disease and graft rejection, respectively, the roles of herpesvirus 6 and 7 (HHV6 and HHV7) and the impact of these herpesviruses on cytokine levels remain unclear, leading to gaps in clinical practice. In this associative study, we measured 17 cytokines using a Bio-Plex assay in a meticulously curated plasma sample pool (N = 158) from pediatric kidney and liver transplant recipients over a one-year follow-up period. The samples included virus-negative and virus-positive cases, either individually or in combination, along with episodes of graft rejection. We observed that the elevation of IL-4, IL-8, and IL-10 correlated with graft rejection. These cytokines were elevated in samples where HCMV or HHV6 were detected alone or where EBV and HHV7 were co-detected. Interestingly, latent EBV, when detected independently, exhibited an immunomodulatory effect by downregulating cytokine levels. However, in co-detection scenarios with ß-herpesviruses, EBV transitioned to a lytic state, also associating with heightened cytokinemia and graft rejection. These findings highlight the complex interactions between the immune response and herpesviruses in transplant recipients. The study advocates for enhanced monitoring of not only EBV and HCMV but also HHV6 and HHV7, providing valuable insights for improved risk assessment and targeted interventions in pediatric SOT recipients.

Oncogenic Animal Herpesviruses.

Oncogenic viruses play a pivotal role in oncology due to their unique role in unraveling the complexities of cancer development. Understanding the role viruses play in specific cancers is important to provide basic insights into the transformation process, which will help identify potential cellular targets for treatment. This review discusses the diverse role of animal herpesviruses in initiating and promoting various forms of cancer. We will summarize the mechanisms that underlie the development of animal herpesvirus-induced cancer that may provide a basis for developing potential therapeutic interventions or preventative strategies in the future.

[Detection rates and high concentration of herpesvirus (Orthoherpesviridae) DNA in autopsy materials from patients with COVID-19 fatal outcome].

INTRODUCTION: SARS-CoV-2 infection causes immune disorders that create conditions for the reactivation of human herpesviruses (HHVs). However, the estimates of the HHVs effect on the course and outcome of COVID-19 are ambiguous. Аim - to study the possible relationship between the HHV reactivation and the adverse outcome of COVID-19. MATERIALS AND METHODS: Postmortem samples from the brain, liver, spleen, lymph nodes and lungs were obtained from 59 patients treated at the Moscow Infectious Diseases Hospital No.1 in 2021-2023. The group 1 comprised 39 patients with fatal COVID-19; group 2 (comparison group) included 20 patients not infected with SARS-CoV-2 who died from various somatic diseases. HHV DNA and SARS-CoV-2 RNA were determined by PCR. RESULTS: HHV DNA was found in autopsy samples from all patients. In group 1, EBV was most often detected in lymph nodes (94%), HHV-6 in liver (68%), CMV in lymph nodes (18%), HSV in brain (16%), VZV in lung and spleen (3% each). The detection rates of HHVs in both groups was similar. Important differences were found in viral load. In patients with COVID-19, the number of samples containing more than 1,000 copies of HHV DNA per 100,000 cells was 52.4%, in the comparison group - 16.6% (p < 0.002). An association has been established between the reactivation of HSV and HHV-6 and the severity of lung damage. Reactivation of EBV correlated with increased levels of liver enzymes. CONCLUSION: Reactivation of HHVs in patients with fatal COVID-19 was associated with severe lung and liver damages, which indicates a link between HHV reactivation and COVID-19 deaths.

Fetal cord plasma herpesviruses and preeclampsia: an observational cohort study.

