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Pathogens
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Cytomegalovirus (CMV) Infection and Latency
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Cytomegalovirus (CMV) Infection and Latency

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 24716

Special Issue Editor

Dr. Christine M. O'Connor

E-Mail Website
Guest Editor
Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Interests: herpesvirus; cytomegalovirus; latency; reactivation; host–pathogen relationships

Special Issue Information

Dear Colleagues,

Cytomegalovirus (CMV) is a herpesvirus that infects the majority of the population worldwide. While latent infection remains, for the most part, asymptomatic in healthy, immune-competent individuals, the virus poses a significant threat to those with weakened immune systems. CMV-associated disease following reactivation of latent infection is a risk factor for transplant patients undergoing immunosuppressive therapies, cancer patients treated with aggressive chemotherapies, immunocompromised AIDS patients, and even otherwise healthy individuals suffering from diseases such as atherosclerosis and inflammatory bowel disease. The current antiviral therapies target late stages of viral replication, when the disease is already primed to occur, underscoring the need for novel treatments targeting CMV prior to disease onset. This necessitates enhanced understanding of the latent and reactivation phases of infection.

Continued efforts aimed at understanding CMV latency and reactivation will undoubtedly provide insights into the mechanisms this pathogen uses to manipulate its host and cause disease. To this end, we are seeking novel manuscripts that address timely and relevant studies addressing these points. For this Pathogens Special Issue, we invite submissions in the form of original research articles, reviews, or case reports relevant to the topic. Current research focusing on broad topics in CMV infection are welcome, including the following, particularly interesting areas: latency and/or reactivation, host–pathogen relationships during latency/reactivation, the contribution of host and/or viral factors to these phases of infection, and clinical case reports. Studies relevant to these topics that use cell culture or animal models, as well as clinical reports, are all welcome. We look forward to receiving your contributions.

Dr. Christine M. O'Connor
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. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • cytomegalovirus
  • cytomegalovirus latency
  • cytomegalovirus reactivation
  • host–pathogen interactions
  • CMV-associated disease

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

2 pages, 147 KiB  
Editorial
Cytomegalovirus (CMV) Infection and Latency
by Christine M. O’Connor
Pathogens 2021, 10(3), 342; https://doi.org/10.3390/pathogens10030342 - 15 Mar 2021
Cited by 4 | Viewed by 1238
Abstract
Cytomegalovirus (CMV) is a herpesvirus that infects a majority of the human population worldwide [...] Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)

