-
Viruses Sep 2021Cell-cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All... (Review)
Review
Cell-cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All enveloped viruses express one or more proteins that drive the fusion of the viral envelope with cellular membranes. The same proteins can mediate the fusion of the plasma membranes of adjacent cells, leading to the formation of multinucleated syncytia. While cell-cell fusion triggered by alpha- and gammaherpesviruses is well-studied, much less is known about the fusogenic potential of betaherpesviruses such as human cytomegalovirus (HCMV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). These are slow-growing viruses that are highly prevalent in the human population and associated with several diseases, particularly in individuals with an immature or impaired immune system such as fetuses and transplant recipients. While HHV-6 and HHV-7 are strictly lymphotropic, HCMV infects a very broad range of cell types including epithelial, endothelial, mesenchymal, and myeloid cells. Syncytia have been observed occasionally for all three betaherpesviruses, both during in vitro and in vivo infection. Since cell-cell fusion may allow efficient spread to neighboring cells without exposure to neutralizing antibodies and other host immune factors, viral-induced syncytia may be important for viral dissemination, long-term persistence, and pathogenicity. In this review, we provide an overview of the viral and cellular factors and mechanisms identified so far in the process of cell-cell fusion induced by betaherpesviruses and discuss the possible consequences for cellular dysfunction and pathogenesis.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Betaherpesvirinae; Cell Fusion; Cytomegalovirus; Giant Cells; Herpesviridae; Herpesviridae Infections; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Viral Envelope Proteins; Virus Internalization
PubMed: 34696402
DOI: 10.3390/v13101973 -
Viruses Jan 2022Treatment options for human cytomegalovirus (CMV) remain limited and are associated with significant adverse effects and the selection of resistant CMV strains in...
Treatment options for human cytomegalovirus (CMV) remain limited and are associated with significant adverse effects and the selection of resistant CMV strains in transplant recipients and congenitally infected infants. Although most approved drugs target and inhibit the CMV DNA polymerase, additional agents with distinct mechanisms of action are needed for the treatment and prevention of CMV. In a large high throughput screen using our CMV-luciferase reporter Towne, we identified several unique inhibitors of CMV replication. Here, we synthesize and test in vitro 13 analogs of the original NCGC2955 hit (). Analogs with no activity against the CMV-luciferase at 10 µM and 30 µM (-, -) were removed from further analysis. Three analogs (-) inhibited CMV replication in infected human foreskin fibroblasts. The EC of () was 1.7 ± 0.6 µM and 1.99 ± 0.15 µM, based on luciferase and plaque assay, respectively. Compounds , , and showed similar activities: the EC values of were 0.21 ± 0.06 µM (luciferase) and 0.55 ± 0.06 (plaque), of : 0.28 ± 0.06 µM and 0.42 ± 0.07, and of : 0.30 ± 0.05 µM (luciferase) and 0.35 ± 0.07 (plaque). The CC for , , and in non-infected human foreskin fibroblasts was > 500µM, yielding a selectivity index of >1500. Compounds , , and were also tested in CMV-infected primary human hepatocytes and showed a dose-response against CMV by luciferase activity and viral protein expression. None of the active compounds inhibited herpes simplex virus 1 or 2. Compounds and inhibited mouse CMV replication in vitro. Both inhibited CMV at late stages of replication; reduced virus yield at all late time points, although not to the same degree as letermovir. Finally, the activity of analog was additive with newly identified CMV inhibitors (MLS8969, NFU1827, MSL8554, and MSL8091) and with ganciclovir. Further structural activity development should provide promising anti-CMV agents for use in clinical studies.
Topics: Animals; Antiviral Agents; Cells, Cultured; Cytomegalovirus; Ganciclovir; Hepatocytes; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Mice; Microbial Sensitivity Tests; Molecular Structure; Muromegalovirus; Structure-Activity Relationship; Viral Load; Virus Replication
PubMed: 35215828
DOI: 10.3390/v14020234 -
Proceedings of the National Academy of... Jan 2022Transmissible vaccines have the potential to revolutionize how zoonotic pathogens are controlled within wildlife reservoirs. A key challenge that must be overcome is...