A previous study suggested that fetal inheritance of chromosomally integrated human herpesvirus 6 (ici-HHV6) is associated with the hypertensive pregnancy disorder preeclampsia (PE). We aimed to study this question utilizing cord plasma samples (n = 1276) of the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 from a pregnancy with PE and 737 without. We studied these samples and 30 placentas from PE pregnancies by a multiplex qPCR for the DNAs of all nine human herpesviruses. To assess the population prevalence of iciHHV-6, we studied whole-genome sequencing data from blood-derived DNA of 3421 biobank subjects. Any herpes viral DNA was detected in only two (0.37%) PE and one (0.14%) control sample (OR 2.74, 95% CI 0.25-30.4). One PE sample contained iciHHV-6B and another HHV-7 DNA. The control's DNA was of iciHHV-6B; the fetus having growth restriction and preterm birth without PE diagnosis. Placentas showed no herpesviruses. In the biobank data, 3 of 3421 subjects (0.08%) had low level HHV-6B but no iciHHV-6. While iciHHV-6 proved extremely rare, both fetuses with iciHHV-6B were growth-restricted, preterm, and from a pregnancy with maternal hypertension. Our findings suggest that human herpesviruses are not a significant cause of PE, whereas iciHHV-6 may pose some fetal risk.

Identifying Protein Interactions with Viral DNA Genomes during Virus Infection.

Viruses exploit the host cell machinery to enable infection and propagation. This review discusses the complex landscape of DNA virus-host interactions, focusing primarily on herpesviruses and adenoviruses, which replicate in the nucleus of infected cells, and vaccinia virus, which replicates in the cytoplasm. We discuss experimental approaches used to discover and validate interactions of host proteins with viral genomes and how these interactions impact processes that occur during infection, including the host DNA damage response and viral genome replication, repair, and transcription. We highlight the current state of knowledge regarding virus-host protein interactions and also outline emerging areas and future directions for research.

Analysis of pulmonary microecology and clinical characteristics of patients carrying human herpesvirus.

Aim: To investigate the impact of human herpes virus (HHV) carriage on lung microbiota, and its correlation with clinical features and laboratory indicators in patients.Methods: Retrospective analysis was conducted on 30 outpatient lung infection cases, which were divided into HHV (n = 15) and non-HHV (n = 15) groups. mNGS detected microbial composition. Microbial diversity and abundance were tested using Shannon and Chao1 indices. Their relationship with laboratory indicators were explored.Results: Significant differences in microbial abundance and distribution were found between two groups (p < 0.05). Moreover, HHV group showed negative correlations (p < 0.05) between Prevotella, Porphyromonas, Streptococcus and basophil/eosinophil percentages.Conclusion: HHV carriage impacts lung microbiota, emphasizing the need for clinicians to pay attention to HHV reactivation in outpatient lung infection patients.

This study looked at how a common virus called human herpesvirus (HHV) affects the bacteria in our lungs. We wanted to see if HHV is linked to how sick we feel and what tests show. We split 30 people who had lung infections into two groups ­ 15 with HHV and 15 without ­ and checked how sick they felt, did some tests, and looked at the types of bacteria in their lungs. Both groups felt similarly sick and got better with medicine, but people with HHV had fewer of a certain type of blood cell. People with and without HHV also had different types of bacteria in their lungs. This study helps us understand why people get sick with lung infections and how to make them better. It might also help doctors decide how to treat people with lung infections.

Molecular plasticity of herpesvirus nuclear egress analysed in situ.

The viral nuclear egress complex (NEC) allows herpesvirus capsids to escape from the nucleus without compromising the nuclear envelope integrity. The NEC lattice assembles on the inner nuclear membrane and mediates the budding of nascent nucleocapsids into the perinuclear space and their subsequent release into the cytosol. Its essential role makes it a potent antiviral target, necessitating structural information in the context of a cellular infection. Here we determined structures of NEC-capsid interfaces in situ using electron cryo-tomography, showing a substantial structural heterogeneity. In addition, while the capsid is associated with budding initiation, it is not required for curvature formation. By determining the NEC structure in several conformations, we show that curvature arises from an asymmetric assembly of disordered and hexagonally ordered lattice domains independent of pUL25 or other viral capsid vertex components. Our results advance our understanding of the mechanism of nuclear egress in the context of a living cell.

Herpesviruses in migrating procellariforms, northeastern Brazil.

