Special Issue "New Insights into Parvovirus Research"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 April 2019).

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A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Giorgio Gallinella
Website
Guest Editor
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Interests: parvovirus B19; virus–cell interactions; viral infections; recombinant viruses; virological diagnosis; antiviral strategies
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Special Issue Information

Dear Colleagues,

Viruses in the parvoviridae family constitute a most diverse and intriguing field of research. While all share an ssDNA genome and a small (Parvo!) capsid, they can differ widely in structure, genome organization and expression, virus-cell interaction, and impact on the host. Exploring such diversity and unravelling the inherent complexity in these apparently simple viruses is an ongoing endeavour and commitment for the scientific community.

The translational implications of research on parvoviruses are relevant. Within the family, some viruses are important human and veterinary pathogens, in need of diagnostic methods and antiviral strategies; other viruses have long been studied and engineered as tools for oncolytic therapy, or as sophisticated gene delivery vectors, and can now display their wide and expanding applicative potential.

The aim of this Special Issue of Viruses is to compile the newest contributions in the field of parvovirus research, especially encouraging new insights and research on unresolved issues, as well as new approaches exploiting systemic (–omic) methodologies. Evolution, structural biology, viral replication, virus-host interaction, pathogenesis and immunity, gene therapy, and viral oncotherapy are only a selection of the topics that can be of relevance to the community involved in parvovirus research and of interest to a wider audience.

Dr. Giorgio Gallinella
Guest Editor

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Keywords

  • Parvoviridae
  • Parvovirus evolution
  • Parvovirus structure
  • Parvovirus-host interactions
  • Parvovirus pathogenesis and immunity
  • Parvovirus oncolytic therapy
  • Parvovirus vectors
  • Antiviral strategies

Published Papers (21 papers)

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Editorial

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Open AccessEditorial
New Insights into Parvovirus Research
Viruses 2019, 11(11), 1053; https://doi.org/10.3390/v11111053 - 13 Nov 2019
Abstract
The family Parvoviridae includes an ample and most diverse collection of viruses. Exploring the biological diversity and the inherent complexity in these apparently simple viruses has been a continuous commitment for the scientific community since their first discovery more than fifty years ago. [...] Read more.
The family Parvoviridae includes an ample and most diverse collection of viruses. Exploring the biological diversity and the inherent complexity in these apparently simple viruses has been a continuous commitment for the scientific community since their first discovery more than fifty years ago. The Special Issue of ‘Viruses’ dedicated to the ‘New Insights into Parvovirus Research’ aimed at presenting a ‘state of the art’ in many aspects of research in the field, at collecting the newest contributions on unresolved issues, and at presenting new approaches exploiting systemic (-omic) methodologies. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available

