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Trends in Microbiology Aug 2012Maturation in herpesviruses initiates in the nucleus of the infected cell, with encapsidation of viral DNA to form nucleocapsids, and concludes with envelopment in the... (Review)
Review
Maturation in herpesviruses initiates in the nucleus of the infected cell, with encapsidation of viral DNA to form nucleocapsids, and concludes with envelopment in the cytoplasm to form infectious virions that egress the cell. The entire process of virus maturation is orchestrated by protein-protein interactions and enzymatic activities of viral and host origin. Viral tegument proteins play important roles in maintaining the structural stability of capsids and directing the acquisition of virus envelope. Envelopment occurs at modified host membranes and exploits host vesicular trafficking. In this review, we summarize current knowledge of and concepts in human cytomegalovirus (HCMV) maturation and their parallels in other herpesviruses, with an emphasis on viral and host factors that regulate this process.
Topics: Cell Nucleus; Cytomegalovirus; DNA, Viral; Herpesviridae; Host-Derived Cellular Factors; Host-Pathogen Interactions; Humans; Nucleocapsid; Virus Replication
PubMed: 22633075
DOI: 10.1016/j.tim.2012.04.008 -
Journal of Clinical Microbiology Jun 1997Human cytomegalovirus (HCMV) is a well-known opportunistic agent that reactivates in human immunodeficiency virus (HIV)-seropositive subjects. Human herpesvirus 6...
Human cytomegalovirus (HCMV) is a well-known opportunistic agent that reactivates in human immunodeficiency virus (HIV)-seropositive subjects. Human herpesvirus 6 (HHV-6) and HHV-7 were discovered recently and, like HCMV, belong to the Betaherpesvirinae subfamily. We looked for the presence of HCMV, HHV-6, and HHV-7 by PCR with saliva and urine samples from 125 HIV-seropositive patients at different stages of HIV infection and with saliva and urine samples from 29 HIV-seronegative subjects. All three viruses were frequently detected in the saliva (overall rates of detection, 61, 43, and 63% for HCMV, HHV-6, and HHV-7, respectively) with no correlation with the stage of immune deficiency. In contrast, HCMV was detected in urine much more frequently than the two other herpesviruses (overall rates of detection, 37, 2, and 6.5% for HCMV, HHV-6, and HHV-7, respectively) and was associated with immune deficiency. This suggests that these three genetically related viruses differ from each other with regard to replication in the urinary tract.
Topics: AIDS-Related Opportunistic Infections; Betaherpesvirinae; CD4 Lymphocyte Count; DNA, Viral; HIV Seropositivity; Herpesviridae Infections; Herpesvirus 7, Human; Humans; Immunocompromised Host; Saliva
PubMed: 9163493
DOI: 10.1128/jcm.35.6.1600-1603.1997 -
Current Opinion in Virology Aug 2015The generation of humanized mouse models in which immune deficient mice are engrafted with human tissues allows for the direct in vivo investigation of human-restricted... (Review)
Review
The generation of humanized mouse models in which immune deficient mice are engrafted with human tissues allows for the direct in vivo investigation of human-restricted viruses. These humanized mouse models have been developed and improved over the past 30 years. It is now possible to achieve high levels of human cell engraftment producing human myeloid and lymphoid lineage cells. Humanized mouse models have been increasingly utilized in the study of human cytomegalovirus (HCMV), a human-specific beta-herpesvirus that infects myeloprogenitor cells and establishes a life-long latency in the infected host. This review focuses on the strengths and limitations of the current humanized mouse models used to study HCMV replication, pathogenesis and treatment.
Topics: Animals; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Humans; Mice
PubMed: 26118890
DOI: 10.1016/j.coviro.2015.06.006 -
PloS One 2023Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected...
Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected animals show acute appearance of red, exudating lesions across the spine. The lesions are painful, evidenced by arching of the back (dipping), and the onset of clinical signs is generally sudden. In order to understand the pathogenesis, histological and virological investigations were performed in affected and unaffected Göttingen Minipigs (GöMPs). The following DNA viruses were screened for using PCR-based methods: Porcine cytomegalovirus (PCMV), which is a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, PLHV-3), porcine circoviruses (PCV1, PCV2, PCV3, PCV4), porcine parvovirus 1 (PPV1), and Torque Teno sus viruses (TTSuV1, TTSuV2). Screening was also performed for integrated porcine endogenous retroviruses (PERV-A, PERV-B, PERV-C) and recombinant PERV-A/C and their expression as well as for the RNA viruses hepatitis E virus (HEV) and SARS-CoV-2. Eight clinically affected and one unaffected GöMPs were analyzed. Additional unaffected minipigs had been analyzed in the past. The analyzed GöMPs contained PERV-A and PERV-B integrated in the genome, which are present in all pigs and PERV-C, which is present in most, but not all pigs. In one affected GöMPs recombinant PERV-A/C was detected in blood. In this animal a very high expression of PERV mRNA was observed. PCMV/PRV was found in three affected animals, PCV1 was found in three animals with DPS and in the unaffected minipig, and PCV3 was detected in two animals with DPS and in the unaffected minipig. Most importantly, in one animal only PLHV-3 was detected. It was found in the affected and unaffected skin, and in other organs. Unfortunately, PLHV-3 could not be studied in all other affected minipigs. None of the other viruses were detected and using electron microscopy, no virus particles were found in the affected skin. No porcine virus RNA with exception of PERV and astrovirus RNA were detected in the affected skin by next generation sequencing. This data identified some virus infections in GöMPs with DPS and assign a special role to PLHV-3. Since PCMV/PRV, PCV1, PCV3 and PLHV-3 were also found in unaffected animals, a multifactorial cause of DPS is suggested. However, elimination of the viruses from GöMPs may prevent DPS.
Topics: Swine; Animals; Swine, Miniature; Transplantation, Heterologous; Endogenous Retroviruses; COVID-19; SARS-CoV-2; Betaherpesvirinae
PubMed: 37319233
DOI: 10.1371/journal.pone.0281521 -
Current Opinion in Infectious Diseases Dec 2011This review assesses recently published data on cytomegalovirus (CMV) antiviral drug resistance. (Review)
Review
PURPOSE OF REVIEW
This review assesses recently published data on cytomegalovirus (CMV) antiviral drug resistance.
RECENT FINDINGS
Resistance is typically encountered after prolonged ganciclovir treatment for posttransplant primary CMV infection and is diagnosed by the detection of characteristic mutations in the viral UL97 kinase and UL54 DNA polymerase genes in clinical specimens. One of seven canonical UL97 mutations is detected in most cases of ganciclovir resistance, but many viral sequence variants of unknown relevance are being reported after drug exposure in vitro and in vivo. Rapid technical advances in recombinant phenotyping have shown that many of these variants confer no detectable drug resistance, whereas some unusual resistance mutations are newly confirmed. All currently marketed CMV antiviral drugs, including foscarnet and cidofovir, target the viral DNA polymerase, and cross-resistance may result from some UL54 mutations. To decrease cross-resistance and toxicity, there is an ongoing effort to develop anti-CMV drugs with different resistance pathways and alternative targets, such as the UL97 kinase or UL56-UL89 terminase enzymes.
SUMMARY
An increasing volume of information correlating CMV genotypes and drug susceptibility phenotypes is becoming available. This will improve the interpretation of sequence-based assays currently used for clinical diagnosis and guide the development of new antiviral drugs.
Topics: Cytomegalovirus; Cytomegalovirus Infections; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Genotype; Humans; Phosphotransferases (Alcohol Group Acceptor); Viral Proteins
PubMed: 22001948
DOI: 10.1097/QCO.0b013e32834cfb58 -
Viruses Aug 2022Animal models that mimic human infections provide insights in virus-host interplay; knowledge that in vitro approaches cannot readily predict, nor easily reproduce.... (Review)
Review
Animal models that mimic human infections provide insights in virus-host interplay; knowledge that in vitro approaches cannot readily predict, nor easily reproduce. Human cytomegalovirus (HCMV) infections are acquired asymptomatically, and primary infections are difficult to capture. The gap in our knowledge of the early events of HCMV colonization and spread limits rational design of HCMV antivirals and vaccines. Studies of natural infection with mouse cytomegalovirus (MCMV) have demonstrated the olfactory epithelium as the site of natural colonization. Systemic spread from the olfactory epithelium is facilitated by infected dendritic cells (DC); tracking dissemination uncovered previously unappreciated DC trafficking pathways. The olfactory epithelium also provides a unique niche that supports efficient MCMV superinfection and virus recombination. In this review, we summarize recent advances to our understanding of MCMV infection and spread and the tissue-specific mechanisms utilized by MCMV to modulate DC trafficking. As these mechanisms are likely conserved with HCMV, they may inform new approaches for preventing HCMV infections in humans.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Herpesviridae Infections; Humans; Mice; Muromegalovirus
PubMed: 36146741
DOI: 10.3390/v14091934 -
Nature Communications Nov 2023Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence,...
Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence, they can differentiate into memory NK cells. The molecular mechanisms controlling this differentiation are yet to be fully elucidated. Here we identify the scaffold protein Themis2 as a critical regulator of memory NK cell differentiation and function. Themis2-deficient NK cells expressing Ly49H, an activating NK receptor for the mouse cytomegalovirus (MCMV) antigen m157, show enhanced differentiation into memory NK cells and augment host protection against MCMV infection. Themis2 inhibits the effector function of NK cells after stimulation of Ly49H and multiple activating NK receptors, though not specific to memory NK cells. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation, and it also translocates to the nucleus, where it promotes Zfp740-mediated repression to regulate the persistence of memory NK cells. Zfp740 deficiency increases the number of memory NK cells and enhances the effector function of memory NK cells, which further supports the relevance of the Themis2-Zfp740 pathway. In conclusion, our study shows that Themis2 quantitatively and qualitatively regulates NK cell memory formation.
Topics: Animals; Mice; Antigens, Viral; Cell Differentiation; Cytomegalovirus; Killer Cells, Natural; Muromegalovirus; Phosphorylation
PubMed: 37938555
DOI: 10.1038/s41467-023-42578-8 -
Nature Communications Sep 2020Gene drives are genetic modifications designed to propagate in a population with high efficiency. Current gene drive strategies rely on sexual reproduction and are...
Gene drives are genetic modifications designed to propagate in a population with high efficiency. Current gene drive strategies rely on sexual reproduction and are thought to be restricted to sexual organisms. Here, we report on a gene drive system that allows the spread of an engineered trait in populations of DNA viruses and, in particular, herpesviruses. We describe the successful transmission of a gene drive sequence between distinct strains of human cytomegalovirus (human herpesvirus 5) and show that gene drive viruses can efficiently target and replace wildtype populations in cell culture experiments. Moreover, by targeting sequences necessary for viral replication, our results indicate that a viral gene drive can be used as a strategy to suppress a viral infection. Taken together, this work offers a proof of principle for the design of a gene drive in viruses.
Topics: Cell Line; Cytomegalovirus; DNA, Viral; Gene Drive Technology; Gene Editing; Herpesviridae; Humans; Virus Replication
PubMed: 32985507
DOI: 10.1038/s41467-020-18678-0 -
Frontiers in Immunology 2022Human roseolovirus U20 and U21 are type I membrane glycoproteins that have been implicated in immune evasion by interfering with recognition of classical and... (Review)
Review
Human roseolovirus U20 and U21 are type I membrane glycoproteins that have been implicated in immune evasion by interfering with recognition of classical and non-classical MHC proteins. U20 and U21 are predicted to be type I glycoproteins with extracytosolic immunoglobulin-like domains, but detailed structural information is lacking. AlphaFold and RoseTTAfold are next generation machine-learning-based prediction engines that recently have revolutionized the field of computational three-dimensional protein structure prediction. Here, we review the structural biology of viral immunoevasins and the current status of computational structure prediction algorithms. We use these computational tools to generate structural models for U20 and U21 proteins, which are predicted to adopt MHC-Ia-like folds with closed MHC platforms and immunoglobulin-like domains. We evaluate these structural models and place them within current understanding of the structural basis for viral immune evasion of T cell and natural killer cell recognition.
Topics: Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Models, Structural; Roseolovirus Infections; Viral Proteins
PubMed: 35444636
DOI: 10.3389/fimmu.2022.864898 -
FEMS Microbiology Reviews Jul 1999Human cytomegalovirus is ubiquitous, yet causes little illness in immunocompetent individuals. Disease is evident in immunodeficient groups such as neonates, transplant... (Review)
Review
Human cytomegalovirus is ubiquitous, yet causes little illness in immunocompetent individuals. Disease is evident in immunodeficient groups such as neonates, transplant recipients and AIDS patients either following a primary infection or reactivation of a latent infection. Little is known of the mechanisms underlying the pathogenicity of the virus. The recent determination of the nucleotide sequence of both human cytomegalovirus (strain AD169) and murine cytomegalovirus (murine cytomegalovirus strain Smith) has allowed an analysis of the biological importance of several virus genes. Studies with human cytomegalovirus have indicated that many viral genes are non-essential for replication in vitro which are thus assumed to be important in the pathogenesis of the virus. This is being examined in the murine model where the role of the gene and its product in disease can be directly examined in vivo using viral mutants in which the relevant gene has been interrupted or deleted. Current information on the role of cytomegalovirus genes in tissue tropism, immune evasion, latency, reactivation from latency and damage is described.
Topics: Animals; Cytomegalovirus; Cytomegalovirus Infections; Herpesviridae Infections; Humans; Muromegalovirus; Virulence; Virus Activation; Virus Latency; Virus Replication
PubMed: 10422262
DOI: 10.1111/j.1574-6976.1999.tb00408.x