Research

Jump to: Editorial, Review

24 pages, 1921 KiB  
Article
Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells
by Iris K. A. Jones, Nicole N. Haese, Philippe Gatault, Zachary J. Streblow, Takeshi F. Andoh, Michael Denton, Cassilyn E. Streblow, Kiley Bonin, Craig N. Kreklywich, Jennifer M. Burg, Susan L. Orloff and Daniel N. Streblow
Pathogens 2020, 9(11), 963; https://doi.org/10.3390/pathogens9110963 - 19 Nov 2020
Cited by 2 | Viewed by 2278
Abstract
Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins [...] Read more.
Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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15 pages, 5501 KiB  
Article
The CMV-Specific CD8+ T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities
by Kilian Schober, Pim Fuchs, Jonas Mir, Monika Hammel, Lorenzo Fanchi, Michael Flossdorf and Dirk H. Busch
Pathogens 2020, 9(8), 650; https://doi.org/10.3390/pathogens9080650 - 13 Aug 2020
Cited by 3 | Viewed by 3358
Abstract
Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its [...] Read more.
Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its peptide epitope and the presenting major histocompatibility complex (pMHC). It remains unclear how many TCR sequences are recruited into an antigen-specific T cell response, both within and across different organisms, and which factors shape both of these distributions. Infection of mice with ovalbumin-expressing cytomegalovirus (IE2-OVA-mCMV) represents a well-studied model system to investigate T cell responses given their size and longevity. Here we investigated > 180,000 H2kb/SIINFEKL-recognizing TCR CDR3α or CDR3β sequences from 25 individual mice spanning seven different time points during acute infection and memory inflation. In-depth repertoire analysis revealed that from a pool of highly diverse, but overall limited sequences, T cell responses were dominated by public clonotypes, partly with unexpectedly extreme degrees of sharedness between individual mice (“supra-public clonotypes”). Public clonotypes were found exclusively in a fraction of TCRs with a high generation probability. Generation probability and degree of sharedness select for highly functional TCRs, possibly mediated through elevating intraindividual precursor frequencies of clonotypes. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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17 pages, 2957 KiB  
Article
MCMV Dissemination from Latently-Infected Allografts Following Transplantation into Pre-Tolerized Recipients
by Sahil Shah, Matthew DeBerge, Andre Iovane, Shixian Yan, Longhui Qiu, Jiao-Jing Wang, Yashpal S. Kanwar, Mary Hummel, Zheng J. Zhang, Michael M. Abecassis, Xunrong Luo and Edward B. Thorp
Pathogens 2020, 9(8), 607; https://doi.org/10.3390/pathogens9080607 - 26 Jul 2020
Cited by 4 | Viewed by 2663
Abstract
Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we [...] Read more.
Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we transfused chemically-fixed donor splenocytes (1-ethyl-3- (3′-dimethyl-aminopropyl)-carbo-diimide (ECDI)-treated splenocytes (ECDIsp)) to induce donor antigen tolerance without immunosuppression. In parallel, we implanted donor islet cells to validate operational tolerance. These pre-tolerized recipients were implanted with murine CMV (MCMV) latently-infected donor kidneys (a validated model of CMV latency) to monitor graft inflammation and viral dissemination. Our results indicate that tolerance to donor islets was sustained in recipients after implantation of donor kidneys. In addition, kidney allografts implanted after ECDIsp and islet implantation exhibited low levels of fibrosis and tubulitis. In contrast, kidney cellular and innate immune infiltrates trended higher in the CMV group and exhibited increased markers of CD8+ T cell activation. Tolerance induction was unable to prevent increases in MCMV-specific CD8+ T cells or dissemination of viral IE-1 DNA. Our data suggest that latently-infected allografts are inherently more susceptible to inflammation that is associated with viral dissemination in pre-tolerized recipients. Thus, CMV latently-infected allografts require enhanced strategies to protect allograft integrity and viral spread. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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Review