Research

Jump to: Editorial, Review

Open AccessArticle
Interaction of a Densovirus with Glycans of the Peritrophic Matrix Mediates Oral Infection of the Lepidopteran Pest Spodoptera frugiperda
Viruses 2019, 11(9), 870; https://doi.org/10.3390/v11090870 - 17 Sep 2019
Cited by 1
Abstract
The success of oral infection by viruses depends on their capacity to overcome the gut epithelial barrier of their host to crossing over apical, mucous extracellular matrices. As orally transmitted viruses, densoviruses, are also challenged by the complexity of the insect gut barriers, [...] Read more.
The success of oral infection by viruses depends on their capacity to overcome the gut epithelial barrier of their host to crossing over apical, mucous extracellular matrices. As orally transmitted viruses, densoviruses, are also challenged by the complexity of the insect gut barriers, more specifically by the chitinous peritrophic matrix, that lines and protects the midgut epithelium; how capsids stick to and cross these barriers to reach their final cell destination where replication goes has been poorly studied in insects. Here, we analyzed the early interaction of the Junonia coenia densovirus (JcDV) with the midgut barriers of caterpillars from the pest Spodoptera frugiperda. Using combination of imaging, biochemical, proteomic and transcriptomic analyses, we examined in vitro, ex vivo and in vivo the early interaction of the capsids with the peritrophic matrix and the consequence of early oral infection on the overall gut function. We show that the JcDV particle rapidly adheres to the peritrophic matrix through interaction with different glycans including chitin and glycoproteins, and that these interactions are necessary for oral infection. Proteomic analyses of JcDV binding proteins of the peritrophic matrix revealed mucins and non-mucins proteins including enzymes already known to act as receptors for several insect pathogens. In addition, we show that JcDV early infection results in an arrest of N-Acetylglucosamine secretion and a disruption in the integrity of the peritrophic matrix, which may help viral particles to pass through. Finally, JcDV early infection induces changes in midgut genes expression favoring an increased metabolism including an increased translational activity. These dysregulations probably participate to the overall dysfunction of the gut barrier in the early steps of viral pathogenesis. A better understanding of early steps of densovirus infection process is crucial to build biocontrol strategies against major insect pests. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Establishment of a Parvovirus B19 NS1-Expressing Recombinant Adenoviral Vector for Killing Megakaryocytic Leukemia Cells
Viruses 2019, 11(9), 820; https://doi.org/10.3390/v11090820 - 04 Sep 2019
Cited by 1
Abstract
Adenoviral viral vectors have been widely used for gene-based therapeutics, but commonly used serotype 5 shows poor transduction efficiency into hematopoietic cells. In this study, we aimed to generate a recombinant adenovirus serotype 5 (rAd5) vector that has a high efficiency in gene [...] Read more.
Adenoviral viral vectors have been widely used for gene-based therapeutics, but commonly used serotype 5 shows poor transduction efficiency into hematopoietic cells. In this study, we aimed to generate a recombinant adenovirus serotype 5 (rAd5) vector that has a high efficiency in gene transfer to megakaryocytic leukemic cells with anticancer potential. We first modified the rAd5 backbone vector with a chimeric fiber gene of Ad5 and Ad11p (rAd5F11p) to increase the gene delivery efficiency. Then, the nonstructural protein NS1 of human parvovirus B19 (B19V), which induces cell cycle arrest at the G2/M phase and apoptosis, was cloned into the adenoviral shuttle vector. As the expression of parvoviral NS1 protein inhibited Ad replication and production, we engineered the cytomegalovirus (CMV) promoter, which governs NS1 expression, with two tetracycline operator elements (TetO2). Transfection of the rAd5F11p proviral vectors in Tet repressor-expressing T-REx-293 cells produced rAd in a large quantity. We further evaluated this chimeric rAd5F11p vector in gene delivery in human leukemic cells, UT7/Epo-S1. Strikingly, the novel rAd5F11p-B19NS1-GFP vector, exhibited a transduction efficiency much higher than the original vector, rAd5-B19NS1-GFP, in UT7/Epo-S1 cells, in particular, when they were transduced at a relatively low multiplicity of infection (100 viral genome copies/cell). After the transduction of rAd5F11p-B19NS1-GFP, over 90% of the UT7/Epo-S1 cells were arrested at the G2/M phase, and approximately 40%–50% of the cells were undergoing apoptosis, suggesting the novel rAd5F11P-B19NS1-GFP vector holds a promise in therapeutic potentials of megakaryocytic leukemia. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessCommunication
Metagenomic Next-Generation Sequencing Reveal Presence of a Novel Ungulate Bocaparvovirus in Alpacas
Viruses 2019, 11(8), 701; https://doi.org/10.3390/v11080701 - 31 Jul 2019
