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Viruses Oct 2023Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions... (Review)
Review
Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of i.e., human herpesvirus-1/herpes simplex virus-1 (), human herpesvirus-5/cytomegalovirus () and human herpesvirus -8/Kaposi's sarcomavirus (). Most of the current knowledge is based on alpha herpesviruses, in particular HSV-1. While some tegument proteins are released into the cytoplasm after virus entry, several tegument proteins remain associated with the capsid and are responsible for transport to and docking at the nucleus. After replication and capsid formation, the capsid is enveloped at the nuclear membrane, which is referred to as primary envelopment, followed by de-envelopment and release into the cytoplasm. This requires involvement of at least three tegument proteins. Subsequently, multiple interactions between tegument proteins and capsid proteins, other tegument proteins and glycoproteins are required for assembly of the virus particles and envelopment at the Golgi, with certain tegument proteins acting as the central hub for these interactions. Some redundancy in these interactions ensures appropriate morphogenesis.
Topics: Humans; Capsid Proteins; Capsid; Virus Assembly; Herpesviridae; Herpesvirus 1, Human; Herpesvirus 8, Human; Morphogenesis; Virion; Viral Structural Proteins
PubMed: 37896835
DOI: 10.3390/v15102058 -
Vaccine Jan 2024In countries where varicella vaccination is not on the routine childhood immunisation schedule, such as those in the United Kingdom (UK), chickenpox is an almost... (Review)
Review
BACKGROUND
In countries where varicella vaccination is not on the routine childhood immunisation schedule, such as those in the United Kingdom (UK), chickenpox is an almost universal disease of childhood. Chickenpox can cause serious complications, particularly in infants, pregnant women, and the immunocompromised. In November 2023 the varicella vaccine was recommended for inclusion in the UK routine childhood immunisation schedule. Successful rollout of the vaccine may be hindered by parental concerns about vaccine safety and efficacy, and perceptions of chickenpox as a mild illness.
OBJECTIVE
To examine parental perceptions of chickenpox and varicella vaccination, which may be crucial to effective vaccination campaigns.
DESIGN
Qualitative systematic review and thematic analysis.
METHODS
Six electronic databases were systematically searched for studies published between 2016 and 2023: CINAHL, EMBASE, MEDLINE, PsycInfo, PubMed, and Web of Science. The included studies were appraised against the Critical Appraisal Skills Program checklist for qualitative studies. Thematic analysis was used to analyse qualitative data, through the development of themes.
RESULTS
22 articles were included in this review, and five themes identified: perceptions that chickenpox is a mild illness, that parents have concerns about varicella vaccine efficacy and safety, a notion of natural immunity as superior, social determinants of health influence vaccine decision making, and vaccination is overwhelming perceived as a parental decision.
CONCLUSIONS
Whilst some parents displayed an acceptance and willingness to vaccinate against chickenpox, many expressed concerns, and perceived chickenpox as a routine unworrying childhood illness. Analysis demonstrated a knowledge gap in understanding UK parental opinions regarding chickenpox and varicella vaccination, highlighting the need for research in this area, particularly given ongoing reconsideration for inclusion in the UK vaccination schedule.
REGISTRATION
The review was registered on PROSPERO, registration ID CRD42021236120.
Topics: Pregnancy; Infant; Humans; Female; Chickenpox Vaccine; Chickenpox; Herpesvirus 3, Human; Parents; Vaccination; Vaccines, Attenuated
PubMed: 38129287
DOI: 10.1016/j.vaccine.2023.12.045 -
Emerging Microbes & Infections Dec 2023In recent years, an increasing number of emerging and remerging virus outbreaks have occurred and the rapid development of vaccines against these viruses has been...
In recent years, an increasing number of emerging and remerging virus outbreaks have occurred and the rapid development of vaccines against these viruses has been crucial. Controlling the replication of premature termination codon (PTC)-containing viruses is a promising approach to generate live but replication-defective viruses that can be used for potent vaccines. Here, we used anticodon-engineered transfer RNAs (ACE-tRNAs) as powerful precision switches to control the replication of PTC-containing viruses. We showed that ACE-tRNAs display higher potency of reading through PTCs than genetic code expansion (GCE) technology. Interestingly, ACE-tRNA has a site preference that may influence its read-through efficacy. We further attempted to use ACE-tRNAs as a novel viral vaccine platform. Using a human immunodeficiency virus type 1 (HIV-1) pseudotyped virus as an RNA virus model, we found that ACE-tRNAs display high potency for read-through viral PTCs and precisely control their production. Pseudorabies virus (PRV), a herpesvirus, was used as a DNA virus model. We found that ACE-tRNAs display high potency for reading through viral PTCs and precisely controlling PTC-containing virus replication. In addition, PTC-engineered PRV completely attenuated and lost virulence in mice , and immunization with PRV containing a PTC elicited a robust immune response and provided complete protection against wild-type PRV challenge. Overall, replication-controllable PTC-containing viruses based on ACE-tRNAs provide a new strategy to rapidly attenuate virus infection and prime robust immune responses. This technology can be used as a platform for rapidly developing viral vaccines in the future.
