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Nature Reviews. Microbiology Dec 2021Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by... (Review)
Review
Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by a vigorous immune response so that infections are asymptomatic or symptoms are mild. However, if the immune system is compromised, HCMV can replicate to high levels and cause serious end organ disease. Substantial progress is being made in understanding the natural history and pathogenesis of HCMV infection and disease in the immunocompromised host. Serial measures of viral load defined the dynamics of HCMV replication and are now used routinely to allow intervention with antiviral drugs in individual patients. They are also used as pharmacodynamic read-outs to evaluate prototype vaccines that may protect against HCMV replication and to define immune correlates of this protection. This novel information is informing the design of randomized controlled trials of new antiviral drugs and vaccines currently under evaluation. In this Review, we discuss immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Humans; Immunity; Immunocompromised Host; Randomized Controlled Trials as Topic; Viral Load; Virus Replication
PubMed: 34168328
DOI: 10.1038/s41579-021-00582-z -
Methods in Molecular Biology (Clifton,... 2021Human cytomegalovirus (HCMV) is a betaherpesvirus with a global seroprevalence of 60-90%. HCMV is the leading cause of congenital infections and poses a great health... (Review)
Review
Human cytomegalovirus (HCMV) is a betaherpesvirus with a global seroprevalence of 60-90%. HCMV is the leading cause of congenital infections and poses a great health risk to immunocompromised individuals. Although HCMV infection is typically asymptomatic in the immunocompetent population, infection can result in mononucleosis and has also been associated with the development of certain cancers, as well as chronic inflammatory diseases such as various cardiovascular diseases. In immunocompromised patients, including AIDS patients, transplant recipients, and developing fetuses, HCMV infection is associated with increased rates of morbidity and mortality. Currently there is no vaccine for HCMV and there is a need for new pharmacological treatments. Ongoing research seeks to further define the complex aspects of HCMV pathogenesis, which could potentially lead to the generation of new therapeutics to mitigate the disease states associated with HCMV infection. The following chapter reviews the advancements in our understanding of HCMV pathogenesis in the immunocompetent and immunocompromised hosts.
Topics: Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Humans; Immunocompromised Host; Seroepidemiologic Studies
PubMed: 33555579
DOI: 10.1007/978-1-0716-1111-1_1 -
PLoS Pathogens May 2023The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially...
The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include >200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model.
Topics: Animals; Mice; Humans; Muromegalovirus; Cytomegalovirus; Base Sequence; Viral Proteins; Open Reading Frames
PubMed: 37172056
DOI: 10.1371/journal.ppat.1010992 -
Annals of the New York Academy of... Jun 2023Human cytomegalovirus (HCMV) is a prevalent herpesvirus, infecting the majority of the human population. Like other herpesviruses, it causes lifelong infection through... (Review)
Review
Human cytomegalovirus (HCMV) is a prevalent herpesvirus, infecting the majority of the human population. Like other herpesviruses, it causes lifelong infection through the establishment of latency. Although reactivation from latency can cause significant morbidity and mortality in immunocompromised hosts, our understanding of HCMV latency and how it is maintained remains limited. Here, we discuss the characterized latency reservoir in hematopoietic cells in the bone marrow and the gaps in our knowledge of mechanisms that facilitate HCMV genome maintenance in dividing cells. We further review clinical evidence that strongly suggests the tissue origin of HCMV reactivation, and we outline similarities to murine cytomegalovirus where latency in tissue-resident cells has been demonstrated. Overall, we think these observations call for a rethinking of HCMV latency reservoirs and point to potential sources of HCMV latency that reside in tissues.
Topics: Animals; Humans; Mice; Cytomegalovirus; Cytomegalovirus Infections; Muromegalovirus; Virus Activation; Virus Latency
PubMed: 37026581
DOI: 10.1111/nyas.14994 -
Frontiers in Cellular and Infection... 2021
Topics: Cytomegalovirus; Virus Activation; Virus Latency
PubMed: 34307201
DOI: 10.3389/fcimb.2021.711551 -
Voprosy Virusologii Nov 2022The review provides information on the mechanisms of the emergence of resistance to antiviral drugs in human viruses from the subfamily Betaherpesvirinae. Data on the...
The review provides information on the mechanisms of the emergence of resistance to antiviral drugs in human viruses from the subfamily Betaherpesvirinae. Data on the principles of action of antiviral drugs and their characteristics are given. The occurrence rates of viral resistance in various groups of patients is described and information about the possible consequences of the emergence of resistance to antiviral drugs is given. Information is provided regarding the virus genes in which mutations occur that lead to viral resistance, and a list of such mutations that have described so far is given. The significance of the study of mutations leading to the resistance of the virus to antiviral drugs for medical practice is discussed.
Topics: Humans; Antiviral Agents; Ganciclovir; Cytomegalovirus; Drug Resistance, Viral; DNA-Directed DNA Polymerase; Betaherpesvirinae; Foscarnet; Cytosine
PubMed: 36515284
DOI: 10.36233/0507-4088-136 -
Viruses Mar 2021Human cytomegalovirus (HCMV), a member of the betaherpesvirinae, can cause life-threatening diseases. HCMV is globally widespread, with a seroprevalence in adults... (Review)
Review
Human cytomegalovirus (HCMV), a member of the betaherpesvirinae, can cause life-threatening diseases. HCMV is globally widespread, with a seroprevalence in adults varying from 50 to 100%. HCMV infection is rarely of significant consequence in immunocompetent individuals. However, although immune control is efficient, it cannot achieve the clearance of the virus. HCMV persists lifelong in the infected host and reactivates in certain circumstances. In neonates and in immunocompromised adults, HCMV is a serious pathogen that can cause fatal organ damage. Different antiviral compounds alone or in combination have been used for the treatment of HCMV diseases. In clinical use, mutations in the viral DNA polymerase or the terminase confer resistance to ganciclovir, foscarnet, cidofovir, and letermovir. There is an urgent need to find new well-tolerated compounds supporting different modes of action. The list of novel small molecules that might have anti-HCMV activity has grown in recent years. In this short review, a selection of compounds in clinical trials and novel inhibitors targeting host-cell factors or viral proteins is presented, and their modes of action, described.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Discovery; Humans; Immunocompromised Host; Viral Proteins; Virus Replication
PubMed: 33809292
DOI: 10.3390/v13030474 -
Clinical & Translational Oncology :... Apr 2020To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. (Review)
Review
PURPOSE
To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus.
METHODS
We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus.
RESULTS
Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus.
CONCLUSIONS
Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.
Topics: Animals; Breast Neoplasms; Cytomegalovirus; Female; Humans; Mice
PubMed: 31256361
DOI: 10.1007/s12094-019-02164-1 -
Journal of Medical Microbiology Apr 1992
Topics: Genome, Viral; Herpesviridae Infections; Herpesvirus 6, Human; Humans; Virus Replication
PubMed: 1313880
DOI: 10.1099/00222615-36-4-221 -
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