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Moulden, Jerome, Cathy Yea Won Sung, Ilija Brizic, Stipan Jonjic, and William Britt. "Murine Models of Central Nervous System Disease following Congenital Human Cytomegalovirus Infections." Pathogens 10, no. 8 (August 21, 2021): 1062. http://dx.doi.org/10.3390/pathogens10081062.
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Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections.
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Pyzik, Michal, Eve-Marie Gendron-Pontbriand, and Silvia M. Vidal. "The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/641702.
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Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses.
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Taher, Husam, Eisa Mahyari, Craig Kreklywich, Luke S. Uebelhoer, Matthew R. McArdle, Matilda J. Moström, Amruta Bhusari, et al. "In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome." PLOS Pathogens 16, no. 11 (November 24, 2020): e1008666. http://dx.doi.org/10.1371/journal.ppat.1008666.
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Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68–1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68–1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68–1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68–1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68–1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques.
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Mach, M., T. Stamminger, and G. Jahn. "Human Cytomegalovirus: Recent Aspects from Molecular Biology." Journal of General Virology 70, no. 12 (December 1, 1989): 3117–46. http://dx.doi.org/10.1099/0022-1317-70-12-3117.
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Vasilev, V. V., N. V. Rogozina, and A. A. Grineva. "Molecular genetic and clinical aspects of socially relevant viruses underlying congenital diseases." Russian Journal of Infection and Immunity 11, no. 4 (September 20, 2021): 635–48. http://dx.doi.org/10.15789/2220-7619-mga-1729.
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Congenital viral infectious diseases are characterized by polyetiologic pathology holding an important place in the structure of perinatal losses. Due to the wide distribution and lack of specific prophylaxis, the problem of herpesvirus infections is of greatest interest, namely of herpes infection caused by herpes simplex virus type 1 and 2, human herpes simplex virus type 6 and cytomegalovirus infection, as well as parvovirus infection B19. The opportunities to investigate a relation between manifestations of the infectious process and host molecular genetic characteristics have been expanded after developing full genome sequencing methods and creating genetic data international banks. It has been proven that herpes virus genetic variations can account for related neurovirulence, showing that diverse cytomegalovirus genotypes are associated with hepatosplenomegaly, hearing impairment and the symptoms of the central nervous system diseases. Nevertheless, the data on correlation between genotypes and clinical manifestations are still scarce and contradictory, whereas high level of variability becomes extremely evident while comparing genomic sequences of viral strains. The herpesvirus type 6 has been proven to integrate into germ cells with potential for subsequent vertical transmission of chromosomally integrated virus to the offspring and its further intergeneration inheritance. А direct relationship between B19V genospecies and disease manifestations including congenital infections has not yet been identified. Taking into account possible differences in the geographical distribution of such viruses on the territory of the Russian Federation, ethnic populational characteristics, and high frequency of related congenital infectious diseases with a wide range of clinical manifestations, it seems promising to expand scientific research on the genotyping of herpes simplex viruses, cytomegalovirus, herpes viruses type 6 and parvovirus B19V in Russia. The results of such studies will be demanded by practical healthcare in order to develop and use more effective etiotropic drugs and specific prophylaxis in the light of trends to develop personalized and preventive medicine.
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Koopmans, Marion. "Molecular aspects of human cytomegalovirus diseases. Frontiers of virology 2 Y." Virus Research 31, no. 2 (February 1994): 275. http://dx.doi.org/10.1016/0168-1702(94)90010-8.
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Griffiths, P. D., and J. E. Grundy. "Molecular biology and immunology of cytomegalovirus." Biochemical Journal 241, no. 2 (January 15, 1987): 313–24. http://dx.doi.org/10.1042/bj2410313.
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The application of modern biochemical techniques has led to a rapid improvement in our knowledge of the molecular biology of CMV. Several coding regions of the DNA genome have been identified with certainty and major virus-coded proteins have been given provisional names. The cascade expression of the CMV genome has been shown to be controlled by mechanisms similar to those found in other herpes viruses, together with novel post-transcriptional controls which remain to be defined. The control of CMV replication by the host involves both non-specific and specific defence mechanisms. The induction of natural killer cells and interferon early after CMV infection appears to be the most important aspects of the non-specific host defence against the virus. The cell-mediated immune response, in particular the generation of Tc cells against CMV early antigens, is probably the most important facet of the specific immune defence against CMV. When intact these defence mechanisms appear to be efficient in restricting viral replication; however, when such immunity is compromised, the balance rapidly swings in favour of the virus. As our understanding of the interaction between the host and the virus increases, it may be possible to redress the balance in such cases in favour of the host.