Cited by 1
Abstract
Viruses belonging to the genus Bocaparvovirus (BoV) are a genetically diverse group of DNA viruses known to cause respiratory, enteric, and neurological diseases in animals, including humans. An intestinal sample from an alpaca (Vicugna pacos) herd with reoccurring diarrhea and [...] Read more.
Viruses belonging to the genus Bocaparvovirus (BoV) are a genetically diverse group of DNA viruses known to cause respiratory, enteric, and neurological diseases in animals, including humans. An intestinal sample from an alpaca (Vicugna pacos) herd with reoccurring diarrhea and respiratory disease was submitted for next-generation sequencing, revealing the presence of a BoV strain. The alpaca BoV strain (AlBoV) had a 58.58% whole genome nucleotide percent identity to a camel BoV from Dubai, belonging to a tentative ungulate BoV 8 species (UBoV8). Recombination events were lacking with other UBoV strains. The AlBoV genome was comprised of the NS1, NP1, and VP1 proteins. The NS1 protein had the highest amino acid percent identity range (57.89–67.85%) to the members of UBoV8, which was below the 85% cut-off set by the International Committee on Taxonomy of Viruses. The low NS1 amino acid identity suggests that AlBoV is a tentative new species. The whole genome, NS1, NP1, and VP1 phylogenetic trees illustrated distinct branching of AlBoV, sharing a common ancestor with UBoV8. Walker loop and Phospholipase A2 (PLA2) motifs that are vital for virus infectivity were identified in NS1 and VP1 proteins, respectively. Our study reports a novel BoV strain in an alpaca intestinal sample and highlights the need for additional BoV research. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
An Ancient Lineage of Highly Divergent Parvoviruses Infects both Vertebrate and Invertebrate Hosts
Viruses 2019, 11(6), 525; https://doi.org/10.3390/v11060525 - 06 Jun 2019
Cited by 8
Abstract
Chapparvoviruses (ChPVs) comprise a divergent, recently identified group of parvoviruses (family Parvoviridae), associated with nephropathy in immunocompromised laboratory mice and with prevalence in deep sequencing results of livestock showing diarrhea. Here, we investigate the biological and evolutionary characteristics of ChPVs via comparative [...] Read more.
Chapparvoviruses (ChPVs) comprise a divergent, recently identified group of parvoviruses (family Parvoviridae), associated with nephropathy in immunocompromised laboratory mice and with prevalence in deep sequencing results of livestock showing diarrhea. Here, we investigate the biological and evolutionary characteristics of ChPVs via comparative in silico analyses, incorporating sequences derived from endogenous parvoviral elements (EPVs) as well as exogenous parvoviruses. We show that ChPVs are an ancient lineage within the Parvoviridae, clustering separately from members of both currently established subfamilies. Consistent with this, they exhibit a number of characteristic features, including several putative auxiliary protein-encoding genes, and capsid proteins with no sequence-level homology to those of other parvoviruses. Homology modeling indicates the absence of a β-A strand, normally part of the luminal side of the parvoviral capsid protein core. Our findings demonstrate that the ChPV lineage infects an exceptionally broad range of host species, including both vertebrates and invertebrates. Furthermore, we observe that ChPVs found in fish are more closely related to those from invertebrates than they are to those of amniote vertebrates. This suggests that transmission between distantly related host species may have occurred in the past and that the Parvoviridae family can no longer be divided based on host affiliation. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Equine Parvovirus-Hepatitis Frequently Detectable in Commercial Equine Serum Pools
Viruses 2019, 11(5), 461; https://doi.org/10.3390/v11050461 - 21 May 2019
Cited by 5
Abstract
An equine parvovirus-hepatitis (EqPV-H) has been recently identified in association with equine serum hepatitis, also known as Theiler’s disease. This disease was first described by Arnold Theiler in 1918 and is often observed after applications with blood products in equines. So far, the [...] Read more.
An equine parvovirus-hepatitis (EqPV-H) has been recently identified in association with equine serum hepatitis, also known as Theiler’s disease. This disease was first described by Arnold Theiler in 1918 and is often observed after applications with blood products in equines. So far, the virus has only been described in the USA and China. In this study, we evaluated the presence of EqPV-H in several commercial serum samples to assess the potential risk of virus transmission by equine serum-based products for medical and research applications. In 11 out of 18 commercial serum samples, EqPV-H DNA was detectable with a viral load up to 105 copies/mL. The same serum batches as well as three additional samples were also positive for antibodies against the EqPV-H VP1 protein. The countries of origin with detectable viral genomes included the USA, Canada, New Zealand, Italy, and Germany, suggesting a worldwide distribution of EqPV-H. Phylogenetic analysis of the EqPV-H NS1 sequence in commercial serum samples revealed high similarities in viral sequences from different geographical areas. As horse sera are commonly used for the production of anti-sera, which are included in human and veterinary medical products, these results implicate the requirement for diagnostic tests to prevent EqPV-H transmission. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Parvovirus B19 Uncoating Occurs in the Cytoplasm without Capsid Disassembly and It Is Facilitated by Depletion of Capsid-Associated Divalent Cations
