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      Cytomegalovirus (CMV) Infection and Latency

      editorial
      Pathogens
      MDPI

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          Abstract

          Cytomegalovirus (CMV) is a herpesvirus that infects a majority of the human population worldwide. While for the most part, latent infection remains 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 full spectrum of CMV-related diseases is still being determined, but it is well-accepted that CMV infections represent a significant and under-addressed medical burden. The current standard of care for antiviral therapies targets the late stages of viral replication, a stage at which the disease is already primed to occur, thus underscoring the need for novel treatments targeting CMV prior to disease onset. This necessitates enhanced understanding of the key biological determinants of the latency and factors that dictate the reactivation phase of infection. The research articles included in this Pathogens Special Issue highlight the need for multifaceted approaches to better understand latency and reactivation, as well as to provide novel insights to these processes. Included in this collection are research articles that leverage novel in vivo model systems using rodent CMVs, which provide important insights to viral reactivation that extend beyond tissue culture studies. The strength of these systems allows investigators to assess viral dissemination [1], immunological responses [2], and the contribution of infection to the pathologies following transplant [3]—a major advancement to the field. In addition, the review articles in this Special Issue illuminate the important advances made by CMV investigators on the latent and reactivation phases of CMV infection [4,5,6,7]. It is evident from these reviews that the success of these stages of infection rely on the interplay of the host and the virus and are highly complex, involving both viral and cellular factors, many of which have yet to be revealed. I hope the reader finds this collection both timely and compelling, and that the wealth of knowledge provided within provides novel insights to this human pathogen.

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          Most cited references7

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          Regulation of the MIE Locus During HCMV Latency and Reactivation

          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.
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            Understanding HCMV Latency Using Unbiased Proteomic Analyses

            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.
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              Regulation of Latency and Reactivation by Human Cytomegalovirus miRNAs

              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.
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                Author and article information

                Journal
                Pathogens
                Pathogens
                pathogens
                Pathogens
                MDPI
                2076-0817
                15 March 2021
                March 2021
                : 10
                : 3
                : 342
                Affiliations
                Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44016, USA; oconnoc6@ 123456ccf.org
                Author information
                https://orcid.org/0000-0003-4943-3774
                Article
                pathogens-10-00342
                10.3390/pathogens10030342
                8001800
                ffd9b4c9-9ff2-4490-ba2e-6e19b8cffd18
                © 2021 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 March 2021
                : 13 March 2021
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                Editorial

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