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Frontiers in Immunology 2022Within the family , sub-family , and genus , there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B...
Within the family , sub-family , and genus , there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the . Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these data and experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.
Topics: Cytopathogenic Effect, Viral; Herpesviridae; Herpesvirus 6, Human; Humans; Neural Stem Cells; Virus Internalization
PubMed: 35911725
DOI: 10.3389/fimmu.2022.847106 -
Microbes and Infection Nov 2003Infection of mice with murine cytomegalovirus (MCMV) is an established model for studying human cytomegalovirus (HCMV) infection. Similarly to HCMV infection,... (Review)
Review
Infection of mice with murine cytomegalovirus (MCMV) is an established model for studying human cytomegalovirus (HCMV) infection. Similarly to HCMV infection, pathological changes and disease manifestations during MCMV infection are mainly dependent on the immune status of the mouse host. This review focuses mainly on the pathogenesis of MCMV infection in immunocompetent and immunodeficient and/or immature mice and discusses the principles of immunosurveillance of infection and the mechanisms by which this virus evades immune control.
Topics: Animals; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Humans
PubMed: 14623023
DOI: 10.1016/j.micinf.2003.09.007 -
Cells Jun 2022Herpesviral nuclear egress is a fine-tuned regulatory process that defines the nucleocytoplasmic release of viral capsids. Nuclear capsids are unable to traverse via... (Review)
Review
Herpesviral nuclear egress is a fine-tuned regulatory process that defines the nucleocytoplasmic release of viral capsids. Nuclear capsids are unable to traverse via nuclear pores due to the fact of their large size; therefore, herpesviruses evolved to develop a vesicular transport pathway mediating the transition across the two leaflets of the nuclear membrane. The entire process involves a number of regulatory proteins, which support the local distortion of the nuclear envelope. In the case of the prototype species of β-, the human cytomegalovirus (HCMV), the nuclear egress complex (NEC) is determined by the core proteins pUL50 and pUL53 that oligomerize, form capsid docking lattices and mediate multicomponent assembly with NEC-associated viral and cellular proteins. The NEC-binding principle is based on the hook-into-groove interaction through an N-terminal hook-like pUL53 protrusion that embraces an α-helical pUL50 binding groove. Thus far, the function and characteristics of herpesviral core NECs have been well studied and point to the groove proteins, such as pUL50, as the multi-interacting, major determinants of NEC formation and egress. This review provides closer insight into (i) sequence and structure conservation of herpesviral core NEC proteins, (ii) experimentation on cross-viral core NEC interactions, (iii) the essential functional roles of hook and groove proteins for viral replication, (iv) an establishment of assay systems for NEC-directed antiviral research and (v) the validation of NEC as putative antiviral drug targets. Finally, this article provides new insights into the conservation, function and antiviral targeting of herpesviral core NEC proteins and, into the complex regulatory role of hook and groove proteins during the assembly, egress and maturation of infectious virus.
Topics: Antiviral Agents; Cytomegalovirus; Humans; Infant, Newborn; Nuclear Envelope; Simplexvirus; Viral Proteins
PubMed: 35681532
DOI: 10.3390/cells11111837 -
Viruses Jul 2020Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in... (Review)
Review
Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients.
Topics: Animals; Cytomegalovirus; Cytomegalovirus Infections; Humans; Viral Proteins; Virus Activation; Virus Latency
PubMed: 32630219
DOI: 10.3390/v12070714 -
Viruses Nov 2019Viruses of the genus belong to the subfamily , family Roseoloviruses have been studied in humans, mice and pigs, but they are likely also present in other species.... (Review)
Review
Viruses of the genus belong to the subfamily , family Roseoloviruses have been studied in humans, mice and pigs, but they are likely also present in other species. This is the first comparative analysis of roseoloviruses in humans and animals. The human roseoloviruses human herpesvirus 6A (HHV-6A), 6B (HHV-6B), and 7 (HHV-7) are relatively well characterized. In contrast, little is known about the murine roseolovirus (MRV), also known as murine thymic virus (MTV) or murine thymic lymphotrophic virus (MTLV), and the porcine roseolovirus (PRV), initially incorrectly named porcine cytomegalovirus (PCMV). Human roseoloviruses have gained attention because they can cause severe diseases including encephalitis in immunocompromised transplant and AIDS patients and febrile seizures in infants. They have been linked to a number of neurological diseases in the immunocompetent including multiple sclerosis (MS) and Alzheimer's. However, to prove the causality in the latter disease associations is challenging due to the high prevalence of these viruses in the human population. PCMV/PRV has attracted attention because it may be transmitted and pose a risk in xenotransplantation, e.g., the transplantation of pig organs into humans. Most importantly, all roseoloviruses are immunosuppressive, the humoral and cellular immune responses against these viruses are not well studied and vaccines as well as effective antivirals are not available.