Viruses 2019, 11(5), 430; https://doi.org/10.3390/v11050430 - 10 May 2019
Cited by 4
Abstract
Human parvovirus B19 (B19V) traffics to the cell nucleus where it delivers the genome for replication. The intracellular compartment where uncoating takes place, the required capsid structural rearrangements and the cellular factors involved remain unknown. We explored conditions that trigger uncoating in vitro [...] Read more.
Human parvovirus B19 (B19V) traffics to the cell nucleus where it delivers the genome for replication. The intracellular compartment where uncoating takes place, the required capsid structural rearrangements and the cellular factors involved remain unknown. We explored conditions that trigger uncoating in vitro and found that prolonged exposure of capsids to chelating agents or to buffers with chelating properties induced a structural rearrangement at 4 °C resulting in capsids with lower density. These lighter particles remained intact but were unstable and short exposure to 37 °C or to a freeze-thaw cycle was sufficient to trigger DNA externalization without capsid disassembly. The rearrangement was not observed in the absence of chelating activity or in the presence of MgCl2 or CaCl2, suggesting that depletion of capsid-associated divalent cations facilitates uncoating. The presence of assembled capsids with externalized DNA was also detected during B19V entry in UT7/Epo cells. Following endosomal escape and prior to nuclear entry, a significant proportion of the incoming capsids rearranged and externalized the viral genome without capsid disassembly. The incoming capsids with accessible genomes accumulated in the nuclear fraction, a process that was prevented when endosomal escape or dynein function was disrupted. In their uncoated conformation, capsids immunoprecipitated from cytoplasmic or from nuclear fractions supported in vitro complementary-strand synthesis at 37 °C. This study reveals an uncoating strategy of B19V based on a limited capsid rearrangement prior to nuclear entry, a process that can be mimicked in vitro by depletion of divalent cations. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Adeno-Associated Virus VP1u Exhibits Protease Activity
Viruses 2019, 11(5), 399; https://doi.org/10.3390/v11050399 - 29 Apr 2019
Cited by 2
Abstract
Adeno-associated viruses (AAVs) are being developed for gene delivery applications, with more than 100 ongoing clinical trials aimed at the treatment of monogenic diseases. In this study, the unique N-terminus of AAV capsid viral protein 1 (VP1u), containing a canonical group XIII PLA [...] Read more.
Adeno-associated viruses (AAVs) are being developed for gene delivery applications, with more than 100 ongoing clinical trials aimed at the treatment of monogenic diseases. In this study, the unique N-terminus of AAV capsid viral protein 1 (VP1u), containing a canonical group XIII PLA2 enzyme domain, was observed to also exhibit proteolytic activity. This protease activity can target casein and gelatin, two standard substrates used for testing protease function but does not self-cleave in the context of the capsid or target globular proteins, for example, bovine serum albumin (BSA). However, heated BSA is susceptible to VP1u-mediated cleavage, suggesting that disordered proteins are substrates for this protease function. The protease activity is partially inhibited by divalent cation chelators ethylenediaminetetraacetic acid (EDTA) and ethylene-bis(oxyethylenenitrilo)tetraacetic acid (EGTA), and human alpha-2-macroglobulin (A2M), a non-specific protease inhibitor. Interestingly, both the bovine pancreatic (group VIIA) and bee venom (group III) PLA2 enzymes also exhibit protease function against casein. This indicates that PLA2 groups, including VP1u, have a protease function. Amino acid substitution of the PLA2 catalytic motif (76HD/AN) in the AAV2 VP1u resulted in attenuation of protease activity, suggesting that the protease and PLA2 active sites are related. However, the amino acid substitution of histidine H38, which is not involved in PLA2 function, to alanine, also affects protease activity, suggesting that the active site/mechanism of the PLA2 and protease function are not identical. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Chapparvovirus DNA Found in 4% of Dogs with Diarrhea
