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
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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, gastrointestinal tract) (salivary glands)/liver progenitors/endothelial progenitors? Shedding in body fluids Yes Yes No Serology IgM IgM/IgG (low to high avidity) IgG (high avidity)/occasional IgM The Journal of Immunology 3883
IFN-I does not directly restrict MCMV replication levels be impacting this NK cell subset (66, 67), and a currently (31), whereas the first phase does (32). unidentified HCMV-encoded NKG2C ligand has also Work with MCMV during the last three decades has been postulated (similar to Ly49H-m157 in mice), but revealed many mechanisms by which NK cells contribute to the precise mechanisms underlying why NKG2Chi NK antiviral defense in various inbred mouse strains (33), and cells expand in CMV+ patients are yet to be fully defined more recent advances in genome sequencing has furthered this (68).However,asNKG2Chi NK cells can comprise as (34). It is clear that altered NK cell licensing and expression of much as 50% of the entire repertoire in some infected disparate activating and inhibitory receptors underlie many of individuals (64), which results in a substantial reduction these differences (35, 36). In C57BL/6 mice ∼50% of splenic inoverallNKpooldiversity,thismayimpacttheability NK cells express the Ly49H activating receptor, which binds to respond to heterologous infections or tumor immune the MCMV m157 protein expressed on the surface of in- surveillance. Interestingly, a population of CD56+CD8+ fected cells, promoting their resistance to viral replication in NKT-like cells also expands in peripheral blood of the spleen (37–42). m157 induces the activation and prolif- middle-aged persons infected with CMV, but may be eration of Ly49H+ NK cells during the first week of infection more a result of aging than being virus imposed per se (69). (43, 44), which then restrict MCMV replication mainly by Phase II: the adaptive immune response during CMV persistence. cytolysis (45). Notably, in the absence of Ly49H–m157 in- The CMV-specific T cell response shows several unique teractions, the role of NK cells in restricting MCMV repli- characteristics (18) and is differentially impacted by the cation can be minimal (e.g., in BALB/c mice) (33, 46), in three infection phases. MCMV replication is ultimately large part due to CMV neutralizing several NK cell effector controlled during the first week in most peripheral organs, Downloaded from pathways (35). correlating with the initial expansion of effector T cells, but Several other innate effector cell types also make important replicates for many more weeks at high levels in selected contributions in both the direct and indirect control of early mucosal sites such as the salivary gland. A robust and MCMV infection. Lymphoid tissue sinus-localized macro- diverse epitope-specific CD8 and CD4 T cell response is phages can capture MCMV during initial infection and primed in mice during this first week, most of which http://www.jimmunol.org/ restrict it from productively infecting reticular stromal cells contract and go on to establish a stable memory pool in (47). Mast cells are activated within hours of infection and the next 1–2 wk (70, 71). In contrast, selected populations produce chemokines that recruit CD8 T cells to infection sites of T cells do not significantly contract, expand only during within the first week (48, 49). Neutrophils are rapidly this second phase, and/or continue to increase during viral recruited by NK-produced IL-22 and contribute to viral persistence, and these have been termed inflationary control via TRAIL (50). Invariant NKT cells are activated memory cells (15, 71–73). These inflationary T cells display by the first and second waves of innate cytokines, indepen- a largely Tem phenotype, are maintained by a relatively small dently of CD1d, and help to control early MCMV replica- population of CD27hi CD8 T cells that are more central tion (51, 52). The importance of invariant NKT cells in memory–like (74), depend less on the immunoproteasome by guest on October 1, 2021 responding to HCMV infection is also suggested by viral than do stable memory cells, are dependent on the initial restriction of CD1d expression (53, 54). Various myeloid dose of viral inoculum (75), and require the continuous cell types also help to shape the earliest response to CMV transcriptional activity of FOXO1 (76). Notably, despite infection, but they also play a key role in disseminating the phenotype of these inflationary T cells being consistent CMV to sites of persistence and harboring latent viral with their continued exposure to Ag, they do not show typical genome in mice and humans, highlighting their complex signs of exhausted T cells induced by several other chronic role in CMV defenses (55–60). viral infections (77, 78). CMV shaping of the NK cell compartment. A key role for NK As in mice, CMV induces a broad CD8 and CD4 T cell cells in controlling HCMV infection is supported from a response that typically comprises 10–20% of all circu- patient case study who lacked them (24). Historically, NK cells lating T cells in CMV+ persons (79). HCMV also induces were thought to respond generally to viral infection, func- the expansion of selected, epitope-specific Tem cell sub- tioning en masse as front-line innate defenders. However, sets