Topics: Animals; Antiviral Agents; Genome, Viral; Humans; Mice; Roseolovirus; Roseolovirus Infections; Swine; Virus Integration; Virus Latency
PubMed: 31801268
DOI: 10.3390/v11121108 -
Virology Sep 2018The MX dynamin GTPases inhibit diverse viruses at early post-entry phases. While MXA acts antiviral against influenza viruses, the anti HIV-1 activity of MXB was...
The MX dynamin GTPases inhibit diverse viruses at early post-entry phases. While MXA acts antiviral against influenza viruses, the anti HIV-1 activity of MXB was discovered recently. Here, we have studied the antiviral effect of MX proteins on murine cytomegalovirus (MCMV). Our data demonstrate that human MXB but not other human or murine MX proteins inhibit MCMV propagation. Evidently, the viral protein expression was delayed and the viral DNA amount in nucleus was diminished in MXB expressing cells indicating an obstruction of nuclear entry. Of note, MCMV did not deplete MX proteins. Considering the role of capsid on HIV-1 sensitivity to MXB, MXB binding to tested MCMV capsids was not detected. Moreover, MCMV restriction occurred only when MXB contained both the nuclear localization signal and a functional GTPase domain. Hence, we propose a new mode of inhibition of MCMV by MXB that is conspicuously different from that of HIV-1.
Topics: HEK293 Cells; Host-Pathogen Interactions; Humans; Immunologic Factors; Muromegalovirus; Myxovirus Resistance Proteins; Virus Internalization; Virus Replication
PubMed: 30032029
DOI: 10.1016/j.virol.2018.07.017 -
Viruses Mar 2014The complete genome of human cytomegalovirus (HCMV) was elucidated almost 25 years ago using a traditional cloning and Sanger sequencing approach. Analysis of the... (Review)
Review
The complete genome of human cytomegalovirus (HCMV) was elucidated almost 25 years ago using a traditional cloning and Sanger sequencing approach. Analysis of the genetic content of additional laboratory and clinical isolates has lead to a better, albeit still incomplete, definition of the coding potential and diversity of wild-type HCMV strains. The introduction of a new generation of massively parallel sequencing technologies, collectively called next-generation sequencing, has profoundly increased the throughput and resolution of the genomics field. These increased possibilities are already leading to a better understanding of the circulating diversity of HCMV clinical isolates. The higher resolution of next-generation sequencing provides new opportunities in the study of intrahost viral population structures. Furthermore, deep sequencing enables novel diagnostic applications for sensitive drug resistance mutation detection. RNA-seq applications have changed the picture of the HCMV transcriptome, which resulted in proof of a vast amount of splicing events and alternative transcripts. This review discusses the application of next-generation sequencing technologies, which has provided a clearer picture of the intricate nature of the HCMV genome. The continuing development and application of novel sequencing technologies will further augment our understanding of this ubiquitous, but elusive, herpesvirus.
Topics: Cytomegalovirus; Genomics; High-Throughput Nucleotide Sequencing; Host-Pathogen Interactions; Humans
PubMed: 24603756
DOI: 10.3390/v6031049 -
Virology Dec 2016Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of...
Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders.
Topics: Amides; Animals; Cell Line; Cells, Cultured; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Female; Humans; Male; Mice; Muromegalovirus; Tranquilizing Agents; Valproic Acid; Viral Load; Virus Replication
PubMed: 27657833
DOI: 10.1016/j.virol.2016.09.012 -
Current Opinion in Virology Feb 2012
Review
Topics: Animals; Cells; Cytomegalovirus; Cytomegalovirus Infections; Humans; Virus Internalization
PubMed: 22440964
DOI: 10.1016/j.coviro.2012.01.001 -
Virology Jul 2014A strain of the porcine cytomegalovirus (PCMV), which causes inclusion body rhinitis in newborn piglets, has been characterized with respect to its complete genome...
A strain of the porcine cytomegalovirus (PCMV), which causes inclusion body rhinitis in newborn piglets, has been characterized with respect to its complete genome sequence. The virus genome is 128,367bp, containing 79 predicted open reading frames (ORFs). Of these ORFs, 69 have counterparts in human herpesvirus 6A (HHV-6A), 6B (HHV-6B) and 7 (HHV-7), and two ORFs are homologous to other members in the subfamily Betaherpesvirinae. Eight ORFs have no homologs in herpesvirus. Homologs had higher identity and possessed similar orientation and location as roseoloviruses. The PCMV genome is a DR-U-DR type, similar to HHV-6A, HHV-6B and HHV-7, but the PCMV DR is shorter and lacks predicted genes and telomere-like sequences. Phylogenetic analyses of several core genes indicate that PCMV could be clustered in a branch with roseoloviruses. We suggest that PCMV could be classified as a member of the genus Roseolovirus of the subfamily Betaherpesvirinae.
Topics: Animals; Base Sequence; Cytomegalovirus; Cytomegalovirus Infections; Genome, Viral; Genomics; Humans; Molecular Sequence Data; Phylogeny; Swine; Swine Diseases; Viral Proteins
PubMed: 25010282
DOI: 10.1016/j.virol.2014.05.014