Seabirds are one of the most threatened avian groups. Viruses, including herpesvirus, represent considerable threats to marine avifauna. Herein, our goal was to survey herpesvirus in Procellariiformes that stranded in Brazil between June and July 2021. We analyzed 12 Cory's shearwaters (Calonectris borealis), two Great Shearwaters (Ardenna gravis, syn. Puffinus gravis) and one Yellow-nosed Albatross (Thalassarche chlororynchos) found in an unusual mortality event in Bahía state, northeastern Brazil. After necropsy, selected tissue samples were tested for herpesvirus using a broad-range nested PCR. Overall, 20% (3/15) of the birds were herpesvirus-positive, i.e., two Cory's Shearwaters and one Great Shearwater. One alphaherpesvirus sequence type was identified in each shearwater species, classified into the genus Mardivirus. This study describes two likely novel herpesviruses in shearwaters, contributing to the currently very scarce data regarding infectious agents in Procellariiformes. Further studies are necessary to evaluate the presence and characteristics of herpesvirus in Procellariiformes, and the presence (or not) of related disease in order to understand the epidemiology of this infectious agent and eventually contribute to the conservation of this endangered seabird group.

Development of multi epitope subunit vaccines against emerging carp viruses Cyprinid herpesvirus 1 and 3 using immunoinformatics approach.

Cyprinid herpesvirus is a causative agent of a destructive disease in common and koi carp (Cyprinus carpio), which leads to substantial global financial losses in aquaculture industries. Among the strains of C. herpesvirus, C. herpesvirus 1 (CyHV-1) and C. herpesvirus 3 (CyHV-3) are known as highly pathogenic to carp fishes in Europe, Asia, and Africa. To date, no effective vaccine has been developed to combat these viruses. This study aimed to develop unique multi-epitope subunit vaccines targeting the CyHV-1 and CyHV-3 using a reverse vaccinology approach. The study began with a comprehensive literature review to identify the most critical proteins, which were then subjected to in silico analyses to predict highly antigenic epitopes. These analyses involved assessing antigenicity, transmembrane topology screening, allergenecity, toxicity, and molecular docking approaches. We constructed two multi-epitope-based vaccines incorporating a suitable adjuvant and appropriate linkers. It revealed that both the vaccines are non-toxic and immunogenic. The tertiary structures of the vaccine proteins were generated, refined, and validated to ensure their suitability. The binding affinity between the vaccine constructs and TLR3 and TLR5 receptors were assessed by molecular docking studies. Molecular dynamics simulations indicated that vaccine construct V1 exhibited greater stability with both TLR3 and TLR5 based on RMSD analysis. Hydrogen bond analysis revealed a stronger binding affinity between the vaccine constructs and TLR5 compared to TLR3. Furthermore, MM-PBSA analysis suggested that both vaccine constructs exhibited a better affinity for TLR5. Considering all aspects, the results suggest that in silico development of CyHV vaccines incorporating multiple epitopes holds promise for management of diseases caused by CyHV-1 and CyHV-3. However, further in vivo trials are highly recommended to validate the efficacies of these vaccines.

Presence of herpesviruses, parvoviruses, and polyomaviruses in sinonasal lymphoma.

PURPOSE: Sinonasal lymphoma (SL) is a rare lymphatic neoplasm of the nasal cavities, paranasal sinuses and nasopharynx. Whereas some risk factors for SL subtypes have been identified, their aetiology is unknown. Along with other predisposing factors, the viral association of lymphomas, such as Epstein-Barr virus (EBV) and Burkitt and Hodgkin lymphomas, is well-established. Modern molecular biology techniques have enabled the discovery of novel human viruses, exemplified by the protoparvovirus cutavirus (CuV), associated with cutaneous T-cell lymphoma. These findings, and the anatomical location of the sinonasal tract with its rich microbiome and infectious agents, justify in-depth studies among SL. METHODS: We analysed the presence of 20 viruses of Orthoherpesviridae, Parvoviridae, and Polyomaviridae by qPCR in 24 SL tumours. We performed RNAscope in situ hybridisation (RISH) to localize the viruses. Parvovirus-specific IgG was analysed by enzyme immunoassay and targeted next-generation sequencing (NGS) was applied to detect CuV in plasma. RESULTS: We detected viral DNA in 15/24 (63%) tumours; nine of EBV, six of human herpesvirus (HHV) -7, four each of HHV-6B and parvovirus B19, two of cytomegalovirus, and one each of CuV and Merkel-cell polyomavirus. We found tumours with up to four viruses per tumour, and localized CuV and EBV DNAs by RISH. Two of the ten plasma samples exhibited CuV IgG, and one plasma sample demonstrated CuV viremia by NGS. CONCLUSION: Viruses were frequent findings in SL. The EBV detection rate was high in diffuse large B-cell lymphoma, and co-detections with other viruses were prevalent.