over time in healthy individuals, reaching stagger- more recent data, many in mice, indicate that populations ingly high numbers in some people (.20% for a single, of memory-like NK cells that display properties of adaptive epitope-specific response) (80, 81), and again typically lymphocytes can be primed during phase I (61) and may be show no signs of exhaustion. The expansion of these Tem preferentially maintained during later phases of infection. cells scores as one of the most prominent CMV-imposed One of these is the m157-driven expansion of Ly49H+ NK impacts in discordant monozygotic twins (7). Interest- cells in C57BL/6 mice, which remain at higher levels for ingly, these inflationary HCMV-specific T cells can use months postinfection and provide better MCMV protection unique cosignaling pathways for their activation (82). Many when adoptively transferred into naive mice (62). Interestingly, lack expression of CD27 and/or CD28 (83), and the emer- healthy CMV-infected people .60 y of age show a significant gence of high numbers of HCMV-specific CD4 T cells dis- increase in the numbers of CD56dim NK cells in blood (63). playing a cytolytic phenotype is also seen (84). Differential These cells also display a unique CD57+NKG2Chi cell surface cosignaling requirements for stable and inflationary memory phenotype (64), a distinct transcription factor expression profile, pools (85–89) and induction of CD4 CTLs (90) is also ob- and epigenetic remodeling of the Ifng gene locus (65). They served in CMV-infected mice. also preferentially expand in CMV-infected transplant patients, CMV-specific Ab responses are strongly induced. Polyclonal correlating with control of systemic viremia (64). Some human Ig containing high HCMV Ab levels has been reported studies indicate that NKG2C/HLA-E interactions might to provide some protection against congenital CMV infection 3884 BRIEF REVIEWS: CMV SHAPES IMMUNITY and/or disease in at-risk pregnant women (91), but not all and good experimental models have been established (59). In trials could reproduce this (92). This may be due to differing mice, MCMV can establish latency in both endothelial and HCMV IgG avidity (93), or its specificity for particular en- lymphoid-tissue reticular cell types (107, 108), and can be velope protein complexes that mediate viral entry into fibro- experimentally reactivated from various tissues (109). blasts (gB/gH/gL, trimer) and other cell types (gH/gL/ Although less is known about the molecular and cell- UL128–131, pentamer) (94, 95). In mice, transfer of MCMV intrinsic regulators of latency for MCMV than HCMV, Ig can reduce viral spread within tissues and restrict dissem- mouse studies have revealed key aspects of how phase III ination from sites of initial infection (96). The levels of infection impacts immune inflation (16). Inflationary T cells MCMV IgG increase steadily throughout persistence/latency, are maintained at higher levels when adoptively transferred although avidity appears to plateau several weeks before phase into latently infected mice than into naive uninfected mice, II is ultimately controlled, whereas IgM levels drop signifi- indicating that sporadic/abortive CMV gene expression dur- cantly after phase I (17). Inflation of HCMV IgG has also ing phase III latency facilitates continued exposure of immune been observed in healthy infected persons (97). Mice deficient cells to viral Ag and accentuates immune inflation (73). The in B7-CD28 cosignaling are severely compromised in relevant cellular source driving this inflation is radioresistant MCMV IgG responses (17), and in combination with their stromal cells (110, 111), suggesting that CMV latency in crippled T cell response never control phase II infection nonmyeloid cells is a major driver. Interestingly, a spread- (R. Arens and C. Benedict, unpublished observations). Adoptive deficient MCMV mutant can also induce memory inflation, 2 2 transfer of memory B cells into immune-deficient RAG / mice albeit at lower absolute levels (112). This suggests that a also reduces MCMV replication in both prophylactic and latency program can be triggered shortly after initial CMV Downloaded from therapeutic settings, and it provides longer protection than entry in some cells, perhaps due to their specific differentiation/ serum Ig transfer (98). As seen for MCMV T cell responses activation state, with other cellular states favoring the initiation (75), the magnitude of the Ig and memory B cell response of lytic replication and phase I infection. Evidence exists for a is dose-dependent, although Ig inflation and affinity mat- key role of lymphotoxin and IFN-I signaling in regulating this uration does still occur at low doses (17). As natural in- choice (113, 114). Importantly, these two paths do not have to fection by nursing or saliva transfer in both mice and be mutually exclusive, and they are likely to be conserved http://www.jimmunol.org/ people is likely to be relatively inefficient (99, 100), the among the Herpesviridae (115). However, recent studies show relative initial infection efficiency may partly explain why that significantly more viral gene expression likely occurs dur- CMV+ individuals often show significant variation in immune ing HCMV latency than dogma might predict (116–118), inflation decades later. Whether selected memory B cell subsets many of which perform immune-modulatory functions (119, inflate