Bocavirus Episome in Infected Human Tissue Contains Non-Identical Termini

Kapoor, Amit; Hornig, Mady; Asokan, Aravind; Williams, Brent L.; Henríquez, José A. Luján; Lipkin, W. Ian

doi:10.1371/journal.pone.0021362

Cited by 87 publications

(104 citation statements)

References 45 publications

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“…Previous studies revealed a remarkable feature of the 3= NCR of primate bocaparvoviruses: those of HBoV1, HBoV2, and HBoV3 fold into almost identical secondary structures (45,46). This feature appears to be unique; it is not shared by the carnivore bocaparvovirus 1 minute virus of canines (MVC) (23), bocaparvoviruses from other nonprimate species, or other parvoviruses.…”

Section: Discussionmentioning

confidence: 98%

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

Wang

Shen

Cheng

et al. 2017

J Virol

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Human bocavirus 1 (HBoV1) belongs to the species Primate bocaparvovirus of the genus Bocaparvovirus of the Parvoviridae family. HBoV1 causes acute respiratory tract infections in young children and has a selective tropism for the apical surface of well-differentiated human airway epithelia (HAE). In this study, we identified an additional HBoV1 gene, bocavirus-transcribed small noncoding RNA (BocaSR), within the 3= noncoding region (nucleotides [nt] 5199 to 5338) of the viral genome of positive sense. BocaSR is transcribed by RNA polymerase III (Pol III) from an intragenic promoter at levels similar to that of the capsid protein-coding mRNA and is essential for replication of the viral DNA in both transfected HEK293 and infected HAE cells. Mechanistically, we showed that BocaSR regulates the expression of HBoV1-encoded nonstructural proteins NS1, NS2, NS3, and NP1 but not NS4. BocaSR is similar to the adenovirus-associated type I (VAI) RNA in terms of both nucleotide sequence and secondary structure but differs from it in that its regulation of viral protein expression is independent of RNA-activated protein kinase (PKR) regulation. Notably, BocaSR accumulates in the viral DNA replication centers within the nucleus and likely plays a direct role in replication of the viral DNA. Our findings reveal BocaSR to be a novel viral noncoding RNA that coordinates the expression of viral proteins and regulates replication of viral DNA within the nucleus. Thus, BocaSR may be a target for antiviral therapies for HBoV and may also have utility in the production of recombinant HBoV vectors.IMPORTANCE Human bocavirus 1 (HBoV1) is pathogenic to humans, causing acute respiratory tract infections in young children. In this study, we identified a novel HBoV1 gene that lies in the 3= noncoding region of the viral positive-sense genome and is transcribed by RNA polymerase III into a noncoding RNA of 140 nt. This bocavirus-transcribed small RNA (BocaSR) diverges from both adenovirus-associated (VA) RNAs and Epstein-Barr virus-encoded small RNAs (EBERs) with respect to RNA sequence, representing a third species of this kind of Pol III-dependent viral noncoding RNA and the first noncoding RNA identified in autonomous parvoviruses. Unlike the VA RNAs, BocaSR localizes to the viral DNA replication centers of the nucleus and is essential for expression of viral nonstructural proteins independent of RNAactivated protein kinase R and replication of HBoV1 genomes. The identification of BocaSR and its role in virus DNA replication reveals potential avenues for developing antiviral therapies.KEYWORDS bocavirus, DNA replication, noncoding RNA, parvovirus H uman bocavirus 1 (HBoV1), which was discovered in 2005 (1), belongs to the species Primate bocaparvovirus 1 in the genus Bocaparvovirus of the Parvoviridae family (2). Increasing evidence suggests that HBoV1 is an etiological pathogen rather than a bystander in acute respiratory tract infections, especially in children under 5

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Section: Discussionmentioning

confidence: 98%

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

Wang

Shen

Cheng

et al. 2017

J Virol

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“…SM protein of EBV during the lytic cycle inhibits protein kinase R activation, whereas EBV LMP-1 protein can prime EBV latency cells for IFN production to establish the viral latency (55)(56)(57). Recent studies have demonstrated that HBoV can establish persistent infection in host cells by forming episomes (58). Persistent HBoV infection of polarized HAE cells has also been reported (59).…”