Topics: Humans; Mice; Animals; Swine; Pseudorabies; Viral Vaccines; Herpesvirus 1, Suid; Vaccination; RNA, Transfer; Antibodies, Viral; Swine Diseases
PubMed: 36482724
DOI: 10.1080/22221751.2022.2157339 -
Journal of Clinical Virology : the... Oct 2023Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have...
BACKGROUND
Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have largely replaced viral culture for HSV diagnosis and molecular antiviral resistance testing is available for many viruses, HSV resistance testing continues to rely on phenotypic, viral culture-based methods, requiring weeks for results. Consequently, treatment of suspected HSV resistance remains largely empiric.
METHODS
We used HSV whole genome sequencing and a database of previously characterized HSV acyclovir and foscarnet resistance mutations to evaluate the performance of genotypic antiviral resistance testing among 19 control strains compared to in-house plaque reduction assay (PRA) and 25 clinical isolates sent for reference lab PRA antiviral resistance testing.
RESULTS
Among control strains, 23/29 (79.3%) results were concordant, 5 (17.2%) were indeterminate, and 1 (3.4%) was discordant. Indeterminate results were caused by variants of uncertain significance (VUS), including mutations without published phenotypes and mutations with contradictory results. Among clinical isolates, 14/40 (35%) results were concordant, 17 (42.5%) were indeterminate, and 9 (22.5%) were discordant. All discordant results were in reportedly phenotypically-susceptible HSV-1 strains yet possessed resistance mutations. Three contained resistant subpopulations. 6/8 (75%) discordant phenotypes were concordant with resistant genotypes upon repeat PRA.
CONCLUSIONS
These data support the combination of genotypic and phenotypic testing to diagnose HSV resistance more accurately and likely more rapidly than phenotypic testing alone. Genotypic context of resistance mutations and the ability of viral strains to form plaques in culture may affect phenotypic resistance results, highlighting the limitations of PRA alone as a gold standard method.
Topics: Humans; Antiviral Agents; Herpesvirus 2, Human; Acyclovir; Foscarnet; Herpesvirus 1, Human; Genotype; Drug Resistance, Viral; Herpes Simplex
PubMed: 37586184
DOI: 10.1016/j.jcv.2023.105554 -
Emerging Microbes & Infections Dec 2024Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster...
Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T-cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signalling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T-cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.
Topics: Animals; Mice; Herpes Zoster Vaccine; Macaca mulatta; mRNA Vaccines; Herpes Zoster; Herpesvirus 3, Human
PubMed: 38258878
DOI: 10.1080/22221751.2024.2309985 -
Virology Journal Aug 2023Viral infections of the central nervous system (CNS) are common worldwide and result in considerable morbidity and mortality associated with neurologic illness. Until...
Viral infections of the central nervous system (CNS) are common worldwide and result in considerable morbidity and mortality associated with neurologic illness. Until now, there have been no epidemiologic data regarding viruses causing aseptic meningitis, encephalitis, and CNS infections in Egypt. We investigated 1735 archived cerebrospinal fluid samples collected from Egyptian patients between 2016 and 2019 and performed molecular characterization for infection for12 different viruses: herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesviruses 6 and 7 (HHV-6 and HHV-7), human enteroviruses (HEVs), human parechovirus (HPeV), parvovirus B19 (B19V), adenovirus (AdV), and mumps virus (MuV). All included samples were negative for bacterial infection. Our results indicated a relatively high prevalence of viral infection, with HEVs being the most prevalent viruses, followed by HSV-1, EBV, and then HSV-2. The highest prevalence was among male patients, peaking during the summer. Data obtained from this study will contribute to improving the clinical management of viral infections of the CNS in Egypt.
Topics: Humans; Male; Egypt; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Polymerase Chain Reaction; Virus Diseases; Viruses; Central Nervous System Infections; Herpesvirus 3, Human; Herpesvirus 2, Human; Enterovirus; DNA, Viral
PubMed: 37533069
DOI: 10.1186/s12985-023-02079-y -
Frontiers in Cellular and Infection... 2023Herpes simplex virus (HSV) is the most widely prevalent herpes virus worldwide, and the herpetic encephalitis and genital herpes caused by HSV infection have caused... (Review)
Review
Herpes simplex virus (HSV) is the most widely prevalent herpes virus worldwide, and the herpetic encephalitis and genital herpes caused by HSV infection have caused serious harm to human health all over the world. Although many anti-HSV drugs such as nucleoside analogues have been ap-proved for clinical use during the past few decades, important issues, such as drug resistance, toxicity, and high cost of drugs, remain unresolved. Recently, the studies on the anti-HSV activities of marine natural products, such as marine polysaccharides, marine peptides and microbial secondary metabolites are attracting more and more attention all over the world. This review discusses the recent progress in research on the anti-HSV activities of these natural compounds obtained from marine organisms, relating to their structural features and the structure-activity relationships. In addition, the recent findings on the different anti-HSV mechanisms and molecular targets of marine compounds and their potential for therapeutic application will also be summarized in detail.