Transmissible vaccines have the potential to revolutionize how zoonotic pathogens are controlled within wildlife reservoirs. A key challenge that must be overcome is identifying viral vectors that can rapidly spread immunity through a reservoir population. Because they are broadly distributed taxonomically, species specific, and stable to genetic manipulation, betaherpesviruses are leading candidates for use as transmissible vaccine vectors. Here we evaluate the likely effectiveness of betaherpesvirus-vectored transmissible vaccines by developing and parameterizing a mathematical model using data from captive and free-living mouse populations infected with murine cytomegalovirus (MCMV). Simulations of our parameterized model demonstrate rapid and effective control for a range of pathogens, with pathogen elimination frequently occurring within a year of vaccine introduction. Our results also suggest, however, that the effectiveness of transmissible vaccines may vary across reservoir populations and with respect to the specific vector strain used to construct the vaccine.
Topics: Algorithms; Animal Diseases; Animals; Bayes Theorem; Betaherpesvirinae; Disease Reservoirs; Disease Vectors; Genetic Vectors; Herpesviridae Infections; Immunogenicity, Vaccine; Mice; Models, Theoretical; Muromegalovirus; Nucleic Acid-Based Vaccines; Prevalence; Vaccines
PubMed: 35046024
DOI: 10.1073/pnas.2108610119 -
Dermatology (Basel, Switzerland) 2016Pityriasis rosea (PR) is an acute, self-limiting exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and/or HHV-7.... (Review)
Review
Pityriasis rosea (PR) is an acute, self-limiting exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and/or HHV-7. The disease typically begins with a single, erythematous plaque followed by a secondary eruption with lesions on the cleavage lines of the trunk (configuration of a 'Christmas tree'). The duration may vary from 2 weeks to a few months. Besides the typical presentation of PR, atypical forms have been described. The previous classifications of PR are mainly based on its atypical morphological features rather than on the pathogenetic mechanisms that underlie the different presentations of the disease. Notably, most of the morphologically atypical forms follow a course amenable to the classic form. The classification that we propose, taking into account the pathogenesis, clinical features, and course of the disease, is easy and intuitive and may be helpful in identifying the atypical forms of PR in order to avoid misdiagnosis and establish the best treatment options. Finally, this classification provides indications for managing potentially harmful forms of PR (such as PR in pregnancy) and PR-like eruptions.
Topics: Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Pityriasis Rosea
PubMed: 27096928
DOI: 10.1159/000445375 -
Xenotransplantation Sep 2022The potential for a donor-derived transmission of porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) to the recipient has been recognized since pigs were considered... (Review)
Review
The potential for a donor-derived transmission of porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) to the recipient has been recognized since pigs were considered candidate donors for xenotransplantation. This review gives a short description of the viral properties and summarizes the current evidence of the effects of PCMV/PRV transmission in preclinical xenotransplantation. Despite evidence that PCMV/PRV does not infect human and non-human primate cells, activation in the transplanted organ and detrimental systemic complications have been described. As PCMV/PRV is a herpesvirus able to establish latency, the importance of adequate screening of donor pigs is emphasized, as no efficient treatment is available. Furthermore, easy and successful ways of elimination of PCMV/PRV from pig herds are indicated.
Topics: Animals; Cytomegalovirus; Cytomegalovirus Infections; Humans; Primates; Roseolovirus; Swine; Tissue Donors; Transplantation, Heterologous
PubMed: 36082418
DOI: 10.1111/xen.12775 -
Current Opinion in Virology Dec 2014Recent technological advances have led to an explosion in the system-wide profiling of biological processes in the study of herpesvirus biology, herein referred to as... (Review)
Review
Recent technological advances have led to an explosion in the system-wide profiling of biological processes in the study of herpesvirus biology, herein referred to as '-omics'. In many cases these approaches have revealed novel virus-induced changes to host cell biology that can be targeted with new antiviral therapeutics. Despite these successes, -omics approaches are not widely applied in the study of roseoloviruses. Here we describe examples of how -omics studies have shaped our understanding of herpesvirus biology, and discuss how these approaches might be used to identify host and viral factors that mediate roseolovirus pathogenesis.
