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Cytomegalovirus: Shape-Shifting the Immune System Gaëlle Picarda and Chris A

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Cytomegalovirus: Shape-Shifting the Immune System Gaëlle Picarda and Chris A Cytomegalovirus: Shape-Shifting the Immune System Gaëlle Picarda and Chris A. Benedict This information is current as J Immunol 2018; 200:3881-3889; ; of October 1, 2021. doi: 10.4049/jimmunol.1800171 http://www.jimmunol.org/content/200/12/3881 References This article cites 169 articles, 65 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/200/12/3881.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 1, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Cytomegalovirus: Shape-Shifting the Immune System Gae¨lle Picarda* and Chris A. Benedict*,† Systems-based based approaches have begun to shed Epidemiology of CMV light on extrinsic factors that contribute to immune HCMV is the prototypic member of the Betaherpesvirinae and system variation. Among these, CMV (HHV-5, a is a dsDNA virus with an ∼236-kb genome expressing up to b-herpesvirus) imposes a surprisingly profound impact. ∼750 protein-encoding open reading frames emanating from + Most of the world’s population is CMV , and the virus complex control of transcription and splicing (8, 9). CMVs, goes through three distinct infection phases en route similar to all Herpesviridae, have coevolved with their indi- to establishing lifelong de´tente with its host. Immune vidual hosts for millions of years to establish a persistent/latent control of CMV in each phase recruits unique arms of infection that is never cleared (10). Consequently, CMV rep- host defense, and in turn the virus employs multiple lication is species specific, in large part because the virus has immune-modulatory strategies that help facilitate the evolved many fine-tuned strategies to inhibit various immune Downloaded from establishment of lifelong persistence. In this review, we defenses unique to those hosts (11, 12). In the United States, explain how CMV shapes immunity and discuss the infection rates of prepubescent children range from 30 to 60%, impact it may have on overall health. The Journal of varying by sex, ethnicity, and socioeconomic status, increasing Immunology, 2018, 200: 3881–3889. steadily to 50–90% by the age of 50 y. In general, infection is lowest in non-Hispanic white males, persons of higher educa- tion, and those living in less crowded conditions (13). The http://www.jimmunol.org/ n recent years, systems approaches have been used to overall incidence of CMV infection is significantly higher in begin elucidating the extent that the immune system South America, Asia, and Africa (.90%) as compared with the I differs between individuals. These have focused largely United States and Western Europe (14). Consequently, the fact on measuring the composition, phenotype, and gene- that many people living today in the Western developed world expression patterns of circulating immune cell populations remain uninfected with CMV into adulthood has facilitated (1–3). The hope is that this will begin to clarify how variation assessing how it impacts immunity. in these parameters relates to disease, how they might im- The phases of CMV infection pact vaccination responses, and, ultimately, how they help by guest on October 1, 2021 develop a blueprint for better overall health. Concurrent CMV infection has three distinct phases: 1) a systemic rep- technological advancements have allowed the measure- lication phase in many peripheral tissues that strongly activates ment of multiple, individual immune cell frequencies and the innate immune system and specific NK cell populations immune-regulating cytokines from patient blood samples and primes a diverse Ab and T effector memory (Tem) cell (e.g., mass cytometry and multiplex ELISA), and in combi- response; 2) a tissue-localized persistent phase that continues nation with unbiased genomics approaches will ultimately for months to years and continues to shape innate and adaptive help to spawn personalized medicine (4, 5). Notably, non- immunity; and 3) multisite latency with restricted viral gene heritable factors are major drivers of immune system varia- expression that promotes immune inflation during a subse- tion, with one prime example being the microbiome (6). quent lifetime (15–18) (Fig. 1, Table I). Despite this pro- However, quite surprisingly, another major factor is human longed and multifaceted interaction with its host, CMV CMV (HCMV) infection (HHV-5, a b-herpesvirus) (7). normally only causes acute disease when immunity is naive or Identical twins discordant for HCMV infection vary in compromised, exemplifying how coevolution over millennia .50% of ∼200 measured immune parameters (7), a re- has resulted in a largely nonpathogenic de´tente. However, the markable impact for a single, common viral infection. In this extremely broad impact of CMV on immune system ho- review, we discuss unique aspects of the broad immune re- meostasis in healthy adults likely impacts aspects of health and sponse to HCMV infection that arise during its distinct disease over time. phases of infection, specific strategies used by CMV to Phase I: the innate immune response to initial CMV infection. target them, and how this may ultimately impact health and Primary CMV infection in healthy people is essentially disease. asymptomatic, and therefore studies assessing the activation *Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, Address correspondence and reprint requests to Prof. Chris A. Benedict, La Jolla La Jolla, CA 92037; and †Center for Infectious Disease, La Jolla Institute for Allergy and Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. Immunology, La Jolla, CA 92037 E-mail address: [email protected] ORCID: 0000-0001-7321-0373 (G.P.). Abbreviations used in this article: CVD, cardiovascular disease; DC, dendritic cell; HCMV, human CMV; IFN-I, type I IFN; MCMV, mouse CMV; Tem, T effector Received for publication February 6, 2018. Accepted for publication March 26, 2018. memory. This work was supported by National Institutes of Health/National Institute for Allergy and Infectious Diseases Grants AI101423 and AI113349 (to C.A.B.). Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800171 3882 BRIEF REVIEWS: CMV SHAPES IMMUNITY FIGURE 1. CMV impacts the immune system during the course of a lifetime. Top panel, Depicted are the three phases of CMV infection: I) the acute/systemic phase, which is controlled after a few weeks; II) the persistent replication phase that can con- tinue for months to years in people (weeks to months in mice); and III) the percolating Downloaded from latency phase where an ongoing de´tente between the virus and its host continues to shape and inflate host defenses. Bottom panel, CMV impacts both innate and adaptive cell populations and immune re- sponses during its three-phase infection, and shown are several that are directly http://www.jimmunol.org/ impacted. by guest on October 1, 2021 and contribution of innate defenses during the phase I in- NK cells and type I IFN (IFN-I) are key regulators of early fection in people are sparse. Additionally, the species-specific CMV control (23, 24). MCMV induces two major systemic replication of CMV necessitates using animal models to help phases of IFN-I. The initial phase is produced by splenic define key innate control mechanisms. In this regard, mouse stromal cells and is proportional to the infecting dose, peaks CMV (MCMV) has been the most instructive (19), but in sera at 10–12 h, and is dependent on B cell–derived rhesus (20, 21) and guinea pig (22) CMV models have also lymphotoxin ab signaling (25). The second phase occurs at been very instructional. Most mouse and guinea pig infections 36–48 h in response to the first burst of MCMV production are done systemically (i.p. or i.v.), with s.c. infection often and is produced by both plasmacytoid dendritic cells (DC) performed in monkeys. How the initial activation/priming of and conventional DC. In addition to IFN-I, these DC subsets innate and adaptive immune responses with these infection produce high levels of tissue-localized and systemic IL-12 routes and doses might differ from that of natural mucosal and IL-18 (26, 27), which further NK cell activation (28–30) infection is an important question and is discussed later. and help to prime adaptive responses. Notably, second-phase Table I. CMV infection phases in healthy individuals Phase I. Acute Infection II. Persistence III. Latency/Reactivation CMV genome expression Yes Yes Minimal/suppression of the major immediate-early promoter Virion production Yes Yes No/sporadic during reactivation Organs implicated Visceral organs (spleen, liver, Mucosal organs CD14+ monocytes/CD34 lung,
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