Topics: Humans; Simplexvirus; Herpes Simplex; Structure-Activity Relationship
PubMed: 38259968
DOI: 10.3389/fcimb.2023.1302096 -
Viruses May 2024Marek's disease (MD), caused by (GaAHV2) or Marek's disease herpesvirus (MDV), is a devastating disease in chickens characterized by the development of lymphomas...
Marek's disease (MD), caused by (GaAHV2) or Marek's disease herpesvirus (MDV), is a devastating disease in chickens characterized by the development of lymphomas throughout the body. Vaccine strains used against MD include 3 (GaAHV3), a non-oncogenic chicken alphaherpesvirus homologous to MDV, and homologous meleagrid alphaherpesvirus 1 (MeAHV1) or turkey herpesvirus (HVT). Previous work has shown most of the MDV gC produced during in vitro passage is secreted into the media of infected cells although the predicted protein contains a transmembrane domain. We formerly identified two alternatively spliced gC mRNAs that are secreted during MDV replication in vitro, termed gC104 and gC145 based on the size of the intron removed for each (gC) transcript. Since gC is conserved within the subfamily, we hypothesized GaAHV3 (strain 301B/1) and HVT also secrete gC due to mRNA splicing. To address this, we collected media from 301B/1- and HVT-infected cell cultures and used Western blot analyses and determined that both 301B/1 and HVT produced secreted gC. Next, we extracted RNAs from 301B/1- and HVT-infected cell cultures and chicken feather follicle epithelial (FFE) skin cells. RT-PCR analyses confirmed one splicing variant for 301B/1 gC (gC104) and two variants for HVT gC (gC104 and gC145). Interestingly, the splicing between all three viruses was remarkably conserved. Further analysis of predicted and validated mRNA splicing donor, branch point (BP), and acceptor sites suggested single nucleotide polymorphisms (SNPs) within the 301B/1 transcript sequence resulted in no gC145 being produced. However, modification of the 301B/1 gC145 donor, BP, and acceptor sites to the MDV sequences did not result in gC145 mRNA splice variant, suggesting mRNA splicing is more complex than originally hypothesized. In all, our results show that mRNA splicing of avian herpesviruses is conserved and this information may be important in developing the next generation of MD vaccines or therapies to block transmission.
Topics: Animals; Chickens; RNA Splicing; Viral Envelope Proteins; RNA, Messenger; Marek Disease; Mardivirus; Viral Proteins; Herpesvirus 2, Gallid; Alternative Splicing; Antigens, Viral
PubMed: 38793663
DOI: 10.3390/v16050782 -
Molecular Therapy : the Journal of the... Jan 2024Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor...
Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor cells, resulting in local inflammation, enhanced tumor antigen presentation, and boosting of antitumor cytotoxic lymphocytes. In contrast to HSV, cytomegalovirus (CMV) is nonlytic and reprograms infected myeloid cells, limiting their antigen-presenting functions and protecting them from recognition by natural killer (NK) cells. Here, we show that when co-injected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of proinflammatory cytokines, and enhanced systemic antitumor immune responses, leading to superior control of both injected and distant contralateral tumors. Deletion of mCMV genes m06, which degrades major histocompatibility complex class I (MHC class I), or m144, a viral MHC class I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, an mCMV recombinant lacking the m04 gene, which escorts MHC class I to the cell surface, showed superior HSV adjuvanticity. CMV is a potentially promising agent with which to reshape and enhance antitumor immune responses following oncolytic HSV therapy.
Topics: Animals; Mice; Herpesvirus 1, Human; Cytomegalovirus; Neoplasms; Oncolytic Virotherapy; Antigen Presentation; Cytomegalovirus Infections; Oncolytic Viruses
PubMed: 37927036
DOI: 10.1016/j.ymthe.2023.11.003 -
PLoS Pathogens Apr 2024Apoptosis is a critical host antiviral defense mechanism. But many viruses have evolved multiple strategies to manipulate apoptosis and escape host antiviral immune...
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.
Topics: Apoptosis; Animals; Herpesvirus 1, Suid; Mice; Mitochondria; Pseudorabies; Viral Proteins; Herpesviridae; Virus Replication; Humans; Mice, Inbred BALB C; Virulence
PubMed: 38669242
DOI: 10.1371/journal.ppat.1012146