Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes

Beisser, Patrick S.; Laurent, Lysiane; Virelizier, Jean-Louis; Michelson, Susan

doi:10.1128/jvi.75.13.5949-5957.2001

Cited by 135 publications

(120 citation statements)

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“…HEL were infected with HCMV AD169 at a multiplicity of infection (m.o.i.) of 0.1 as described earlier (18). At 72 h postinfection, infected as well as uninfected HEL were detached from culture flasks by using a cell scraper.…”

Section: Methodsmentioning

confidence: 99%

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Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

Casarosa¹,

Gruijthuijsen

Michel

et al. 2003

Journal of Biological Chemistry

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The human cytomegalovirus (HCMV) UL33 gene is conserved among all ␤-herpesviruses and encodes a protein that shows sequence similarity with chemokine receptors belonging to the family of G protein-coupled receptors. Here, we show that HCMV UL33 is predominantly transcribed as a spliced mRNA of which the 5 terminus is localized 55 bp upstream of the start codon. Like its homolog from rat cytomegalovirus (RCMV), R33, UL33 activates multiple signaling pathways in a ligandindependent manner. Although both receptors constitutively activate phospholipase C via G q/11 , and partially via G i/o -mediated pathways, they exhibit profound differences in the modulation of cAMP-responsive element (CRE) activation. R33 constitutively inhibits, whereas UL33 constitutively enhances CRE-mediated transcription. For R33, the inhibition of CRE-driven transcription is entirely G i/o -mediated. For UL33, however, CREmediated transcription is modulated not only through coupling to G␣ i/o but also through coupling to G␣ s. In addition, UL33 was found to enhance CRE activation through the Rho/p38 pathway, via G␤␥. Interestingly, by studying chimeric UL33/R33 proteins, we found the Cterminal cytoplasmic tail of UL33, but not that of R33, to be responsible for the activation of G i/o proteins. A UL33-deficient variant of HCMV was generated to analyze UL33-signaling properties in a physiologically relevant model system. Data obtained with infected cells show that HCMV induces CRE activation, and this effect is, at least in part, dependent on UL33 expression. Taken together, our data indicate that constitutive signaling of UL33 differs from that of R33 by promiscuous activation of G proteins of the G q , G i/o , as well as G s class. Thus, HCMV may effectively use UL33 to orchestrate multiple signaling networks within infected cells.

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Section: Methodsmentioning

confidence: 99%

“…Determination of cDNA Ends-Propagation of human embryo lung fibroblasts (HEL) and HCMV AD169 was performed as previously described (18,19). HEL were infected with HCMV AD169 at a multiplicity of infection (m.o.i.)…”

Section: Methodsmentioning

confidence: 99%

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

Casarosa¹,

Gruijthuijsen

Michel

et al. 2003

Journal of Biological Chemistry

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“…10,47 There is now much published data detailing expression of specific viral genes during natural or experimental latent infection in CD34 1 cells or their myeloid derivatives. Transcripts expressed during natural latency are known to include RNAs from the major IE region (UL122-123 CLTs), 31 as well as UL81-82ast (LUNA), 34 UL138, 35 UL111a, 33 UL144 28 and US28, 49 but more recently, additional latency-associated viral transcripts have also been identified. 29 The detailed functions of these viral genes, where known, are beyond the scope of this article but have been described in recent reviews.…”

Section: Establishment Of Latency and The Molecular Biology Of The Lamentioning

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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“…Latency unique nuclear antigen (LUNA) RNA is coded opposite to the UL81-82 coding region, and it accumulates during latency in monocytes and bone marrow cells (29). Bone marrow cells from infected donors express latency-associated cmvIL-10 (LAcmvIL-10) RNA (30), which encodes a variant of the HCMV IL-10 (vIL-10), and infected THP1 monocyte-like cells express RNA encoding the US28 chemokine receptor (31). All four RNAs were detected on days 1-10 after infection of monocytes (Fig.…”

Section: Transient Expression Of Lytic Transcripts With Prolonged Expmentioning

confidence: 99%

Experimental human cytomegalovirus latency in CD14⁺monocytes

Hargett

Shenk²

2010

Proc. Natl. Acad. Sci. U.S.A.

153

200

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CD14 + monocytes are a reservoir for latent human cytomegalovirus, and virus replication is reactivated during their differentiation to macrophages or dendritic cells. It has not been clear whether the virus can establish latency upon direct infection of monocytes or whether it must first become quiescent in a progenitor cell that subsequently differentiates to generate a monocyte. We report that infection of primary human monocytes with a clinical strain of human cytomegalovirus exhibits the hallmarks of latency. We established conditions for culturing monocytes that prevent differentiation for at least 25 d, as evidenced by cell surface marker expression. Infection of these monocytes with the FIX clinical strain resulted in transient accumulation of many viral lytic RNAs and sustained expression of four previously described latency-associated transcripts. The amount of viral DNA remained constant after infection, and cell surface and total HLA-DR proteins were substantially reduced on a continuing basis after infection. When treated with cytokine mixtures that stimulate differentiation to a macrophage or dendritic cell phenotype, infected monocytes reactivated virus replication and produced infectious progeny. Treatment of infected monocytes with IL-6 alone also was sufficient for reactivation, and the particles produced after exposure to this cytokine were about fivefold more infectious than virions produced by other treatments. We propose that in vivo microenvironments influence not only the efficiency of reactivation but also the infectivity of the virions produced from latently infected monocytes.herpesvirus | myeloid biology | cell culture | antigen presentation | immunology H uman cytomegalovirus (HCMV) is a dangerous opportunistic pathogen (1) that replicates in many cell types but enters latency in others, allowing persistence of the viral genome without production of progeny. Viral DNA and a small subset of viral RNAs have been found in naturally infected CD34 + hematopoietic stem cells (HSCs) and CD33 + progenitor cells (2). Experimental infections of CD34 + and CD33 + cells also display the hallmarks of latency. HCMV DNA and a subset of viral transcripts are present in these cells after infection in culture, and the virus can be reactivated to produce progeny if the cells differentiate (2). The choice of HCMV strain can influence the outcome of infections (3). Two clinical isolates entered and exited latency, whereas the AD169 laboratory strain failed to become latent in CD34 + cells. AD169 lacks the UL138 gene, which is important for entry into latency (3, 4).Like HSCs, naturally infected CD14 + monocytes harbor HCMV DNA (5-7), and viral replication is activated by differentiation (8, 9). Monocytes from peripheral blood are nonpermissive for HCMV replication (10), but when differentiated to a macrophage phenotype, they support the production of infectious progeny (11, 12). Thus, natural and experimental infections argue that differentiation from monocyte to macrophage or dendritic cell marks a divi...

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Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes

Cited by 135 publications

References 46 publications

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

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

Experimental human cytomegalovirus latency in CD14⁺monocytes

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Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes

Cited by 135 publications

References 46 publications

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

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

Experimental human cytomegalovirus latency in CD14+monocytes

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Experimental human cytomegalovirus latency in CD14⁺monocytes