NF-κB-Mediated Activation of the Chemokine CCL22 by the Product of the Human Cytomegalovirus Gene UL144 Escapes Regulation by Viral IE86

Poole, Emma; Atkins, Elizabeth; Nakayama, Takashi; Yoshie, Osamu; Groves, Ian J.; Alcamı́, Antonio; Sinclair, John

doi:10.1128/jvi.02156-07

Cited by 45 publications

(45 citation statements)

References 34 publications

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“…69 UL144 has two putative immune evasion functions; the ectodomian has been shown to interact with B and T lymphocyte attenuator and inhibits T-cell proliferation in vitro 70 and the intracellular domain signals via NFkB, TRAF6 and TRIM23 to induce the chemokine CCL22 which acts as a TH2 chemoattractant possibly subverting the TH1 immune response. 69,71,72 Manipulation of the cellular microenvironment by changes in the cell secretome HCMV lytic infection is also known to induce profound alterations in levels of secreted cellular proteins (secretome) and this includes a number of chemokines and cytokines with immune functions. 73,74 However, until recently, little was known about latency-associated changes in the cell secretome.…”

Section: Immune Evasion Strategies During Latent Infectionmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Section: Immune Evasion Strategies During Latent Infectionmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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“…Two of the UL/b' region gene products, UL144 and UL138, upregulate the TNFα-mediated NF-κB signaling (19,20). UL138, which is expressed during latent infection, modulates the cell surface expression of TNFR1, suggesting that TNF signaling may affect HCMV latency (20,21).…”

Section: (2) Activation Mechanisms Observed In Clinical Strainsmentioning

confidence: 99%

“…CCL22 is a chemoattractant for T helper 2 (Th2) and regulatory T (Treg) cells. Therefore, upregulation of NF-κB signaling by UL144 may be a viral strategy to reduce Th1-mediated immune responses (19).…”

Section: (2) Activation Mechanisms Observed In Clinical Strainsmentioning

confidence: 99%

Differential Regulation of NF-κB Signaling during Human Cytomegalovirus Infection

Kwon

Ahn

2015

J Bacteriol Virol

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NF-κB transcription factors are key regulators of immune and stress responses, apoptosis, and differentiation. Human cytomegalovirus (HCMV) activates or represses NF-κB signaling at different times during infection. An initial increase in NF-κB activity occurs within a few hours of infection. The virus appears to adapt to this change since initial viral gene expression is promoted by the elevated NF-κB activity. Because NF-κB upregulates innate immune responses and inflammation, it has also been suggested that HCMV needs to downregulate NF-κB signaling. Recent studies have shown that HCMV has various mechanisms that inhibit NF-κB signaling. HCMV reduces cell surface expression of tumor necrosis factor receptor 1 (TNFR1) and blocks the DNA binding activity of NF-κB. Furthermore, some HCMV tegument proteins antagonize NF-κB activation by targeting the key components of NF-κB signaling at late stages of infection. In this review, we summarize the recent findings on the relationship between HCMV and NF-κB signaling, focusing, in particular, on the viral mechanisms by which the NF-κB signaling pathway is inhibited.

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“…Compared with the genome of the prototype laboratory strain, AD169, genomes of low-passage HCMV clinical isolates contain the UL/b' region, including ORFs UL133-UL151, considered as a critical candidate cluster to clinical pathogenesis (3). Although the UL/b' region is not essential to viral growth or replication (4), products of this region, including UL141, UL142 and UL144 have been experimentally identified to aid in viral escape from immune surveillance through interactions with cellular molecules (5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Identification of immediate early gene X-1 as a cellular target gene of hcmv-mir-UL148D

Wang

Huang

et al. 2013

International Journal of Molecular Medicine

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Abstract. Human cytomegalovirus (HCMV) is a herpesvirus that causes congenital diseases and opportunistic infections in immunocompromised individuals. Its functional proteins and microRNAs (miRNAs) facilitate efficient viral propagation by altering host cell behavior. The identification of functional target genes of miRNAs is an important step in the study of HCMV pathogenesis. HCMV encodes at least 14 miRNAs, including hcmv-mir-UL148D, which resides in the HCMV UL/b' region. hcmv-mir-UL148D is the only miRNA encoded by the HCMV UL/b' region; however, its targets and functional effects have not yet been eludidated. In this study, hybrid-PCR screening was used to identify target genes and dual luciferase reporter assay was used to evaluate the binding effect of hcmv-miR-UL148D to the 3' untranslated region (3'UTR) of IEX-1. In addition, western blot analysis was used to detect the expression kinetics of IEX-1 protein and apoptosis assay was used to identify the effects of hcmv-miR-UL148D on cell apoptosis. The hybrid-PCR results showed that only one binding site in the 3'UTR of the cellular gene, human immediate early gene X-1 (IEX-1), was completely complementary to an 11 nucleotide (nt) sequence in the 5' terminus of hcmvmir-UL148D, including the entire seed region. The binding site was demonstrated to be functional by dual luciferase reporter assay with a 47% repression of the relative luciferase activity. In an in vitro system of human embryonic kidney 293 (HEK293) cells, the ectopically expressed hcmv-mir-UL148D exhibited a downregulatory effect on IEX-1 expression, and decreased the cell apoptosis induced by transfected IEX-1. Our data demonstrate that hcmv-mir-UL148D targets the cellular gene, IEX-1, downregulating its expression and thus results in anti-apoptotic effects.

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NF-κB-Mediated Activation of the Chemokine CCL22 by the Product of the Human Cytomegalovirus Gene UL144 Escapes Regulation by Viral IE86

Cited by 45 publications

References 34 publications

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Differential Regulation of NF-κB Signaling during Human Cytomegalovirus Infection

Identification of immediate early gene X-1 as a cellular target gene of hcmv-mir-UL148D

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