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15 pages, 1731 KiB  
Review
Regulation of Latency and Reactivation by Human Cytomegalovirus miRNAs
by Nicole L. Diggins, Rebecca L. Skalsky and Meaghan H. Hancock
Pathogens 2021, 10(2), 200; https://doi.org/10.3390/pathogens10020200 - 13 Feb 2021
Cited by 16 | Viewed by 2772
Abstract
Human cytomegalovirus (HCMV) encodes 22 mature microRNAs (miRNAs), which regulate a myriad of cellular processes, including vesicular trafficking, cell cycle progression, apoptosis, and immune evasion, as well as viral gene expression. Recent evidence points to a critical role for HCMV miRNAs in mediating [...] Read more.
Human cytomegalovirus (HCMV) encodes 22 mature microRNAs (miRNAs), which regulate a myriad of cellular processes, including vesicular trafficking, cell cycle progression, apoptosis, and immune evasion, as well as viral gene expression. Recent evidence points to a critical role for HCMV miRNAs in mediating latency in CD34+ hematopoietic progenitor cells through modulation of cellular signaling pathways, including attenuation of TGFβ and EGFR signaling. Moreover, HCMV miRNAs can act in concert with, or in opposition to, viral proteins in regulating host cell functions. Here, we comprehensively review the studies of HCMV miRNAs in the context of latency and highlight the novel processes that are manipulated by the virus using these small non-coding RNAs. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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30 pages, 1456 KiB  
Review
Regulation of the MIE Locus During HCMV Latency and Reactivation
by Abigail L. Dooley and Christine M. O’Connor
Pathogens 2020, 9(11), 869; https://doi.org/10.3390/pathogens9110869 - 23 Oct 2020
Cited by 23 | Viewed by 4905
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous herpesviral pathogen that results in life-long infection. HCMV maintains a latent or quiescent infection in hematopoietic cells, which is broadly defined by transcriptional silencing and the absence of de novo virion production. However, upon cell differentiation coupled [...] Read more.
Human cytomegalovirus (HCMV) is a ubiquitous herpesviral pathogen that results in life-long infection. HCMV maintains a latent or quiescent infection in hematopoietic cells, which is broadly defined by transcriptional silencing and the absence of de novo virion production. However, upon cell differentiation coupled with immune dysfunction, the virus can reactivate, which leads to lytic replication in a variety of cell and tissue types. One of the mechanisms controlling the balance between latency and reactivation/lytic replication is the regulation of the major immediate-early (MIE) locus. This enhancer/promoter region is complex, and it is regulated by chromatinization and associated factors, as well as a variety of transcription factors. Herein, we discuss these factors and how they influence the MIE locus, which ultimately impacts the phase of HCMV infection. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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12 pages, 374 KiB  
Review
Control of Cytokines in Latent Cytomegalovirus Infection
by Pearley Chinta, Erica C. Garcia, Kiran Hina Tajuddin, Naomi Akhidenor, Allyson Davis, Lionel Faure and Juliet V. Spencer
Pathogens 2020, 9(10), 858; https://doi.org/10.3390/pathogens9100858 - 21 Oct 2020
Cited by 8 | Viewed by 3455
Abstract
Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny [...] Read more.
Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny virions, occurs in differentiated cell types, while undifferentiated myeloid precursor cells are the primary site of latent infection. The outcome of HCMV infection depends partly on the cell type and differentiation state but is also influenced by the composition of the immune environment. In this review, we discuss the role of early interactions between HCMV and the host immune system, particularly cytokine and chemokine networks, that facilitate the establishment of lifelong latent infection. A better understanding of these cytokine signaling pathways could lead to novel therapeutic targets that might prevent latency or eradicate latently infected cells. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
9 pages, 433 KiB  
Review
Understanding HCMV Latency Using Unbiased Proteomic Analyses
by Emma Poole and John Sinclair
Pathogens 2020, 9(7), 590; https://doi.org/10.3390/pathogens9070590 - 20 Jul 2020
Cited by 12 | Viewed by 2970
Abstract
Human cytomegalovirus (HCMV) establishes either a latent (non-productive) or lytic (productive) infection depending upon cell type, cytokine milieu and the differentiation status of the infected cell. Undifferentiated cells, such as precursor cells of the myeloid lineage, support a latent infection whereas terminally differentiated [...] Read more.
Human cytomegalovirus (HCMV) establishes either a latent (non-productive) or lytic (productive) infection depending upon cell type, cytokine milieu and the differentiation status of the infected cell. Undifferentiated cells, such as precursor cells of the myeloid lineage, support a latent infection whereas terminally differentiated cells, such as monocytes or dendritic cells are an environment conducive to reactivation and support a lytic infection. The mechanisms which regulate HCMV in either a latent or lytic infection have been the focus of intense investigation with a view to developing novel treatments for HCMV-associated disease which can have a heavy clinical burden after reactivation or primary infection in, especially, the immune compromised. To this end, a number of studies have been carried out in an unbiased manner to address global changes occurring within the latently infected cell to address the molecular changes associated with HCMV latency. In this review, we will concentrate on the proteomic analyses which have been carried out in undifferentiated myeloid cells which either stably express specific viral latency associated genes in isolation or on cells which have been latently infected with virus. Full article
(This article belongs to the Special Issue Cytomegalovirus (CMV) Infection and Latency)
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