in CMV-infected mice or humans is currently unknown, 120), and this may help to explain why T cells of particular Ag but B cells in CMV+ twins do show altered IL-10 signaling specificity undergo immune inflation and others do not. responses (7). Interestingly, some HCMV Ags appear to induce Intriguingly, healthy CMV+ people with strong pre-existing poor memory B cell responses during primary infection (101), immunity can be reinfected (121), and in mice reinfection by guest on October 1, 2021 suggesting that well-designed vaccine approaches may be able to enhances T cell inflation (122). The significant variability in outperform natural immunity. Despite all evidence that CMV the magnitude of immune inflation between individuals may induces a robust B cell/Ig response that is protective in several depend in part on reinfection frequency. As many genetically therapeutic settings, it is noteworthy that immune control of distinct strains of HCMV exist (123), reinfection may just phase I and II MCMV infection is unchanged in mice simply represent an insufficient ability of prior immunity to lacking B cells (102), although control of viral reac- protect against a heterologous virus. However, a genetically tivation in phase III is compromised to some extent (103), identical rhesus CMV isolate can reinfect monkeys multiple indicating that significant redundancy exists for immune times and induce strong primary Tem responses, a strategy control of primary infection. that is being developed as a vaccination approach (124). In- Phase III: percolating CMV latency and its impact on the immune terestingly, the ability of rhesus CMV to superinfect in the system. After high-level persistent CMV replication during presence of strong pre-existing immunity is dependent phase II is ultimately brought under control, viral latency is on viral immune evasion strategies that dampen CD8 T cell established and a host–virus de´tente ensues for life in phase responses (125). III. Latency as defined originally for HSV is generally Finally, gd T cells also contribute to controlling MCMV appreciated to be 1) stable, nuclear, and extrachromosomal replication and limiting virus-induced organ disease (126), maintenance of the viral genome in selected cells and tissue and specific clonotypes expand in mice and show inflation sites for the life of the host, 2) a state of restricted gene within selected organs, similar to that observed for ab T cells. expression with no viral production, and 3) associated with Support for a role of gd T cells in controlling, or at a mini- the ability to reactivate from this state to full-replicative mum strongly responding to, HCMV infection also exists in potential under the right conditions (104). CMV encodes both healthy persons and transplant patients (7, 127, 128). the largest genome of the Herpesviridae (105), displays a However, as it remains unclear what self and/or CMV Ags gd broad cellular tropism, and is capable of establishing latency T cells recognize, it is difficult to know what phase of infec- in several cell types (106). This differs from HSV, which tion may be most critical in promoting their inflation. establishes latency only in neurons. For HCMV, latency has been studied almost exclusively in hematopoietic precursor CMV counterstrategies targeting the immune system and myeloid lineage cells, in part because these cells are Despite inducing a robust and diverse innate and adaptive relatively easy to access from patients, but primarily because immune response, CMV successfully progresses through its these cells clearly harbor latent viral genome in CMV+ people three-phase infection and establishes lifelong de´tente with The Journal of Immunology 3885 its host. To aid in this, CMV has developed many sophisti- orthologs of IL-10 (150), and HCMV viral IL-10 is expressed cated mechanisms targeting host immunity. It is likely that during both lytic and latent infection, perhaps contributing to only about a third of the .750 CMV open reading frames are the creation of a latency niche where effector T cells are required for the nuts-and-bolts of entry and lytic replication suppressed (117). Notably, HCMV can also promote (129), suggesting that the rest have evolved to combat the host production of host IL-10 by virus-specific CD4 T cells that immune response. Our laboratory has studied several of these encounter MHC class II–presented latency Ags (119, 151). immune-modulatory genes during the last two decades, pri- This strategy of hijacking host IL-10 immunosuppression to marily focusing on those that target and/or intersect with promote viral persistence is similarly employed by MCMV CD28 family and TNF family immune signaling pathways. (152, 153). Finally, CMV encodes both chemokines and These and many other CMV immune evasion mechanisms chemokine receptors, which impact T cells and operate to have been reviewed in recent years (12, 35, 55, 130–135), so fine-tune the inflammatory environment during all phases of we only briefly discuss those that we deem to be the most infection (154). likely to impact immune inflation. CMV targeting of NK cells. As already discussed, CMV induces Does immune shaping by CMV contribute to disease? the expansion of specific NK cell subsets. In addition to Does the broad impact of CMV on the immune system encoding proteins that specifically bind and activate NK cells ultimately contribute to human disease? CMV