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Boeckh, Michael, and Guy Boivin. "Quantitation of Cytomegalovirus: Methodologic Aspects and Clinical Applications." Clinical Microbiology Reviews 11, no. 3 (July 1, 1998): 533–54. http://dx.doi.org/10.1128/cmr.11.3.533.
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SUMMARY Cytomegalovirus (CMV) is an important pathogen in transplant recipients and human immunodeficiency virus (HIV)-infected individuals. Major progress has been made in developing quantitative detection methods for CMV in recent years. Due to their high sensitivity, these assays can detect CMV early, and quantitation may be useful in predicting the patient’s risk for disease and in monitoring the effect of antiviral therapy. This review discusses methodological aspects of currently used quantitative assays for CMV (i.e., viral culture techniques, antigen detection assays, DNA detection assays including PCR, branched-DNA assay, and the DNA hybrid capture assay) and addresses the correlation of systemic and site-specific CMV load and CMV disease in different populations of immunosuppressed patients as well as the response to antiviral treatment. To date, direct antigen detection and molecular techniques have largely replaced traditional culture-based techniques for CMV quantitation. In general, a high systemic CMV load is correlated with CMV disease. This correlation is strong in the HIV-infected population and in solid-organ transplant recipients but less clear in allogeneic marrow transplant recipients. Measuring the viral load at specific anatomic sites may be an alternative way to assess disease activity in situations where the systemic viral load correlates poorly with disease activity. A reduction of the systemic CMV load also correlates with a response to antiviral treatment, but more research is needed to evaluate the role of viral load as a surrogate marker for drug resistance. Due to the widespread use of quantitative CMV detection techniques to direct and monitor antiviral treatment, there is a great need for an assessment of the reproducibility of test results and better standardization of the assays.
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Ynga-Durand, Dekhtiarenko, and Cicin-Sain. "Vaccine Vectors Harnessing the Power of Cytomegaloviruses." Vaccines 7, no. 4 (October 17, 2019): 152. http://dx.doi.org/10.3390/vaccines7040152.
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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.
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Tugizov, S. M., J. Y. Webster-Cyriaque, S. Syrianen, A. Chattopadyay, H. Sroussi, L. Zhang, and A. Kaushal. "Mechanisms of Viral Infections Associated with HIV." Advances in Dental Research 23, no. 1 (March 25, 2011): 130–36. http://dx.doi.org/10.1177/0022034511400076.
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HIV infection is commonly associated with activation and dissemination of several other viral pathogens, including herpes simplex virus 1/2, human cytomegalovirus, human herpesvirus 8, Epstein-Barr virus, Varicella Zoster virus, and human papillomavirus, which behave as opportunistic agents and cause various diseases in immunocompromised hosts. The increased frequency and severity of diseases caused by these viruses in HIV-infected individuals is due mainly to dysfunction of both the adaptive and innate immune responses to viral pathogens. In addition, molecular interactions between HIV and these opportunistic viruses are likely to play critical roles in the progression of disease, including neoplasia. This report reviews the critical aspects of HIV interaction with opportunistic viruses, including Epstein-Barr virus, human cytomegalovirus, herpes simplex virus, Varicella Zoster virus, human herpesvirus 8, and human papillomavirus.
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Kyritsis, Christoph, Stanislav Gorbulev, Silke Hutschenreiter, Kurt Pawlitschko, Rupert Abele, and Robert Tampé. "Molecular Mechanism and Structural Aspects of Transporter Associated with Antigen Processing Inhibition by the Cytomegalovirus Protein US6." Journal of Biological Chemistry 276, no. 51 (October 17, 2001): 48031–39. http://dx.doi.org/10.1074/jbc.m108528200.
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Erice, Alejo. "Resistance of Human Cytomegalovirus to Antiviral Drugs." Clinical Microbiology Reviews 12, no. 2 (April 1, 1999): 286–97. http://dx.doi.org/10.1128/cmr.12.2.286.
