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Cytomegalovirus Infection and Cytomegalovirus Vaccine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 9565

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Special Issue Editor

Dr. Pero Lucin

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Guest Editor

Department of Physiology, Immunology and Pathophysiology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
Interests: endocytosis; endosomal system; endosomal recycling; cytomegalovirus; assembly compartment; murine cytomegalovirus secondary envelopment and egress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human cytomegalovirus (HCMV) is a widespread herpesvirus that infects most of the human population. In immunocompetent individuals, the infection is asymptomatic, but the virus remains in the lifelong latent state from which reactivation may occur. In immunocompromised people and congenitally infected children, it can cause severe and life-threatening conditions. However, its lifelong persistence and occasional reactivation may also be associated with various pathophysiological conditions in normal individuals. Thus, the development of a vaccine against HCMV is considered a priority in the scientific community. However, the progress toward a vaccine for HCMV has been slow. It appears that additional knowledge about the biology of the virus, its interaction with host cells and the immune system, and the pathophysiology of CMV infection is required for the progress. This knowledge is also essential for vaccine development strategies and should be aligned with the progress in the vaccine development field, such as recent progress in vector vaccines or mRNA vaccines. In order to move towards these goals, alignment with additional studies related to many public health issues is necessary, such as identifying the target population for vaccination, the proper way of vaccination to establish an effective vaccination schedule, and the development of natural models to test vaccination strategies. Thus, this Special Issue aims to collect original research and review articles which can elucidate molecular and biochemical mechanisms of all aspects of CMV pathophysiology and vaccine development.

Topics of interest for this Special Issue include, but are not limited to, molecular studies of:

CMV biology and CMV gene products;
Cell biology of CMV infection;
Interactions of CMV with host cells and exploitation of the host-cell machinery for virus replication after acute infection and reactivation from latency;
Cytopathogenic effects of acute and latent CMV infection;
High-throughput studies of virus–host interaction;
Experimental models of CMV infection;
Pathophysiology of CMV infection;
CMV immune evasion mechanisms;
CMV vaccine development and vaccination strategies.

Dr. Pero Lucin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

betaherpesviruses
cytomegalovirus
virus–host interaction
CMV assembly
CMV replication cycle
CMV immunization
CMV vaccine
CMV DNA-based vaccine
CMV RNA-based vaccine
subunit vaccine

Published Papers (4 papers)

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Research

Jump to: Review

15 pages, 3463 KiB

Open AccessArticle

Promyelocytic Leukemia Protein Potently Restricts Human Cytomegalovirus Infection in Endothelial Cells

by Sven Seitz, Anna Theresa Heusel, Thomas Stamminger and Myriam Scherer

Int. J. Mol. Sci. 2022, 23(19), 11931; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911931 - 08 Oct 2022

Cited by 3 | Viewed by 1590

Abstract

PML nuclear bodies (PML-NBs) are dynamic macromolecular complexes that mediate intrinsic immunity against viruses of different families, including human cytomegalovirus (HCMV). Upon HCMV infection, PML-NBs target viral genomes entering the nucleus and restrict viral immediate–early gene expression by epigenetic silencing. Studies from several groups performed in human fibroblast cells have shown that the major PML-NB components PML, Daxx, Sp100 and ATRX contribute to this repression in a cooperative manner. Their role for HCMV restriction in endothelial cells, however, has not yet been characterized although infected endothelium is thought to play a crucial role for HCMV dissemination and development of vascular disease in vivo. Here, we use conditionally immortalized umbilical vein endothelial cells (HEC-LTT) as a cell culture model to elucidate the impact of PML-NB proteins on lytic HCMV infection. Depletion of individual PML-NB proteins by lentiviral transduction showed a particularly strong antiviral effect of PML in HEC-LTT, compared to human fibroblasts. A closer characterization of this antiviral function revealed that PML may not only effectively inhibit HCMV immediate-early gene expression but also act at later steps of the viral replication cycle. At contrast, we surprisingly noted an antiviral behavior of Daxx in complementary approaches: Depletion of Daxx resulted in decreased viral gene expression, while overexpression of Daxx promoted HCMV infection. In summary, our data demonstrate a cell type-specific effect of PML-NB components on lytic HCMV infection and suggest an important role of PML in the inhibition of HCMV dissemination through infected endothelial cells. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection and Cytomegalovirus Vaccine)

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21 pages, 3799 KiB

Open AccessArticle

UL34 Deletion Restricts Human Cytomegalovirus Capsid Formation and Maturation

by Declan L. Turner, Rachel M. Templin, Adele A. Barugahare, Brendan E. Russ, Stephen J. Turner, Georg Ramm and Rommel A. Mathias

Int. J. Mol. Sci. 2022, 23(10), 5773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105773 - 21 May 2022

