Block to the Production of Full-Length B19 Virus Transcripts by Internal Polyadenylation Is Overcome by Replication of the Viral Genome

Guan, Wuxiang; Cheng, Fang; Yoto, Yuko; Kleiboeker, Steve; Wong, Susan; Zhi, Ning; Pintel, David J.; Qiu, Jianming

doi:10.1128/jvi.01162-08

Cited by 66 publications

(117 citation statements)

References 49 publications

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Section: Human Parvovirus B19 (B19v)mentioning

confidence: 94%

“…We and others (11,12,14,16,17) have analyzed the transcription profile obtained when COS-7 cells were transfected with a replication-competent, nearly full-length B19V genome and found that it resembles that observed during B19V infec-tion of B19V-permissive cells. Using this system, we have identified multiple cis-acting elements that facilitate inclusion of the second exon (from the A1-1/A1-2 acceptor site to the D2 donor site), which was confirmed by monitoring transcription profiles during B19V infection of human primary erythroid progenitor cells (18).…”

Section: Human Parvovirus B19 (B19v)mentioning

confidence: 95%

“…In B19V-permissive erythroid progenitor cells, production of VP1/VP2-and 11-kDa-encoding mRNA transcripts involves preventing polyadenylation of the B19V pre-mRNA at the (pA)p site (14). More than half of the B19V mRNAs are spliced at the second intron, which leads to the generation of sufficient VP2-encoding transcripts to enable viruses to assemble, as well as the 11-kDa-encoding transcripts.…”

Section: Human Parvovirus B19 (B19v)mentioning

confidence: 99%

“…More than half of the B19V mRNAs are spliced at the second intron, which leads to the generation of sufficient VP2-encoding transcripts to enable viruses to assemble, as well as the 11-kDa-encoding transcripts. However, in B19V-nonpermissive cells, and even early in permissive infection of erythroid progenitor cells, the majority of B19V mRNA transcripts are polyadenylated at the (pA)p site and thus produce only the nonstructural proteins NS1 and the 7.5 kDa protein (14,15). These facts indicate that alternative processing of the B19V pre-mRNA must be tightly controlled so that the amounts of B19V mRNA transcripts and proteins necessary to produce progeny virus are generated.…”

mentioning

confidence: 99%

“…However, in B19V-nonpermissive cells, and even early in permissive infection of erythroid progenitor cells, the majority of B19V mRNA transcripts are polyadenylated at the (pA)p site and thus produce only the nonstructural proteins NS1 and the 7.5 kDa protein (14,15). These facts indicate that alternative processing of the B19V pre-mRNA must be tightly controlled so that the amounts of B19V mRNA transcripts and proteins necessary to produce progeny virus are generated.We and others (11,12,14,16,17) have analyzed the transcription profile obtained when COS-7 cells were transfected with a replication-competent, nearly full-length B19V genome and found that it resembles that observed during B19V infec- …”

mentioning

confidence: 99%

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Internal Polyadenylation of the Parvovirus B19 Precursor mRNA Is Regulated by Alternative Splicing

Guan

Huang

Cheng

et al. 2011

Journal of Biological Chemistry

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Alternative processing of parvovirus B19 (B19V) pre-mRNA is critical to generating appropriate levels of B19V mRNA transcripts encoding capsid proteins and small nonstructural proteins. Polyadenylation of the B19V pre-mRNA at the proximal polyadenylation site ((pA)p), which prevents generation of fulllength capsid proteins encoding mRNA transcripts, has been suggested as a step that blocks B19V permissiveness. We report here that efficient splicing of the B19V pre-mRNA within the first intron (upstream of the (pA)p site) stimulated the polyadenylation; in contrast, splicing of the B19V pre-mRNA within the second intron (in which the (pA)p site resides) interfered with the polyadenylation, leading to the generation of a sufficient number of B19V mRNA transcripts polyadenylated at the distal polyadenylation site ((pA)d). We also found that splicing within the second intron and polyadenylation at the (pA)p site compete during processing of the B19V pre-mRNA. Furthermore, we discovered that the U1 RNA that binds to the 5 splice donor site of the second intron is fully responsible for inhibiting polyadenylation at the (pA)p site, whereas actual splicing, and perhaps assembly of the functional spliceosome, is not required. Finally, we demonstrated that inhibition of B19V pre-mRNA splicing within the second intron by targeting an intronic splicing enhancer using a Morpholino antisense oligonucleotide prevented B19V mRNA transcripts polyadenylated at the (pA)d site during B19V infection of human erythroid progenitors. Thus, our study reveals the mechanism by which alternative splicing coordinates alternative polyadenylation to generate full-length B19V mRNA transcripts at levels sufficient to support productive B19V infection. Human parvovirus B19 (B19V)2 is a member of the genus Erythrovirus of the family Parvoviridae. B19V causes several diseases in humans (1), the most common of which is erythema infectiosum or Fifth disease. Other diseases include acute and chronic arthropathy, transient aplastic crisis (infection of patients with a high rate of red blood cell turnover), pure red cell aplasia (infection of immunocompromised patients), and hydrops fetalis (infection of pregnant women). Like other parvoviruses, B19V contains a linear single-stranded DNA genome of approximately (ϳ)5.6 kb, which is encapsidated by an icosahedrally symmetric capsid without an envelope (2, 3). In addition to infecting only humans, B19V infection shows a remarkable tropism for human erythroid progenitor cells (4 -7).Like members in the genus Bocavirus (8, 9) and Aleutian mink disease virus (10), also of the Parvoviridae family, the transcription profile of B19V is unusual for a DNA virus in that all of the mRNA transcripts are generated from a single precursor mRNA (pre-mRNA) transcribed from a single promoter at map unit 6 (P6) and feature alternative polyadenylation and splicing (see Fig. 1A) (11, 12). The only unspliced mRNA encoding the large nonstructural protein (NS1) is polyadenylated at the proximal poly(A) site ((pA)p) and retains...