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SUMMARY Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting. Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease. Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of CMV to ganciclovir is related to mutations in the UL97 region of the viral genome and/or mutations in the viral DNA polymerase. Resistance to foscarnet and cidofovir is associated with mutations in the viral DNA polymerase. Antiviral susceptibility of CMV strains containing DNA polymerase mutations is dependent on the region of the DNA polymerase where the mutations are located. Some DNA polymerase mutant viruses are cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition that specific UL97 and UL54 mutations are associated with resistance to antiviral agents has led to the development of molecular methods for detection of mutant viruses. This article reviews the mechanisms of resistance of CMV to antiviral agents, the laboratory methods for detection of resistant CMV, and the clinical aspects of infections caused by antiviral-resistant CMV.
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Fisher, Michelle A., and Megan L. Lloyd. "A Review of Murine Cytomegalovirus as a Model for Human Cytomegalovirus Disease—Do Mice Lie?" International Journal of Molecular Sciences 22, no. 1 (December 28, 2020): 214. http://dx.doi.org/10.3390/ijms22010214.
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Since murine cytomegalovirus (MCMV) was first described in 1954, it has been used to model human cytomegalovirus (HCMV) diseases. MCMV is a natural pathogen of mice that is present in wild mice populations and has been associated with diseases such as myocarditis. The species-specific nature of HCMV restricts most research to cell culture-based studies or to the investigation of non-invasive clinical samples, which may not be ideal for the study of disseminated disease. Initial MCMV research used a salivary gland-propagated virus administered via different routes of inoculation into a variety of mouse strains. This revealed that the genetic background of the laboratory mice affected the severity of disease and altered the extent of subsequent pathology. The advent of genetically modified mice and viruses has allowed new aspects of disease to be modeled and the opportunistic nature of HCMV infection to be confirmed. This review describes the different ways that MCMV has been used to model HCMV diseases and explores the continuing difficulty faced by researchers attempting to model HCMV congenital cytomegalovirus disease using the mouse model.
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Andoniou, Christopher E., Daniel M. Andrews, Mitali Manzur, Paola Ricciardi-Castagnoli, and Mariapia A. Degli-Esposti. "A novel checkpoint in the Bcl-2–regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells." Journal of Cell Biology 166, no. 6 (September 7, 2004): 827–37. http://dx.doi.org/10.1083/jcb.200403010.
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Infection with murine cytomegalovirus (MCMV) has contributed to understanding many aspects of human infection and, additionally, has provided important insight to understanding complex cellular responses. Dendritic cells (DCs) are a major target for MCMV infection. Here, we analyze the effects of MCMV infection on DC viability, and show that infected DCs become resistant to apoptosis induced by growth factor deprivation. The precise contribution of changes in the expression of Bcl-2 family proteins has been assessed and a new checkpoint in the apoptotic pathway identified. Despite their resistance to apoptosis, MCMV-infected DCs showed Bax to be tightly associated with mitochondria and, together with Bak, forming high molecular weight oligomers, changes normally associated with apoptotic cell death. Exposure of a constitutively occluded Bax NH2-terminal epitope was blocked after infection. These results suggest that MCMV has evolved a novel strategy for inhibiting apoptosis and provide evidence that apoptosis can be regulated after translocation, integration, and oligomerization of Bax at the mitochondrial membrane.
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Wade, James C. "Viral Infections in Patients with Hematological Malignancies." Hematology 2006, no. 1 (January 1, 2006): 368–74. http://dx.doi.org/10.1182/asheducation-2006.1.368.
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AbstractViral infections are important causes of morbidity and mortality for patients with a hematological malignancy. However, the true incidence and consequences of viral infections for these patients who undergo conventional nontransplant therapy are poorly defined. The difference in incidence and outcome of viral infections among patient groups is wide, but dependent upon the intensity and duration of T-cell–mediated immune suppression. Infections caused by cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), respiratory syncytial virus (RSV), parainfluenza viruses and influenza viruses have been intensely studied, yet newly recognized aspects of these viral infections including late CMV infection; the emergence of new viral pathogens (human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus); the development of molecular diagnostic techniques, and the potential of new agents for viral prophylaxis (maribavir), or preemptive therapy (valganciclovir) form the basis of this review. Well-designed prospective studies are needed to better clarify the spectrum of these viral infections and develop effective prevention and treatment strategies. Yet the increased use of agents like alemtuzumab that induce profound T-cell depletion demands that we develop a better understanding of viral infections that occur in patients with hematological malignancy who receive nontransplant therapy.