Cited by 3 | Viewed by 2495

Abstract

Over 50% of the world’s population is infected with Human Cytomegalovirus (HCMV). HCMV is responsible for serious complications in the immuno-compromised and is a leading cause of congenital birth defects. The molecular function of many HCMV proteins remains unknown, and a deeper understanding of the viral effectors that modulate virion maturation is required. In this study, we observed that UL34 is a viral protein expressed with leaky late kinetics that localises to the nucleus during infection. Deletion of UL34 from the HCMV genome (ΔUL34) did not abolish the spread of HCMV. Instead, over >100-fold fewer infectious virions were produced, so we report that UL34 is an augmenting gene. We found that ΔUL34 is dispensable for viral DNA replication, and its absence did not alter the expression of IE1, MCP, gB, UL26, UL83, or UL99 proteins. In addition, ΔUL34 infections were able to progress through the replication cycle to form a viral assembly compartment; however, virion maturation in the cytoplasm was abrogated. Further examination of the nucleus in ΔUL34 infections revealed replication compartments with aberrant morphology, containing significantly less assembled capsids, with almost none undergoing subsequent maturation. Therefore, this work lays the foundation for UL34 to be further investigated in the context of nuclear organization and capsid maturation during HCMV infection. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection and Cytomegalovirus Vaccine)

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27 pages, 7002 KiB

Open AccessArticle

Human MicroRNAs Attenuate the Expression of Immediate Early Proteins and HCMV Replication during Lytic and Latent Infection in Connection with Enhancement of Phosphorylated RelA/p65 (Serine 536) That Binds to MIEP

by Yeon-Mi Hong, Seo Yeon Min, Dayeong Kim, Subin Kim, Daekwan Seo, Kyoung Hwa Lee and Sang Hoon Han

Int. J. Mol. Sci. 2022, 23(5), 2769; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052769 - 02 Mar 2022

Viewed by 2302

Abstract

Attenuating the expression of immediate early (IE) proteins is essential for controlling the lytic replication of human cytomegalovirus (HCMV). The human microRNAs (hsa-miRs), miR-200b-3p and miR-200c-3p, have been identified to bind the 3′-untranslated region (3′-UTR) of the mRNA encoding IE proteins. However, whether hsa-miRs can reduce IE72 expression and HCMV viral load or exhibit a crosstalk with the host cellular signaling machinery, most importantly the NF-κB cascade, has not been evaluated. In this study, argonaute-crosslinking and immunoprecipitation-seq revealed that miR-200b-3p and miR-200c-3p bind the 3′-UTR of UL123, which is a gene that encodes IE72. The binding of these miRNAs to the 3′-UTR of UL123 was verified in transfected cells stably expressing GFP. We used miR-200b-3p/miR-200c-3p mimics to counteract the downregulation of these miRNA after acute HCMV infection. This resulted in reduced IE72/IE86 expression and HCMV VL during lytic infection. We determined that IE72/IE86 alone can inhibit the phosphorylation of RelA/p65 at the Ser⁵³⁶ residue and that p-Ser⁵³⁶ RelA/p65 binds to the major IE promoter/enhancer (MIEP). The upregulation of miR-200b-3p and miR-200c-3p resulted in the phosphorylation of RelA/p65 at Ser⁵³⁶ through the downregulation of IE, and the binding of the resultant p-Ser⁵³⁶ RelA/p65 to MIEP resulted in a decreased production of pro-inflammatory cytokines. Overall, miR-200b-3p and miR-200c-3p—together with p-Ser⁵³⁶ RelA/p65—can prevent lytic HCMV replication during acute and latent infection. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection and Cytomegalovirus Vaccine)

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Review

Jump to: Research

35 pages, 4111 KiB

Open AccessReview

Host Cell Signatures of the Envelopment Site within Beta-Herpes Virions

by Hana Mahmutefendić Lučin, Gordana Blagojević Zagorac, Marina Marcelić and Pero Lučin

Int. J. Mol. Sci. 2022, 23(17), 9994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179994 - 01 Sep 2022

Cited by 4 | Viewed by 2089

Abstract

Beta-herpesvirus infection completely reorganizes the membrane system of the cell. This system is maintained by the spatiotemporal arrangement of more than 3000 cellular proteins that continuously adapt the configuration of membrane organelles according to cellular needs. Beta-herpesvirus infection establishes a new configuration known as the assembly compartment (AC). The AC membranes are loaded with virus-encoded proteins during the long replication cycle and used for the final envelopment of the newly formed capsids to form infectious virions. The identity of the envelopment membranes is still largely unknown. Electron microscopy and immunofluorescence studies suggest that the envelopment occurs as a membrane wrapping around the capsids, similar to the growth of phagophores, in the area of the AC with the membrane identities of early/recycling endosomes and the trans-Golgi network. During wrapping, host cell proteins that define the identity and shape of these membranes are captured along with the capsids and incorporated into the virions as host cell signatures. In this report, we reviewed the existing information on host cell signatures in human cytomegalovirus (HCMV) virions. We analyzed the published proteomes of the HCMV virion preparations that identified a large number of host cell proteins. Virion purification methods are not yet advanced enough to separate all of the components of the rich extracellular material, including the large amounts of non-vesicular extracellular particles (NVEPs). Therefore, we used the proteomic data from large and small extracellular vesicles (lEVs and sEVs) and NVEPs to filter out the host cell proteins identified in the viral proteomes. Using these filters, we were able to narrow down the analysis of the host cell signatures within the virions and determine that envelopment likely occurs at the membranes derived from the tubular recycling endosomes. Many of these signatures were also found at the autophagosomes, suggesting that the CMV-infected cell forms membrane organelles with phagophore growth properties using early endosomal host cell machinery that coordinates endosomal recycling. Full article

(This article belongs to the Special Issue Cytomegalovirus Infection and Cytomegalovirus Vaccine)

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