Section: Discussionmentioning

confidence: 99%

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Luo

Zhang

Zheng

et al. 2013

The Journal of Immunology

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Precise regulation of innate immunity is crucial for maintaining optimal immune responses against infections. Whereas positive regulation of IFN signaling elicits rapid type I IFNs, negative regulation is equally important in preventing the production of superfluous IFNs that can be hazardous to the host. The positive regulators of IFN pathway are known to be the main targets of viruses to antagonize the innate immune system. Whether viruses target the negative regulators of IFN pathway remains to be fully investigated. In this study, we report that the structural protein VP2 of human Bocavirus modulates IFN pathway by targeting the ring finger protein 125 (RNF125), a negative regulator of type I IFN signaling, which conjugates Lys48-linked ubiquitination to retinoic acid–inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. VP2 not only upregulated Sendai virus (SeV)–induced IFNB promoter activity, but also enhanced SeV-induced IFN-β production at both mRNA and protein levels. In agreement, the level of Ser396-phosphorylated IFN regulatory factor 3 stimulated by SeV was enhanced in the presence of VP2. Furthermore, VP2 was demonstrated to physically interact with RNF125, resulting in the reduction of RNF125-mediated ubiquitination and proteasome-dependent degradation of RIG-I. Additional study indicated that endogenous RIG-I degradation was decreased in VP2-expressing cells. Our study delineates a unique phenomenon for aberrant activation of IFN regulatory factor 3 pathway and may represent a new mechanism underlying viral manipulation of the host immune system.

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“…Recent studies demonstrate that feline bocaviruses (51), minute virus of canines (51), porcine bocaviruses (52), and canine bocavirus (53) are genetically distinct from other related bocaviruses, including bocaviruses infecting primates. In addition, differences in splicing (54), length of nonstructural proteins (54), and replication strategies (55) have been documented between bocaviruses infecting primates and bocaviruses infecting other animals. Differences in genome organization and the lack of evidence supporting common ancestry and between bocaviruses infecting primates and those infecting other animals could potentially explain the differences in the relative abundance of CpG dinucleotides between these viruses.…”

Section: Fig 5 Role Of Cpg Depletion In Parvovirus Evolution (A) Commentioning

confidence: 99%

CpG Dinucleotide Frequencies Reveal the Role of Host Methylation Capabilities in Parvovirus Evolution

Upadhyay

Samal

Kandpal

et al. 2013

J Virol

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Parvoviruses are rapidly evolving viruses that infect a wide range of hosts, including vertebrates and invertebrates. Extensive methylation of the parvovirus genome has been recently demonstrated. A global pattern of methylation of CpG dinucleotides is seen in vertebrate genomes, compared to "fractional" methylation patterns in invertebrate genomes. It remains unknown if the loss of CpG dinucleotides occurs in all viruses of a given DNA virus family that infect host species spanning across vertebrates and invertebrates. We investigated the link between the extent of CpG dinucleotide depletion among autonomous parvoviruses and the evolutionary lineage of the infected host. We demonstrate major differences in the relative abundance of CpG dinucleotides among autonomous parvoviruses which share similar genome organization and common ancestry, depending on the infected host species. Parvoviruses infecting vertebrate hosts had significantly lower relative abundance of CpG dinucleotides than parvoviruses infecting invertebrate hosts. The strong correlation of CpG dinucleotide depletion with the gain in TpG/CpA dinucleotides and the loss of TpA dinucleotides among parvoviruses suggests a major role for CpG methylation in the evolution of parvoviruses. Our data present evidence that links the relative abundance of CpG dinucleotides in parvoviruses to the methylation capabilities of the infected host. In sum, our findings support a novel perspective of host-driven evolution among autonomous parvoviruses.T he relative abundance of dinucleotides, particularly the CpG dinucleotide, has received much attention recently. The CpG dinucleotide content is normally expressed as a ratio of the actual (observed) number of CpG dinucleotides and the expected number of CpG dinucleotides (O/E ratio). The relative abundance of CpG dinucleotides varies greatly across viruses (1, 2). Depletion of CpG dinucleotides has been reported to occur in all small DNA viruses (Ͻ30 kb) infecting humans (2), while most large DNA viruses (Ͼ30 kb) infecting humans show little or no CpG dinucleotide depletion. Several possible reasons have been suggested to play a role in the depletion of CpG dinucleotides, including (i) lower transcription rate for CpG-containing codons (3), (ii) stimulation of Toll-like receptor 9-mediated innate immune response by unmethylated CpGs (4), and (iii) spontaneous deamination of methylated cytosines in CpG dinucleotides (5). Deamination of unmethylated cytosines results in C-to-U transitions which are amenable to mismatch repair mechanisms, whereas the deamination of 5-methylcytosine leads to C-to-T transitions that are often irreversible, resulting in high mutation rates in methylated CpGs and a depletion of CpG dinucleotides (6, 7).In most vertebrate genomes, the O/E ratio for CpG dinucleotides is Ͻ0.35, suggesting that vertebrate genomes have lost about two-thirds of CpG dinucleotides (5, 8). In contrast, invertebrate genomes show minor or no depletion of CpG dinucleotides (5). Early investigations on insects showed that...

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Bocavirus Episome in Infected Human Tissue Contains Non-Identical Termini

Cited by 87 publications

References 45 publications

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

Parvovirus Expresses a Small Noncoding RNA That Plays an Essential Role in Virus Replication

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

CpG Dinucleotide Frequencies Reveal the Role of Host Methylation Capabilities in Parvovirus Evolution

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