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Juranic Lisnic, Vanda, Marina Babic Cac, Berislav Lisnic, Tihana Trsan, Adam Mefferd, Chitrangada Das Mukhopadhyay, Charles H. Cook, Stipan Jonjic, and Joanne Trgovcich. "Dual Analysis of the Murine Cytomegalovirus and Host Cell Transcriptomes Reveal New Aspects of the Virus-Host Cell Interface." PLoS Pathogens 9, no. 9 (September 26, 2013): e1003611. http://dx.doi.org/10.1371/journal.ppat.1003611.
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Spiesschaert, Bart, Björn Goldenbogen, Selina Taferner, Matthias Schade, Medhat Mahmoud, Edda Klipp, Nikolaus Osterrieder, and Walid Azab. "Role of gB and pUS3 in Equine Herpesvirus 1 Transfer between Peripheral Blood Mononuclear Cells and Endothelial Cells: a DynamicIn VitroModel." Journal of Virology 89, no. 23 (September 16, 2015): 11899–908. http://dx.doi.org/10.1128/jvi.01809-15.
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ABSTRACTInfected peripheral blood mononuclear cells (PBMC) effectively transport equine herpesvirus type 1 (EHV-1), but not EHV-4, to endothelial cells (EC) lining the blood vessels of the pregnant uterus or central nervous system, a process that can result in abortion or myeloencephalopathy. We examined, using a dynamicin vitromodel, the differences between EHV-1 and EHV-4 infection of PBMC and PBMC-EC interactions. In order to evaluate viral transfer between infected PBMC and EC, cocultivation assays were performed. Only EHV-1 was transferred from PBMC to EC, and viral glycoprotein B (gB) was shown to be mainly responsible for this form of cell-to-cell transfer. For addressing the more dynamic aspects of PBMC-EC interaction, infected PBMC were perfused through a flow channel containing EC in the presence of neutralizing antibodies. By simulating capillary blood flow and analyzing the behavior of infected PBMC through live fluorescence imaging and automated cell tracking, we observed that EHV-1 was able to maintain tethering and rolling of infected PBMC on EC more effectively than EHV-4. Deletion of US3 reduced the ability of infected PBMC to tether and roll compared to that of cells infected with parental virus, which resulted in a significant reduction in virus transfer from PBMC to EC. Taking the results together, we conclude that systemic spread and EC infection by EHV-1, but not EHV-4, is caused by its ability to infect and/or reprogram mononuclear cells with respect to their tethering and rolling behavior on EC and consequent virus transfer.IMPORTANCEEHV-1 is widespread throughout the world and causes substantial economic losses through outbreaks of respiratory disease, abortion, and myeloencephalopathy. Despite many years of research, no fully protective vaccines have been developed, and several aspects of viral pathogenesis still need to be uncovered. In the current study, we investigated the molecular mechanisms that facilitate the cell-associated viremia, which is arguably the most important aspect of EHV-1 pathogenesis. The newly discovered functions of gB and pUS3 add new facets to their previously reported roles. Due to the conserved nature of cell-associated viremia among numerous herpesviruses, these results are also very relevant for viruses such as varicella-zoster virus, pseudorabies virus, human cytomegalovirus, and others. In addition, the constructed mutant and recombinant viruses exhibit potentin vitroreplication but have significant defects in certain stages of the disease course. These viruses therefore show much promise as candidates for future live vaccines.
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Voigt, Sebastian, Gordon R. Sandford, Lijun Ding, and William H. Burns. "Identification and Characterization of a Spliced C-Type Lectin-Like Gene Encoded by Rat Cytomegalovirus." Journal of Virology 75, no. 2 (January 15, 2001): 603–11. http://dx.doi.org/10.1128/jvi.75.2.603-611.2001.