Viruses 2019, 11(5), 398; https://doi.org/10.3390/v11050398 - 27 Apr 2019
Cited by 5
Abstract
Feces from dogs in an unexplained outbreak of diarrhea were analyzed by viral metagenomics revealing the genome of a novel parvovirus. The parvovirus was named cachavirus and was classified within the proposed Chapparvovirus genus. Using PCR, cachavirus DNA was detected in two of [...] Read more.
Feces from dogs in an unexplained outbreak of diarrhea were analyzed by viral metagenomics revealing the genome of a novel parvovirus. The parvovirus was named cachavirus and was classified within the proposed Chapparvovirus genus. Using PCR, cachavirus DNA was detected in two of nine tested dogs from that outbreak. In order to begin to elucidate the clinical impact of this virus, 2,053 canine fecal samples were screened using real-time PCR. Stool samples from 203 healthy dogs were positive for cachavirus DNA at a rate of 1.47%, while 802 diarrhea samples collected in 2017 and 964 samples collected in 2018 were positive at rates of 4.0% and 4.66% frequencies, respectively (healthy versus 2017-2018 combined diarrhea p-value of 0.05). None of 83 bloody diarrhea samples tested positive. Viral loads were generally low with average real-time PCR Ct values of 36 in all three positive groups. The species tropism and pathogenicity of cachavirus, the first chapparvovirus reported in feces of a placental carnivore, remains to be fully determined. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessCommunication
Characterization of the RNA Transcription Profile of Bombyx mori Bidensovirus
Viruses 2019, 11(4), 325; https://doi.org/10.3390/v11040325 - 03 Apr 2019
Cited by 1
Abstract
Bombyx mori bidensovirus (BmBDV) is a single-stranded DNA (ssDNA) virus from the genus Bidensovirus of the Bidnaviridae family, which, thus far, solely infects insects. It has a unique genome that contains bipartite DNA molecules (VD1 and VD2). In this study, we explored the [...] Read more.
Bombyx mori bidensovirus (BmBDV) is a single-stranded DNA (ssDNA) virus from the genus Bidensovirus of the Bidnaviridae family, which, thus far, solely infects insects. It has a unique genome that contains bipartite DNA molecules (VD1 and VD2). In this study, we explored the detailed transcription mapping of the complete BmBDV genome (VD1 and VD2) by rapid amplification of cDNA ends (RACE), reverse transcription quantitative real-time PCR (RT-qPCR), and luciferase assays. For the first time, we report the transcription map of VD2. Our mapping of the transcriptional start sites reveals that the NS genes in VD1 have separate transcripts that are derived from overlapping promoters, P5 and P5.5. Thus, our study provides a strategy for alternative promoter usage in the expression of BmBDV genes. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Molecular Characterization and Evolutionary Analyses of Carnivore Protoparvovirus 1 NS1 Gene
Viruses 2019, 11(4), 308; https://doi.org/10.3390/v11040308 - 29 Mar 2019
Cited by 6
Abstract
Carnivore protoparvovirus 1 is the etiological agent of a severe disease of terrestrial carnivores. This unique specie encompasses canine parvovirus type 2 (CPV-2) and feline panleukopenia virus (FPLV). Studies widely analyzed the main capsid protein (VP2), but limited information is available on the [...] Read more.
Carnivore protoparvovirus 1 is the etiological agent of a severe disease of terrestrial carnivores. This unique specie encompasses canine parvovirus type 2 (CPV-2) and feline panleukopenia virus (FPLV). Studies widely analyzed the main capsid protein (VP2), but limited information is available on the nonstructural genes (NS1/NS2). This paper analyzed the NS1 gene sequence of FPLV and CPV strains collected in Italy in 2009–2017, along with worldwide related sequences. Differently from VP2, only one NS1 amino-acid residue (248) clearly and constantly distinguished FPLV from CPV-2, while five possible convergent amino-acid changes were observed that may affect the functional domains of the NS1. Some synonymous mutation in NS1 were non-synonymous in NS2 and vice versa. No evidence for recombination between the two lineages was found, and the predominance of negative selection pressure on NS1 proteins was observed, with low and no overlap between the two lineages in negatively and positively selected codons, respectively. More sites were under selection in the CPV-2 lineage. NS1 phylogenetic analysis showed divergent evolution between FPLV and CPV, and strains were clustered mostly by country and year of detection. We highlight the importance of obtaining the NS1/NS2 coding sequence in molecular epidemiology investigations. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
A New Prevalent Densovirus Discovered in Acari. Insight from Metagenomics in Viral Communities Associated with Two-Spotted Mite (Tetranychus urticae) Populations
Viruses 2019, 11(3), 233; https://doi.org/10.3390/v11030233 - 07 Mar 2019
Cited by 4
Abstract
