Host MicroRNA Regulation of Human Cytomegalovirus Immediate Early Protein Translation Promotes Viral Latency

O’Connor, Christine M.; Vaníček, Jiří; Murphy, Eain A.

doi:10.1128/jvi.00481-14

Cited by 88 publications

(98 citation statements)

References 56 publications

(58 reference statements)

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“…73 Overexpression of the miR-200 cluster decreases HCMV titers in fibroblasts, 74 and miR-200 levels were high in latently infected CD34 þ cells and in persistently infected monocytes, but not in lytically infected macrophages. 75 In addition, miR-200 family members target HCMV UL122 3 0 untranslated region, inhibiting IE2 translation, 75 and target Sec23a, which is involved in endoplasmic reticulum-toGolgi vesicle transport and could modulate VAC formation. 76 Interestingly, miR-200 was expressed in HCMVinfected AmEpCs and increased late in persistent infection (T.T., unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from midgestation placentas formed foci of infection, and interferon-b production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x L by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x L , indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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“…Extracellular viral genomes were quantified by qPCR as described previously (37). Viral genomes were detected using primers directed at UL123 ( Table 2).…”

Section: Cells and Virusesmentioning

confidence: 99%

“…To determine the contribution of US28 toward a successful latent infection of Kasumi-3 cells, we assessed the production of extracellular virions over a 5-day time course following latent infection of Kasumi-3 cells and assessed viral DNA using qPCR (37). The cells infected with either the US28⌬ or all⌬ virus yielded an increase in extracellular viral genomes (Fig.…”

Section: Us28 Is Required For Latent Infection In Kasumi-3 Cellsmentioning

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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confidence: 99%

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

Humby

O’Connor

2016

J Virol

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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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“…This virus overlaps the binding site of cellular miRNA, miR-373 (122,123). Due to the presence of adjacent sites for miR-433a and miR-367a in MICB mRNA, interaction between viral miR-UL112 and cellular miR-376a is feasible, which leads to silencing of MICB expression in a human cytomegalovirus-infected person (124,125). It has also been shown that expression of two miRNAs, miR-429 and miR200b, regulates entry to the lytic phase of Epstein-Barr virus by suppressing expression of ZEB1 and ZEB2.…”

Section: Viral Microrna-mediated Response In Therapeuticsmentioning

confidence: 99%

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

Bhadra

Patra

Chhatai

et al. 2016

Mol Med

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MicroRNAs (miRNAs) are well preserved in every animal. These pygmy-sized (21-23 nt) noncoding RNAs scattered in the genome are responsible for micromanaging versatile gene regulation. There is involvement of miRNAs as surveillance cops in all human diseases including cardiovascular defects, tumor formation, reproductive pathways, and neurological and autoimmune disorders. The effective functional role of miRNA can be reduced by chemical entities of antisense oligonucleotides and versatile small molecules that support the views of novel therapies of different human diseases. In this study, we have updated our current understanding of designing and synthesizing miRNA-controlled therapeutic chemicals. We have also proposed various in vivo delivery strategies and discuss their ongoing challenges to combat incorporation hurdles in live cells and animals. Lastly, we have demonstrated the current progress of miRNA modulation in the treatment of human diseases to provide an alternative approach to gene therapy.

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Host MicroRNA Regulation of Human Cytomegalovirus Immediate Early Protein Translation Promotes Viral Latency

Cited by 88 publications

References 56 publications

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

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

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

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