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ABSTRACT The English isolate of rat cytomegalovirus (RCMV) encodes a 20-kDa protein with a C-type lectin-like domain that is expressed in the delayed-early and late phases of the viral replication cycle. Genomic sequence analysis of the restriction fragment KpnR of RCMV revealed significant homology to several C-type lectin-containing molecules implicated in natural killer (NK) and T-cell interactions, as well as genes from four poxviruses and African swine fever virus. The gene is spliced into five exons and shows a splicing pattern with exon boundaries similar to those observed in the human differentiation antigen CD69. The cap site of the gene was mapped by RNase protection, 5′ rapid amplification of cDNA ends, and primer extension experiments. This analysis demonstrated that the core promoter of the RCMV lectin-like gene contains a GATA rather than a TATA box. Splicing patterns were confirmed with isolates from an infected-cell cDNA library. A unique aspect of the protein is that its translation is not initiated by the canonical methionine but rather by alanine. To study its role in virus replication and pathogenesis, a recombinant virus was constructed in which the gene is interrupted. Replication in tissue culture was similar to that of wild-type virus.
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Franceschi, R. T. "Biological Approaches to Bone Regeneration by Gene Therapy." Journal of Dental Research 84, no. 12 (December 2005): 1093–103. http://dx.doi.org/10.1177/154405910508401204.
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Safe, effective approaches for bone regeneration are needed to reverse bone loss caused by trauma, disease, and tumor resection. Unfortunately, the science of bone regeneration is still in its infancy, with all current or emerging therapies having serious limitations. Unlike current regenerative therapies that use single regenerative factors, the natural processes of bone formation and repair require the coordinated expression of many molecules, including growth factors, bone morphogenetic proteins, and specific transcription factors. As will be developed in this article, future advances in bone regeneration will likely incorporate therapies that mimic critical aspects of these natural biological processes, using the tools of gene therapy and tissue engineering. This review will summarize current knowledge related to normal bone development and fracture repair, and will describe how gene therapy, in combination with tissue engineering, may mimic critical aspects of these natural processes. Current gene therapy approaches for bone regeneration will then be summarized, including recent work where combinatorial gene therapy was used to express groups of molecules that synergistically interacted to stimulate bone regeneration. Last, proposed future directions for this field will be discussed, where regulated gene expression systems will be combined with cells seeded in precise three-dimensional configurations on synthetic scaffolds to control both temporal and spatial distribution of regenerative factors. It is the premise of this article that such approaches will eventually allow us to achieve the ultimate goal of bone tissue engineering: to reconstruct entire bones with associated joints, ligaments, or sutures. Abbreviations used: BMP, bone morphogenetic protein; FGF, fibroblast growth factor; AER, apical ectodermal ridge; ZPA, zone of polarizing activity; PZ, progress zone; SHH, sonic hedgehog; OSX, osterix transcription factor; FGFR, fibroblast growth factor receptor; PMN, polymorphonuclear neutrophil; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; TGF-β, tumor-derived growth factor β; CAR, coxsackievirus and adenovirus receptor; MLV, murine leukemia virus; HIV, human immunodeficiency virus; AAV, adeno-associated virus; CAT, computer-aided tomography; CMV, cytomegalovirus; GAM, gene-activated matrix; MSC, marrow stromal cell; MDSC, muscle-derived stem cell; VEGF, vascular endothelial growth factor.
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Frick, Marie Antoinette, Ignasi Barba, Marina Fenoy-Alejandre, Paula López-López, Fernando Baquero-Artigao, Paula Rodríguez-Molino, Antoni Noguera-Julian, et al. "1H-NMR Urinary Metabolic Profile, A Promising Tool for the Management of Infants with Human Cytomegalovirus-Infection." Metabolites 9, no. 12 (November 25, 2019): 288. http://dx.doi.org/10.3390/metabo9120288.
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Congenital human cytomegalovirus (HCMV) infection is the most common mother-to-child transmitted infection in the developed world. Certain aspects of its management remain a challenge. Urinary metabolic profiling is a promising tool for use in pediatric conditions. The aim of this study was to investigate the urinary metabolic profile in HCMV-infected infants and controls during acute care hospitalization. Urine samples were collected from 53 patients at five hospitals participating in the Spanish congenital HCMV registry. Thirty-one cases of HCMV infection and 22 uninfected controls were included. Proton nuclear magnetic resonance (1H-NMR) spectra were obtained using NOESYPR1D pulse sequence. The dataset underwent orthogonal projection on latent structures discriminant analysis to identify candidate variables affecting the urinary metabolome: HCMV infection, type of infection, sex, chronological age, gestational age, type of delivery, twins, and diet. Statistically significant discriminative models were obtained only for HCMV infection (p = 0.03) and chronological age (p < 0.01). No significant differences in the metabolomic profile were found between congenital and postnatal HCMV infection. When the HCMV-infected group was analyzed according to chronological age, a statistically significant model was obtained only in the neonatal group (p = 0.01), with the differentiating metabolites being betaine, glycine, alanine, and dimethylamine. Despite the considerable variation in urinary metabolic profiles in a real-life setting, clinical application of metabolomics to the study of HCMV infection seems feasible.