Development of real-time recombinase polymerase amplification (RPA) and RPA combined with lateral flow dipstick (LFD) assays for the rapid and sensitive detection of cyprinid herpesvirus 3.

In this issue, we established rapid, cost-effective, and simple detection methods including recombines polymerase amplification with lateral flow dipstick (RPA-LFD) and real-time RPA for cyprinid herpesvirus 3(CyHV-3), and evaluated their sensitivity, specificity, and applicability, the real-time RPA method could achieve sensitive diagnosis of CyHV-3 within 1.3 copies per reaction, respectively. The real-time RPA method is 10-fold more sensitive than RPA-LFD method. The exact number of CyHV-3 can be calculated in each sample by real-time RPA. The sera from koi also can be tested in these methods. In addition, no cross-reaction was observed with other related pathogens, including carp oedema virus (CEV), spring viraemia of carp virus (SVCV), cyprinid herpesvirus 1(CyHV-1), cyprinid herpesvirus 2(CyHV-2), type I grass carp reovirus (GCRV-I), type II GCRV (GCRV-II), type III GCRV (GCRV-III), and Aeromonas hydrophila.

Alzheimer's disease and herpes viruses: Current events and perspectives.

Alzheimer's disease (AD) is a real and current scientific and societal challenge. Alzheimer's disease is characterised by a neurodegenerative neuroinflammatory process, but the etiopathogenetic mechanisms are still unclear. The possible infectious aetiology and potential involvement of Herpes viruses as triggers for the formation of extracellular deposits of amyloid beta (Aß) peptide (amyloid plaques) and intraneuronal aggregates of hyperphosphorylated and misfold could be a possible explanation. In fact, the possible genetic interference of Herpes viruses with the genome of the host neuronal cell or the stimulation of the infection to a continuous immune response with a consequent chronic inflammation could constitute those mechanisms underlying the development of AD, with possible implications in the understanding and management of the disease. Herpes viruses could be significantly involved in the pathogenesis of AD and in particular, their ability to reactivate in particular conditions such as immunocompromise and immunosenescence, could explain the neurological damage characteristic of AD. Our review aims to evaluate the state of the art of knowledge and perspectives regarding the potential relationship between Herpes viruses and AD, in order to be able to identify the possible etiopathogenetic mechanisms and the possible therapeutic implications.

Therapeutic vaccines for herpesviruses.

Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine-zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.

First detection of Koi herpesvirus disease (KHVD) in Garmian, Kurdistan region of Iraq: A clinical and molecular study.

