Characterization of an Antisense Transcript Spanning the UL81-82 Locus of Human Cytomegalovirus

Bego, Mariana G.; Maciejewski, Jaroslaw P.; Khaiboullina, Svetlana F.; Pari, Gregory S.; Jeor, Stephen St.

doi:10.1128/jvi.79.17.11022-11034.2005

Cited by 108 publications

(134 citation statements)

References 50 publications

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…Antisense transcription is prevalent among different families of DNA viruses, and it has been suggested to affect viral gene expression (48)(49)(50)(51)(52). Antisense transcripts have the potential to form dsRNA by base-pairing with sense transcripts.…”

Section: Discussionmentioning

confidence: 99%

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

Bronkhorst

Cleef²,

Vodovar³

et al. 2012

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

134

155

View full text Add to dashboard Cite

RNA viruses in insects are targets of an RNA interference (RNAi)-based antiviral immune response, in which viral replication intermediates or viral dsRNA genomes are processed by Dicer-2 (Dcr-2) into viral small interfering RNAs (vsiRNAs). Whether dsDNA virus infections are controlled by the RNAi pathway remains to be determined. Here, we analyzed the role of RNAi in DNA virus infection using Drosophila melanogaster infected with Invertebrate iridescent virus 6 (IIV-6) as a model. We show that Dcr-2 and Argonaute-2 mutant flies are more sensitive to virus infection, suggesting that vsiRNAs contribute to the control of DNA virus infection. Indeed, small RNA sequencing of IIV-6-infected WT and RNAi mutant flies identified abundant vsiRNAs that were produced in a Dcr-2-dependent manner. We observed a highly uneven distribution with strong clustering of vsiRNAs to small defined regions (hotspots) and modest coverage at other regions (coldspots). vsiRNAs mapped in similar proportions to both strands of the viral genome, suggesting that long dsRNA derived from convergent overlapping transcripts serves as a substrate for Dcr-2. In agreement, strand-specific RT-PCR and Northern blot analyses indicated that antisense transcripts are produced during infection. Moreover, we show that vsiRNAs are functional in silencing reporter constructs carrying fragments of the IIV-6 genome. Together, our data indicate that RNAi provides antiviral defense against dsDNA viruses in animals. Thus, RNAi is the predominant antiviral defense mechanism in insects that provides protection against all major classes of viruses.insect immunity | Iridoviridae | siRNA | antiviral immunity | small RNA profiling | next-generation sequencing

show abstract

Section: Discussionmentioning

confidence: 99%

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

Bronkhorst

Cleef²,

Vodovar³

et al. 2012

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

134

155

View full text Add to dashboard Cite

show abstract

“…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. In latent myeloid cells in vivo, this suppression of the lytic transcription programme appears to involve repression of the viral major immediate early promoter (MIEP), which would normally drive lytic cycle, through post-translational modification of histones around the MIEP resulting in the presence of well characterized repressive chromatin marks (reviewed in Ref.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…UL138 RNA is expressed in CD14 + and CD34 + cells from HCMV seropositive individuals, and a UL138-deficient FIX derivative failed to enter latency after infection of CD34 + cells (3). 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).…”

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

View full text Add to dashboard Cite

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...

show abstract

Characterization of an Antisense Transcript Spanning the UL81-82 Locus of Human Cytomegalovirus

Cited by 108 publications

References 50 publications

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

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

Experimental human cytomegalovirus latency in CD14⁺monocytes

Contact Info

Product

Resources

About

Characterization of an Antisense Transcript Spanning the UL81-82 Locus of Human Cytomegalovirus

Cited by 108 publications

References 50 publications

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery

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

Experimental human cytomegalovirus latency in CD14+monocytes

Contact Info

Product

Resources

About

Experimental human cytomegalovirus latency in CD14⁺monocytes