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Jarvis, Michael A., Jamie A. Borton, Amy M. Keech, John Wong, William J. Britt, Bruce E. Magun, and Jay A. Nelson. "Human Cytomegalovirus Attenuates Interleukin-1β and Tumor Necrosis Factor Alpha Proinflammatory Signaling by Inhibition of NF-κB Activation." Journal of Virology 80, no. 11 (June 1, 2006): 5588–98. http://dx.doi.org/10.1128/jvi.00060-06.
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ABSTRACT Viral infection is associated with a vigorous inflammatory response characterized by cellular infiltration and release of the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α). In the present study, we identified a novel function of human cytomegalovirus (HCMV) that results in inhibition of IL-1 and TNF-α signaling pathways. The effect on these pathways was limited to cells infected with the virus, occurred at late times of infection, and was independent of cell type or virus strain. IL-1 and TNF-α signaling pathways converge at a point upstream of NF-κB activation and involve phosphorylation and degradation of the NF-κB inhibitory molecule IκBα. The HCMV inhibition of IL-1 and TNF-α pathways corresponded to a suppression of NF-κB activation. Analysis of IκBα phosphorylation and degradation suggested that HCMV induced two independent blocks in NF-κB activation, which occurred upstream from the point of convergence of the IL-1 and TNF-α pathways. We believe that the ability of HCMV to inhibit these two major proinflammatory pathways reveals a critical aspect of HCMV biology, with possible importance for immune evasion, as well as establishment of infection in cell types persistently infected by this virus.
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Sinclair, John. "Frontiers of Virology 2: Molecular aspects of human cytomegalovirus diseaseedited by Y. Becker, G. Daria and E-S. Huang Springer-Verlag, 1993. DM168.00 hbk (xv + 486 pages) ISBN 3 540 55948 5." Trends in Microbiology 2, no. 4 (April 1994): 145. http://dx.doi.org/10.1016/0966-842x(94)90605-x.
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Aiello, Anna, Giulia Accardi, Giuseppina Candore, Calogero Caruso, Claudia Colomba, Danilo Di Bona, Giovanni Duro, Caterina Maria Gambino, Mattia Emanuela Ligotti, and Janardan P. Pandey. "Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing." International Journal of Molecular Sciences 20, no. 3 (February 5, 2019): 685. http://dx.doi.org/10.3390/ijms20030685.
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The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity.
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Wild, Markus, Friedrich Hahn, Benedikt Grau, Lars Herrmann, Aischa Niesar, Martin Schütz, Melanie M. Lorion, Lutz Ackermann, Svetlana B. Tsogoeva, and Manfred Marschall. "The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism." International Journal of Molecular Sciences 21, no. 15 (August 4, 2020): 5578. http://dx.doi.org/10.3390/ijms21155578.
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Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.
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Hare, David N., Susan E. Collins, Subhendu Mukherjee, Yueh-Ming Loo, Michael Gale, Luke J. Janssen, and Karen L. Mossman. "Membrane Perturbation-Associated Ca2+Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry." Journal of Virology 90, no. 6 (December 30, 2015): 3018–27. http://dx.doi.org/10.1128/jvi.02642-15.
