Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells

Cheung, Allen Ka Loon; Abendroth, Allison; Cunningham, Anthony L.; Slobedman, Barry

doi:10.1182/blood-2005-12-026682

Cited by 116 publications

(143 citation statements)

References 46 publications

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“…CD34 1 progenitors, monocytes and granulocyte-macrophage progenitors, as well as some established myeloid cell lines, can be infected in culture allowing the maintenance of latent viral genomes which can then be reactivated by differentiation signals. 21,30,[35][36][37][45][46][47] However, it is clear that some experimental models using established cell lines do not appear to fully recapitulate all aspects of control of latency and reactivation observed in primary myeloid cells. 48 A totally quiescent viral genome during latent infection would clearly be the ideal way to avoid immune surveillance-if viral proteins are not expressed at all there would be no processing and presentation of viral antigens to specific T cells and, thus, latently infected cells would be ignored by the host immune response.…”

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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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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“…A subset of lytic HCMV RNAs is transiently expressed after infection of CD34 + HSCs (25) or granulocyte-macrophage progenitor cells (26). We infected monocytes with FIX and monitored the accumulation of the UL122 and UL123 immediate-early RNAs, whose immediate early 2 and 1 (IE2 and IE1) protein products are essential for lytic replication (1).…”

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.

160

204

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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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“…We did not identify a significant difference in the timing or frequency of reactivation of viral IL-10 deletion virus in comparison to parental virus using our previously described reactivation assay, whereby latently infected cells were cocultured with monolayers of primary human foreskin fibroblasts to stimulate reactivation, and monolayers were monitored daily for the appearance of cytopathic effect (CPE) as an indicator of virus reactivation (8,9,22). Specifically, in four independent experiments, both parental virus and viral IL-10 deletion virus reactivated at the same time (mean time of 12 days after reactivation stimulus), and the frequencies of reactivation were very similar for the parental virus (1.2 ϫ 10 Ϫ4 ) and viral IL-10 deletion virus (1.3 ϫ 10 Ϫ4 ).…”

Section: Relative To Mock-infected Cells) Measured By Qrt-pcr Of Tnf-mentioning

confidence: 99%

“…Following terminal cell differentiation of these cells into myeloid dendritic cells (DCs) and macrophages, latent virus has the ability to reactivate, resulting in the production of new, infectious virions and often severe disease in immunocompromised individuals (11,14,28,37,49,50,59,63). Only a subset of viral genes are transcriptionally active during latency (2,8,12,13,17,23,34,47), including HCMV UL111A, a gene that encodes homologs of the potent immunomodulatory cytokine human interleukin-10 (hIL-10). UL111A is transcriptionally active during both productive and latent phases of infection and encodes several viral IL-10 proteins (17,(24)(25)(26)46) which exert a diverse range of immunomodulatory functions, including inhibition of cytokine synthesis and major histocompatibility complex (MHC) expression by myeloid cells, stimulation of B cells, and suppression of DC maturation and cytotrophoblast function (5-7, 9, 16, 18, 36, 51, 52, 61).…”

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confidence: 99%

“…To determine whether HCMV UL111A-encoded viral IL-10 affected expression of proinflammatory cytokines involved in modulating myeloid cell differentiation, we first evaluated mRNA expression of interleukin-1␤ (IL-1␤) and tumor necrosis factor alpha (TNF-␣) in cells latently infected with RVAdIL10C, a recombinant virus that cannot express any viral IL-10 (33), or its parent strain AD169. Primary human CD34 ϩ myeloid progenitors were latently infected as previously described (8,22), and cells and culture supernatants were harvested at day 8 postinfection (p.i.). We have previously demonstrated that this viral IL-10 deletion virus infects and maintains a latent infection in CD34 ϩ myeloid progenitors as efficiently as the parental virus does (9).…”

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confidence: 99%

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Viral Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection Modulates Latently Infected Myeloid Cell Differentiation

Avdic

Cao

Cheung

et al. 2011

J Virol

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The human cytomegalovirus UL111A gene is expressed during latent and productive infections, and it codes for homologs of interleukin-10 (IL-10). We examined whether viral IL-10 expressed during latency altered differentiation of latently infected myeloid progenitors. In comparison to infection with parental virus or mock infection, latent infection with a virus in which the gene encoding viral IL-10 has been deleted upregulated cytokines associated with dendritic cell (DC) formation and increased the proportion of myeloid DCs. These data demonstrate that viral IL-10 restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies an immunomodulatory role for viral IL-10 which may limit the host's ability to clear latent virus.

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Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells

Cited by 116 publications

References 46 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?

Experimental human cytomegalovirus latency in CD14⁺monocytes

Viral Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection Modulates Latently Infected Myeloid Cell Differentiation

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Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells

Cited by 116 publications

References 46 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?

Experimental human cytomegalovirus latency in CD14+monocytes

Viral Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection Modulates Latently Infected Myeloid Cell Differentiation

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Experimental human cytomegalovirus latency in CD14⁺monocytes