can be a se- (e.g., m157-Ly49H), CMV commensurately uses proteins rious human pathogen when immunity is compromised or to restrict NK cell–activating ligands and their receptors naive, as in the case of transplant patients and fetal infection, Downloaded from on the surface of infected cells. HCMV blocks expression and this is why vaccine development is a top priority (19, of NKG2D ligands such as MICA/B and ULBP family 155). However, there is a paucity of direct evidence for proteins (35). HCMV UL141 restricts the surface expression whether the lifelong de´tente in healthy people is deleterious, of CD155 and CD122, which activate NK via DNAM-1 and and the field remains largely agnostic on whether CMV is a CD94 (136). Additionally, UL141 also binds and inhibits driver or a passenger in associated diseases. CMV+ persons expression of the TRAIL death receptors to block NK-mediated
have been reported to exhibit a higher incidence of all-cause http://www.jimmunol.org/ killing by this TNF family cytokine (137), highlighting the mortality, mainly from increased cardiovascular disease polyfunctionality that a single CMV immunomodulatory (CVD) (156–158), and recent meta-analysis indicates CMV+ protein can have. MCMV utilizes a similar strategy via m166 to individuals have a 22% higher risk of developing CVD (159). inhibit TRAIL apoptosis (46). HCMV also encodes proteins As CMV infects vascular endothelial cells, a direct role for the that bind NK inhibitory receptors, such as the MHC class I virus is possible. Intriguingly, CMV CD4 T cells can express homolog UL18 that binds to LIR-1 (138), and UL40 that CX3CR1, which binds fractalkine expressed by activated/ stabilizes HLA-E expression to promote NKG2A engagement damaged endothelium, suggesting a mechanism by which (66). In fact, m157 can bind the inhibitory receptor Ly49i 2 CMV may kick-start or amplify CVD during multiple phases encoded in Ly49H 129/J mice, which likely attenuates NK of infection (81, 160, 161). CVD is an autoinflammatory by guest on October 1, 2021 cell activation (39). Collectively, this multilayered approach will disease, and consequently whether CMV infection may be almost certainly contribute to the CMV-induced expansion, linked with other common autoimmune disorders such as function, and/or memory of specific NK subsets rheumatoid arthritis, systemic sclerosis, systemic lupus CMV targeting of T cells. CMV also utilizes multiple strategies to erythematosus, diabetes, Sjo¨gren’s syndrome, and several regulate detection by both CD8 and CD4 T cells. First, intestinal disorders has also been examined (162). How- multiple HCMV and MCMV proteins operate to reduce ever, because most data are from small patient cohorts cell surface MHC expression during lytic replication, and/or case studies, causation remains unclear. thereby limiting T cell activation during phase I and II Evidence for CMV negatively impacting immune function of infection (133, 139). In infected cells, the HCMV US2, over time is suggested by its association with inflammaging 3, 6, 10, and 11 and MCMV m152/gp140, m04/gp34, and immune senescence in the elderly (163), with recent re- and m05/gp48 proteins downregulate MHC membrane sults indicating that it likely accelerates these processes (164). expression and limit peptide presentation to T cells. Very old Swedish cohorts exhibit an immune risk pheno- MCMV restricts expression of costimulatory molecules (e.g., type that includes CD4T/CD8T ratios ,1 in blood (165, B7 and CD40) and preferentially enhances expression of 166). However, the apparent ability of CMV to dial up the inhibitory ligands (e.g., PD-L1) as another T cell blockade homeostatic rheostat of the immune system may also provide strategy (140–143), and viral mutants unable to block B7- some benefit, as younger CMV+ people have been reported to CD28 signaling induce higher CD4 T cell response and show mount better vaccination responses to influenza (167). reduced replication in phase II (144). HCMV employs similar Although HCMV is not generally considered an oncogenic strategies to inhibit B7-CD28 signaling and promote death virus, viral nucleic acid has been reported to be present in of T cells that encounter infected DC (145), although the various tumor types at high frequency (168), with the most specific viral proteins responsible have not been identified notable example in recent years being that of glioblastoma as for MCMV. HCMV UL144 is an ortholog of HVEM (169). However, the absence of replicating virus, the low that selectively binds the coinhibitory molecule BTLA and percentage of glioma cells harboring viral genomes, and the potently blocks T cell proliferation (146–148). UL144 can inability of some groups to detect HCMV at all has again also activate NF-kB and is expressed during latency (120, made the contribution of CMV controversial. Nevertheless, 149), suggesting that it may impact T cell responses in some recent clinical results suggest that including CMV- phase III of infection. Additionally, all primate CMVs encode targeted approaches in the treatment of glioblastoma may 3886 BRIEF REVIEWS: CMV SHAPES IMMUNITY be helpful (170, 171). Future studies assessing whether the 14. Cannon, M. J., D. S. Schmid, and T. B. Hyde. 2010. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev. high proportions of inflationary CMV Tem might be pref- Med. 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