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ABSTRACTThe type I interferon (IFN) response is an important aspect of innate antiviral defense, and the transcription factor IRF3 plays an important role in its induction. Membrane perturbation during fusion, a necessary step for enveloped virus particle entry, appears sufficient to induce transcription of a subset of IFN-stimulated genes (ISGs) in an IRF3-dependent, IFN-independent fashion. IRF3 is emerging as a central node in host cell stress responses, although it remains unclear how different forms of stress activate IRF3. Here, we investigated the minimum number of Sendai virus (SeV) and human cytomegalovirus (HCMV) particles required to activate IRF3 and trigger an antiviral response. We found that Ca2+signaling associated with membrane perturbation and recognition of incoming viral genomes by cytosolic nucleic acid receptors are required to activate IRF3 in response to fewer than 13 particles of SeV and 84 particles of HCMV per cell. Moreover, it appears that Ca2+signaling is important for activation of STING and IRF3 following HCMV particle entry, suggesting that Ca2+signaling sensitizes cells to recognize genomes within incoming virus particles. To our knowledge, this is the first evidence that cytosolic nucleic acid sensors recognize genomes within incoming virus particles prior to virus replication. These studies highlight the exquisite sensitivity of the cellular response to low-level stimuli and suggest that virus particle entry is sensed as a stress signal.IMPORTANCEThe mechanism by which replicating viruses trigger IRF3 activation and type I IFN induction through the generation and accumulation of viral pathogen-associated molecular patterns has been well characterized. However, the mechanism by which enveloped virus particle entry mediates a stress response, leading to IRF3 activation and the IFN-independent response, remained elusive. Here, we find that Ca2+signaling associated with membrane perturbation appears to sensitize cells to recognize genomes within incoming virus particles. To our knowledge, this is the first study to show that cytosolic receptors recognize genomes within incoming virus particles prior to virus replication. These findings not only highlight the sensitivity of cellular responses to low-level virus particle stimulation, but provide important insights into how nonreplicating virus vectors or synthetic lipid-based carriers used as clinical delivery vehicles activate innate immune responses.
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Morrison, Kristen M., Matthew J. Beucler, Emily O. Campbell, Margaret A. White, Rachel E. Boody, Keith C. Wilson, and William E. Miller. "Development of a Primary Human Cell Model for the Study of Human Cytomegalovirus Replication and Spread within Salivary Epithelium." Journal of Virology 93, no. 3 (November 7, 2018). http://dx.doi.org/10.1128/jvi.01608-18.
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ABSTRACTVarious aspects of human cytomegalovirus (HCMV) pathogenesis, including its ability to replicate in specific cells and tissues and the mechanism(s) of horizontal transmission, are not well understood, predominantly because of the strict species specificity exhibited by HCMV. Murine CMV (MCMV), which contains numerous gene segments highly similar to those of HCMV, has been useful for modeling some aspects of CMV pathogenesis; however, it remains essential to build relevant human cell-based systems to investigate how the HCMV counterparts function. The salivary gland epithelium is a site of persistence for both human and murine cytomegaloviruses, and salivary secretions appear to play an important role in horizontal transmission. Therefore, it is important to understand how HCMV is replicating within the glandular epithelial cells so that it might be possible to therapeutically prevent transmission. In the present study, we describe the development of a salivary epithelial model derived from primary human “salispheres.” Initial infection of these primary salivary cells with HCMV occurs in a manner similar to that reported for established epithelial lines, in that gH/gL/UL128/UL130/UL131A (pentamer)-positive strains can infect and replicate, while laboratory-adapted pentamer-null strains do not. However, while HCMV enters the lytic phase and produces virus in salivary epithelial cells, it fails to exhibit robust spread throughout the culture and persists in a low percentage of salivary cells. The present study demonstrates the utility of these primary tissue-derived cells for studying HCMV replication in salivary epithelial cellsin vitro.IMPORTANCEHuman cytomegalovirus (HCMV) infects the majority of the world’s population, and although it typically establishes a quiescent infection with little to no disease in most individuals, the virus is responsible for a variety of devastating sequelae in immunocompromised adults and in developing fetuses. Therefore, identifying the viral properties essential for replication, spread, and horizontal transmission is an important area of medical science. Our studies use novel human salivary gland-derived cellular models to investigate the molecular details by which HCMV replicates in salivary epithelial cells and provide insight into the mechanisms by which the virus persists in the salivary epithelium, where it gains access to fluids centrally important for horizontal transmission.
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"Molecular aspects human cytomegalovirus disease." Biomedicine & Pharmacotherapy 48, no. 1 (January 1994): 44. http://dx.doi.org/10.1016/0753-3322(94)90198-8.
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Penkert, Rhiannon R., and Robert F. Kalejta. "Human Embryonic Stem Cell Lines Model Experimental Human Cytomegalovirus Latency." mBio 4, no. 3 (May 28, 2013). http://dx.doi.org/10.1128/mbio.00298-13.