Topics: Gene Expression Profiling; Genomics; Host-Pathogen Interactions; Humans; Metabolomics; Proteomics; Roseolovirus; Systems Biology; Virology
PubMed: 25437230
DOI: 10.1016/j.coviro.2014.09.021 -
Microbiology and Molecular Biology... Jun 2008Human cytomegalovirus (HCMV) is a common, medically relevant human herpesvirus. The tegument layer of herpesvirus virions lies between the genome-containing capsids and... (Review)
Review
Human cytomegalovirus (HCMV) is a common, medically relevant human herpesvirus. The tegument layer of herpesvirus virions lies between the genome-containing capsids and the viral envelope. Proteins within the tegument layer of herpesviruses are released into the cell upon entry when the viral envelope fuses with the cell membrane. These proteins are fully formed and active and control viral entry, gene expression, and immune evasion. Most tegument proteins accumulate to high levels during later stages of infection, when they direct the assembly and egress of progeny virions. Thus, viral tegument proteins play critical roles at the very earliest and very last steps of the HCMV lytic replication cycle. This review summarizes HCMV tegument composition and structure as well as the known and speculated functions of viral tegument proteins. Important directions for future investigation and the challenges that lie ahead are identified and discussed.
Topics: Cytomegalovirus; Cytomegalovirus Infections; Humans; Viral Structural Proteins; Virion; Virus Replication
PubMed: 18535146
DOI: 10.1128/MMBR.00040-07 -
Oncotarget Sep 2015
Topics: Cytomegalovirus; Cytomegalovirus Infections; Endothelial Cells; Endothelium; Genome, Viral; Humans; Immune System; Inflammation; Phenotype; Viral Proteins; Virus Replication
PubMed: 26309089
DOI: 10.18632/oncotarget.5246 -
International Journal of Molecular... Jul 2021The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of... (Review)
Review
The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of viruses, include human cytomegalovirus (HCMV), human herpesvirus (HHV) 6A, HHV-6B, and HHV-7. These viruses have evolved numerous mechanisms for evading the host response. In this review, we will highlight the complex interplay between betaherpesviruses and the human immune response, focusing on protein function. We will explore methods by which the immune system first responds to betaherpesvirus infection as well as mechanisms by which viruses subvert normal cellular functions to evade the immune system and facilitate viral latency, persistence, and reactivation. Lastly, we will briefly discuss recent advances in vaccine technology targeting betaherpesviruses. This review aims to further elucidate the dynamic interactions between betaherpesviruses and the human immune system.
Topics: Betaherpesvirinae; Herpesviridae Infections; Humans; Immune Evasion; Immunity
PubMed: 34299120
DOI: 10.3390/ijms22147503 -
Journal of Virology Dec 2014Elephant populations are under intense pressure internationally from habitat destruction and poaching for ivory and meat. They also face pressure from infectious agents,...
Elephant populations are under intense pressure internationally from habitat destruction and poaching for ivory and meat. They also face pressure from infectious agents, including elephant endotheliotropic herpesvirus 1 (EEHV1), which kills ~20% of Asian elephants (Elephas maximus) born in zoos and causes disease in the wild. EEHV1 is one of at least six distinct EEHV in a phylogenetic lineage that appears to represent an ancient but newly recognized subfamily (the Deltaherpesvirinae) in the family Herpesviridae.
Topics: Animals; Betaherpesvirinae; Blood; Genetic Variation; Herpesviridae Infections
PubMed: 25231304
DOI: 10.1128/JVI.02359-14