The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

Poole, Emma; Walther, Anett; Raven, Kathy E.; Benedict, Christopher; Mason, Gavin M.; Sinclair, John

doi:10.1128/jvi.03497-12

Cited by 63 publications

(103 citation statements)

References 65 publications

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“…25 This may in part be explained by recent evidence suggesting that latent infection itself may result in some partial commitment of CD34 1 progenitors to the myeloid lineage. 28 Consistent with cells of the myeloid lineage being sites of latent infection, analyses of the viral transcription programme in these cells generally shows a suppression of viral lytic gene expression 2,29-32 but concomitant expression of known latency-associated viral genes. 31,[33][34][35][36][37] Importantly, these cells do not produce infectious virions; an essential characteristic of latent infection.…”

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

confidence: 85%

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: 85%

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

et al. 2014

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“…Investigators have previously reported that US28 is expressed during latency in natural (32,45) and experimental (4-6, 44, 49) …”

Section: Generation Of Viral Recombinantsmentioning

confidence: 99%

“…Although many studies have focused on understanding US28's functions during lytic replication (reviewed in reference 48), there is little known about the role US28 plays during latency although it is one of only a few genes associated with latent transcription. US28 transcripts have been detected both during natural latency (32,45) and during ex vivo latent infection studies (4-6, 44, 49). To begin to elucidate the role of US28 during latency, we have utilized the Kasumi-3 model for HCMV latency and reactivation (23).…”

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confidence: 99%

“…However, during latency only a small subset of genes is expressed (5,44). US28 is one of four HCMVencoded G-protein coupled receptor (GPCR) homologs and is expressed during both the latent (5,32,44,45) and lytic (46,47) cycles. Although many studies have focused on understanding US28's functions during lytic replication (reviewed in reference 48), there is little known about the role US28 plays during latency although it is one of only a few genes associated with latent transcription.…”

mentioning

confidence: 99%

“…For example, viral proteins including UL138 (29,30), pp71 (13), LUNA (31), UL144 (32), and viral interleukin-10 (latency-associated HCMV ho-molog of IL-10 [LAcmvIL-10]) (33)(34)(35)(36) contribute to successful latency and reactivation in culture. HCMV has co-opted cellular factors as well, such as cellular microRNAs (miRNAs) (36)(37)(38), transcription factors (32,38), and cell signaling (38,39). It is clear that HCMV latency and reactivation are multifaceted processes and thus likely that our full understanding of these stages of infection remains incomplete.…”

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Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells

Humby

O’Connor

2016

J Virol

102

163

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Human cytomegalovirus (HCMV) resides latently in hematopoietic progenitor cells (HPCs). During latency, only a subset of HCMV genes is transcribed, including one of the four virus-encoded G protein-coupled receptors (GPCRs), US28. Although US28 is a multifunctional lytic protein, its function during latency has remained undefined. We generated a panel of US28 recombinant viruses in the bacterial artificial chromosome (BAC)-derived clinical HCMV strain TB40/E-mCherry. We deleted the entire US28 open reading frame (ORF), deleted all four of the viral GPCR ORFs, or deleted three of the HCMV GPCRs but not the US28 wild-type protein. Using these recombinant viruses, we assessed the requirement for US28 during latency in the Kasumi-3 in vitro latency model system and in primary ex vivo-cultured CD34 ؉ HPCs. Our data suggest that US28 is required for latency as infection with viruses lacking the US28 ORF alone or in combination with the remaining HCMV-encoded GPCR results in transcription from the major immediate early promoter, the production of extracellular virions, and the production of infectious virus capable of infecting naive fibroblasts. The other HCMV GPCRs are not required for this phenotype as a virus expressing only US28 but not the remaining virus-encoded GPCRs is phenotypically similar to that of wild-type latent infection. Finally, we found that US28 copurifies with mature virions and is expressed in HPCs upon virus entry although its expression at the time of infection does not complement the US28 deletion latency phenotype. This work suggests that US28 protein functions to promote a latent state within hematopoietic progenitor cells. IMPORTANCEHuman cytomegalovirus (HCMV) is a widespread pathogen that, once acquired, remains with its host for life. HCMV remains latent, or quiescent, in cells of the hematopoietic compartment and upon immune challenge can reactivate to cause disease. HCMV-encoded US28 is one of several genes expressed during latency although its biological function during this phase of infection has remained undefined. Here, we show that US28 aids in promoting experimental latency in tissue culture. The betaherpesvirus human cytomegalovirus (HCMV) is a ubiquitous pathogen that, once acquired, remains with its host for life. HCMV establishes a latent infection in CD34 ϩ hematopoietic progenitor cells (HPCs), and individuals with a competent immune system are, for the most part, asymptomatic for disease. Under weakened immune conditions, however, the virus can reactivate, causing severe morbidity and often mortality. In developed countries, such as the United States, approximately 80% of the population is HCMV positive by 40 years of age (reviewed in reference 1). In adults, HCMV-associated disease is due mostly to reactivation of latent infection, whereas primary infections rarely cause significant health burdens in this population (reviewed in reference 1). Current treatments administered in clinical settings to sequester HCMV infection include those that predominantly target la...

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Molecular and immune interactions between β- and γ-herpesviruses in the immunocompromised host

Sánchez-Ponce

Fuentes‐Pananá

2022

Journal of Leukocyte Biology

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βand γ-herpesviruses persistently infect most of the world population, largely without clinical manifestations. However, in immunosuppressive settings like transplantation, these viruses are often jointly reactivated, associating with graft dysfunction/rejection, HCMV disease, and lymphoproliferation. In HIV/AIDS, direct interaction mechanisms have been described for EBV and KSHV in primary effusion lymphoma, demonstrating that the cooperation between both viruses enhances lymphomagenesis. Here, we discuss the clinical evidence supporting that the simultaneous reactivation of these viruses increases the probability of mutual interactions, also providing a conceptual framework explaining how one virus can influence another. Specifically, we propose mechanisms of indirect communication through immune soluble mediators, mainly cytokines, chemokines, and IFN regulatory molecules, based on common features of their infectious cycles and the convergent need on immunomodulatory mechanisms.

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The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

Cited by 63 publications

References 65 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?

Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells

Molecular and immune interactions between β- and γ-herpesviruses in the immunocompromised host

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