INTRODUCTION: Koi herpesvirus disease (KHVD) is attributed to cyprinid herpesvirus-3 (CyHV-3) and predominantly affects common carp and ornamental koi carp (Cyprinus carpio). This viral infection leads to substantial morbidity and mortality among these fish species. This study aimed to confirm the presence of KHVD in the Kurdistan region of Iraq by employing clinical and optimized molecular assays on fish populations experiencing high mortality among common carp in carp farms. METHODOLOGY: The present research was conducted in the Kalar district, situated at the heart of Garmian province in Iraqi Kurdistan. four samples from common carp fish farms were received by our laboratory. These samples specifically displaying clinical signs associated with koi herpesvirus (KHV) infection, were subjected to clinical examinations, and PCR assay in addition to sequence analysis. RESULTS: The results of the current study revealed that the observed clinical signs, particularly gill necrosis, skin lesions, and sunken eyes, closely resembled the clinical signs of KHVD in common carp fish. In addition, PCR, nested PCR, and sequence analysis assay detected appropriate DNA fragments of the CyHV-3 major capsid protein gene confirming the first detection of KHVD in common carp fish in the Kurdistan region of Iraq. CONCLUSION: In this study, the results confirm the detection of KHVD in the Kurdistan region, Iraq, for the first time. This study revealed that CyHV-3 was responsible for KHVD-related signs and symptoms. Based on these results, it is strongly recommended that comprehensive studies be initiated to investigate the prevalence and distribution of CyHV-3.

The Terminase Complex of Each Human Herpesvirus.

The human herpesviruses (HHVs) are classified into the following three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. These HHVs have distinct pathological features, while containing a highly conserved viral replication pathway. Among HHVs, the basic viral particle structure and the sequential processes of viral replication are nearly identical. In particular, the capsid formation mechanism has been proposed to be highly similar among herpesviruses, because the viral capsid-organizing proteins are highly conserved at the structural and functional levels. Herpesviruses form capsids containing the viral genome in the nucleus of infected cells during the lytic phase, and release infectious virus (i.e., virions) to the cell exterior. In the capsid formation process, a single-unit-length viral genome is encapsidated into a preformed capsid. The single-unit-length viral genome is produced by cleavage from a viral genome precursor in which multiple unit-length viral genomes are tandemly linked. This encapsidation and cleavage is carried out by the terminase complex, which is composed of viral proteins. Since the terminase complex-mediated encapsidation and cleavage is a virus-specific mechanism that does not exist in humans, it may be an excellent inhibitory target for anti-viral drugs with high virus specificity. This review provides an overview of the functions of the terminase complexes of HHVs.

Pseudorabies virus gM and its homologous proteins in herpesviruses induce mitochondria-related apoptosis involved in viral pathogenicity.

Apoptosis is a critical host antiviral defense mechanism. But many viruses have evolved multiple strategies to manipulate apoptosis and escape host antiviral immune responses. Herpesvirus infection regulated apoptosis; however, the underlying molecular mechanisms have not yet been fully elucidated. Hence, the present study aimed to study the relationship between herpesvirus infection and apoptosis in vitro and in vivo using the pseudorabies virus (PRV) as the model virus. We found that mitochondria-dependent apoptosis was induced by PRV gM, a late protein encoded by PRV UL10, a virulence-related gene involved in enhancing PRV pathogenicity. Mechanistically, gM competitively combines with BCL-XL to disrupt the BCL-XL-BAK complex, resulting in BCL-2-antagonistic killer (BAK) oligomerization and BCL-2-associated X (BAX) activation, which destroys the mitochondrial membrane potential and activates caspase-3/7 to trigger apoptosis. Interestingly, similar apoptotic mechanisms were observed in other herpesviruses (Herpes Simplex Virus-1 [HSV-1], human cytomegalovirus [HCMV], Equine herpesvirus-1 [EHV-1], and varicella-zoster virus [VZV]) driven by PRV gM homologs. Compared with their parental viruses, the pathogenicity of PRV-ΔUL10 or HSV-1-ΔUL10 in mice was reduced with lower apoptosis and viral replication, illustrating that UL10 is a key virulence-related gene in PRV and HSV-1. Consistently, caspase-3 deletion also diminished the replication and pathogenicity of PRV and HSV-1 in vitro and in mice, suggesting that caspase-3-mediated apoptosis is closely related to the replication and pathogenicity of PRV and HSV-1. Overall, our findings firstly reveal the mechanism by which PRV gM and its homologs in several herpesviruses regulate apoptosis to enhance the viral replication and pathogenicity, and the relationship between gM-mediated apoptosis and herpesvirus pathogenicity suggests a promising approach for developing attenuated live vaccines and therapy for herpesvirus-related diseases.