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Section: Human Parvovirus B19 (B19v)mentioning

confidence: 94%

Section: Human Parvovirus B19 (B19v)mentioning

confidence: 95%

Section: Human Parvovirus B19 (B19v)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Internal Polyadenylation of the Parvovirus B19 Precursor mRNA Is Regulated by Alternative Splicing

Guan

Huang

Cheng

et al. 2011

Journal of Biological Chemistry

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A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression

et al. 2013

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Recent studies have detected erythrovirus genomes in the hearts of cardiomyopathy and cardiac transplant patients. Assessment of the functional status of viruses may provide clinically important information beyond detection of the viral genomes. Here, we report transcriptional activation of cardiotropic erythrovirus to be associated with strongly altered myocardial gene expression in a distinct subgroup of cardiomyopathy patients. Endomyocardial biopsies (EMBs) from 415 consecutive cardiac erythrovirus (B19V)-positive patients with clinically suspected cardiomyopathy were screened for virus-encoded VP1/VP2 mRNA indicating transcriptional activation of the virus, and correlated with cardiac host gene expression patterns in transcriptionally active versus latent infections, and in virus-free control hearts. Transcriptional activity was detected in baseline biopsies of only 66/415 patients (15.9 %) harbouring erythrovirus. At the molecular level, significant differences between cardiac B19V-positive patients with transcriptionally active versus latent virus were revealed by expression profiling of EMBs. Importantly, latent B19V infection was indistinguishable from controls. Genes involved encode proteins of antiviral immune response, B19V receptor complex, and mitochondrial energy metabolism. Thus, functional mapping of erythrovirus allows definition of a subgroup of B19V-infected cardiomyopathy patients characterized by virus-encoded VP1/VP2 transcripts and anomalous host myocardial transcriptomes. Cardiac B19V reactivation from latency, as reported here for the first time, is a key factor required for erythrovirus to induce altered cardiac gene expression in a subgroup of cardiomyopathy patients. Virus genome detection is insufficient to assess pathogenic potential, but additional transcriptional mapping should be incorporated into future pathogenetic and therapeutic studies both in cardiology and transplantation medicine.

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The RNA profile of porcine parvovirus 4, a boca-like virus, is unique among the parvoviruses

et al. 2011

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PPV4 transcribes its genome from a single promoter, and the RNAs are generated via alternate splicing coupled with alternate polyadenylation, a strategy similar to that of the bocaviruses; however, several differences were detected. The PPV4 ORF1 codes for four NS proteins, while the bocavirus ORF1 codes for 1-3 NS proteins. Whereas the VP1/VP2 capsid proteins of bocavirus are encoded by a single RNA, VP1 and VP2 of PPV4 are encoded by two separate RNAs. While ORF3 of PPV4 encodes two NP proteins, ORF3 of bocavirus codes for only one NP polypeptide. Taken together, PPV4 is unique among the parvoviruses.

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Block to the Production of Full-Length B19 Virus Transcripts by Internal Polyadenylation Is Overcome by Replication of the Viral Genome

Cited by 66 publications

References 49 publications

Internal Polyadenylation of the Parvovirus B19 Precursor mRNA Is Regulated by Alternative Splicing

Internal Polyadenylation of the Parvovirus B19 Precursor mRNA Is Regulated by Alternative Splicing

A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression

The RNA profile of porcine parvovirus 4, a boca-like virus, is unique among the parvoviruses

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