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ABSTRACTHerpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34+hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34+cellsex vivohas demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34+cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivatein vitrofrom experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.IMPORTANCEHuman cytomegalovirus (HCMV) is a significant human pathogen that is known for causing birth defects, blindness in AIDS patients, and organ transplant rejection. The ability of HCMV to cause disease is dependent upon its capacity to establish and maintain latent infections. Very few of the molecular mechanisms of latency have been elucidated, due in part to the lack of a tractable cell culture model. Here we present embryonic stem cells (ESCs) as a model for HCMV latency, one in which genome maintenance and reactivation could be closely monitored. HCMV establishes latency in ESCs in the same fashion as it does in CD34+cells, the currently favoredin vitromodel. Hence, ESCs represent a novel model with unique properties, such as the ability to be genetically manipulated and cultured indefinitely in an undifferentiated state, that will facilitate the mechanistic examination of certain aspects of HCMV latency that have proven technically challenging in other model systems.
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Crawford, Lindsey B., Patrizia Caposio, Craig Kreklywich, Andrew H. Pham, Meaghan H. Hancock, Taylor A. Jones, Patricia P. Smith, Andrew D. Yurochko, Jay A. Nelson, and Daniel N. Streblow. "Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34+Hematopoietic Progenitor Cells and Humanized NSG Mice." mBio 10, no. 4 (August 20, 2019). http://dx.doi.org/10.1128/mbio.01889-19.
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ABSTRACTHuman cytomegalovirus (HCMV) infection of CD34+hematopoietic progenitor cells (CD34+HPCs) provides a critical reservoir of virus in stem cell transplant patients, and viral reactivation remains a significant cause of morbidity and mortality. The HCMV chemokine receptor US28 is implicated in the regulation of viral latency and reactivation. To explore the role of US28 signaling in latency and reactivation, we analyzed protein tyrosine kinase signaling in CD34+HPCs expressing US28. US28-ligand signaling in CD34+HPCs induced changes in key regulators of cellular activation and differentiation.In vitrolatency and reactivation assays utilizing CD34+HPCs indicated that US28 was required for viral reactivation but not latency establishment or maintenance. Similarly, humanized NSG mice (huNSG) infected with TB40E-GFP-US28stop failed to reactivate upon treatment with granulocyte-colony-stimulating factor, but viral genome levels were maintained. Interestingly, HCMV-mediated changes in hematopoiesis during latencyin vivoandin vitrowas also dependent upon US28, as US28 directly promoted differentiation toward the myeloid lineage. To determine whether US28 constitutive activity and/or ligand-binding activity were required for latency and reactivation, we infected both huNSG mice and CD34+HPCsin vitrowith HCMV TB40E-GFP containing the US28-R129A mutation (no CA) or Y16F mutation (no ligand binding). TB40E-GFP-US28-R129A was maintained during latency and exhibited normal reactivation kinetics. In contrast, TB40E-GFP-US28-Y16F exhibited high levels of viral genome during latency and reactivation, indicating that the virus did not establish latency. These data indicate that US28 is necessary for viral reactivation and ligand binding activity is required for viral latency, highlighting the complex role of US28 during HCMV latency and reactivation.IMPORTANCEHuman cytomegalovirus (HCMV) can establish latency following infection of CD34+hematopoietic progenitor cells (HPCs), and reactivation from latency is a significant cause of viral disease and accelerated graft failure in bone marrow and solid-organ transplant patients. The precise molecular mechanisms of HCMV infection in HPCs are not well defined; however, select viral gene products are known to regulate aspects of latency and reactivation. The HCMV-encoded chemokine receptor US28, which binds multiple CC chemokines as well as CX3CR1, is expressed both during latent and lytic phases of the virus life cycle and plays a role in latency and reactivation. However, the specific timing of US28 expression and the role of ligand binding in these processes are not well defined. In this report, we determined that US28 is required for reactivation but not for maintaining latency. However, when present during latency, US28 ligand binding activity is critical to maintaining the virus in a quiescent state. We attribute the regulation of both latency and reactivation to the role of US28 in promoting myeloid lineage cell differentiation. These data highlight the dynamic and multifunctional nature of US28 during HCMV latency and reactivation.
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Weisblum, Yiska, Esther Oiknine-Djian, Olesya M. Vorontsov, Ronit Haimov-Kochman, Zichria Zakay-Rones, Karen Meir, David Shveiky, et al. "Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface." Journal of Virology 91, no. 4 (December 14, 2016). http://dx.doi.org/10.1128/jvi.01905-16.
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ABSTRACT Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.