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      Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein

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          Abstract

          Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, and one viral gene expressed by latently infected myeloid cells is US28. This viral gene encodes a cell surface G protein-coupled receptor (GPCR) that binds chemokines, triggering its endocytosis. We show that the expression of US28 on the surface of latently infected cells allows monocytes and their progenitor CD34+ cells to be targeted and killed by F49A-FTP, a highly specific fusion toxin protein that binds this viral GPCR. As expected, this specific targeting of latently infected cells by F49A-FTP also robustly reduces virus reactivation in vitro. Consequently, such specific fusion toxin proteins could form the basis of a therapeutic strategy for eliminating latently infected cells before haematopoietic stem cell transplantation.

          Abstract

          Reactivation of human cytomegalovirus in immunosuppressed transplant patients can cause severe complications. Here, Krishna et al. show that a fusion toxin protein that specifically binds the viral surface protein US28 can be used to kill latently infected monocytes and their progenitor cells in vitro.

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          How we treat cytomegalovirus in hematopoietic cell transplant recipients.

          Cytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.
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            Latency and reactivation of human cytomegalovirus.

            Human cytomegalovirus (HCMV) persists as a subclinical, lifelong infection in the normal human host, maintained at least in part by its carriage in the absence of detectable infectious virus--the hallmark of latent infection. Reactivation from latency in immunocompromised individuals, in contrast, often results in serious disease. Latency and reactivation are defining characteristics of the herpesviruses and key to understanding their biology. However, the precise cellular sites in which HCMV is carried and the mechanisms regulating its latency and reactivation during natural infection remain poorly understood. This review will detail our current knowledge of where HCMV is carried in healthy individuals, which viral genes are expressed upon carriage of the virus and what effect this has on cellular gene expression. It will also address the accumulating evidence suggesting that reactivation of HCMV from latency appears to be linked intrinsically to the differentiation status of the myeloid cell, and how the cellular mechanisms that normally control host gene expression play a critical role in the differential regulation of viral gene expression during latency and reactivation.
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              Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency.

              Human cytomegalovirus (HCMV) resides latently in hematopoietic cells of the bone marrow. Although viral genomes can be found in CD14+ monocytes and CD34+ progenitor cells, the primary reservoir for latent cytomegalovirus is unknown. We analyzed human hematopoietic subpopulations infected in vitro with a recombinant virus that expresses a green fluorescent protein marker gene. Although many hematopoietic cell subsets were infected in vitro, CD14+ monocytes and various CD34+ subpopulations were infected with the greatest efficiency. We have developed an in vitro system in which to study HCMV infection and latency in CD34+ cells cultured with irradiated stromal cells. Marker gene expression was substantially reduced by 4 days postinfection, and infectious virus was not made during the culture period. However, viral DNA sequences were maintained in infected CD34+ cells for >20 days in culture, and, importantly, virus replication could be reactivated by coculture with human fibroblasts. Using an HCMV gene array, we examined HCMV gene expression in CD34+ cells. The pattern of viral gene expression was distinct from that observed during productive or nonproductive infections. Some of these expressed viral genes may function in latency and are targets for further analysis. Altered gene expression in hematopoietic progenitors may be indicative of the nature and outcome of HCMV infection.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                02 February 2017
                2017
                : 8
                : 14321
                Affiliations
                [1 ]Department of Medicine, Addenbrooke's Hospital, University of Cambridge , Cambridge CB20QQ, UK
                [2 ]Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen DK-2200, Denmark
                [3 ]Department of Infectious Diseases, Robert Koch Institute , Nordufer 20, Berlin 13353, Germany
                [4 ]Department of Pediatric Oncology/Hematology/SCT, Charité-Universitätsmedizin , Berlin 13353, Germany
                [5 ]Section for Virology, The National Veterinary Institute, Technical University of Denmark , Frederiksberg DK-1870, Denmark
                Author notes
                [*]

                Present address: Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom

                Article
                ncomms14321
                10.1038/ncomms14321
                5296658
                28148951
                f3a01cd1-ed0e-4135-8fff-a2bf3535ae62
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 01 July 2016
                : 16 December 2016
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