Viral metagenomics and high throughput sequence mining have revealed unexpected diversity, and the potential presence, of parvoviruses in animals from all phyla. Among arthropods, this diversity highlights the poor knowledge that we have regarding the evolutionary history of densoviruses. The aim of this [...] Read more.
Viral metagenomics and high throughput sequence mining have revealed unexpected diversity, and the potential presence, of parvoviruses in animals from all phyla. Among arthropods, this diversity highlights the poor knowledge that we have regarding the evolutionary history of densoviruses. The aim of this study was to explore densovirus diversity in a small arthropod pest belonging to Acari, the two-spotted spider mite Tetranychus urticae, while using viral metagenomics based on virus-enrichment. Here, we present the viromes obtained from T. urticae laboratory populations made of contigs that are attributed to nine new potential viral species, including the complete sequence of a novel densovirus. The genome of this densovirus has an ambisens genomic organization and an unusually compact size with particularly small non-structural proteins and a predicted major capsid protein that lacks the typical PLA2 motif that is common to all ambidensoviruses described so far. In addition, we showed that this new densovirus had a wide prevalence across populations of mite species tested and a genomic diversity that likely correlates with the host phylogeny. In particular, we observed a low densovirus genomic diversity between the laboratory and natural populations, which suggests that virus within-species evolution is probably slower than initially thought. Lastly, we showed that this novel densovirus can be inoculated to the host plant following feeding by infected mites, and circulate through the plant vascular system. These findings offer new insights into densovirus prevalence, evolution, and ecology. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessCommunication
Telbivudine Reduces Parvovirus B19-Induced Apoptosis in Circulating Angiogenic Cells
Viruses 2019, 11(3), 227; https://doi.org/10.3390/v11030227 - 06 Mar 2019
Cited by 2
Abstract
Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral [...] Read more.
Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (−39% and −40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessCommunication
Methylation Status of the Adeno-Associated Virus Type 2 (AAV2)
Viruses 2019, 11(1), 38; https://doi.org/10.3390/v11010038 - 09 Jan 2019
Cited by 2
Abstract
To analyze the methylation status of wild-type adeno-associated virus type 2 (AAV2), bisulfite PCR sequencing (BPS) of the packaged viral genome and its integrated form was performed and 262 of the total 266 CG dinucleotides (CpG) were mapped. In virion-packaged DNA, the ratio [...] Read more.
To analyze the methylation status of wild-type adeno-associated virus type 2 (AAV2), bisulfite PCR sequencing (BPS) of the packaged viral genome and its integrated form was performed and 262 of the total 266 CG dinucleotides (CpG) were mapped. In virion-packaged DNA, the ratio of the methylated cytosines ranged between 0–1.7%. In contrast, the chromosomally integrated AAV2 genome was hypermethylated with an average of 76% methylation per CpG site. The methylation level showed local minimums around the four known AAV2 promoters. To study the effect of methylation on viral rescue and replication, the replication initiation capability of CpG methylated and non-CpG methylated AAV DNA was compared. The in vitro hypermethylation of the viral genome does not inhibit its rescue and replication from a plasmid transfected into cells. This insensitivity of the viral replicative machinery to methylation may permit the rescue of the integrated heavily methylated AAV genome from the host’s chromosomes. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
A Comprehensive RNA-seq Analysis of Human Bocavirus 1 Transcripts in Infected Human Airway Epithelium
Viruses 2019, 11(1), 33; https://doi.org/10.3390/v11010033 - 07 Jan 2019
Cited by 2
Abstract
Human bocavirus 1 (HBoV1) infects well-differentiated (polarized) human airway epithelium (HAE) cultured at an air-liquid interface (ALI). In the present study, we applied next-generation RNA sequencing to investigate the genome-wide transcription profile of HBoV1, including viral mRNA and small RNA transcripts, in HBoV1-infected [...] Read more.
Human bocavirus 1 (HBoV1) infects well-differentiated (polarized) human airway epithelium (HAE) cultured at an air-liquid interface (ALI). In the present study, we applied next-generation RNA sequencing to investigate the genome-wide transcription profile of HBoV1, including viral mRNA and small RNA transcripts, in HBoV1-infected HAE cells. We identified novel transcription start and termination sites and confirmed the previously identified splicing events. Importantly, an additional proximal polyadenylation site (pA)p2 and a new distal polyadenylation site (pA)dREH lying on the right-hand hairpin (REH) of the HBoV1 genome were identified in processing viral pre-mRNA. Of note, all viral nonstructural proteins-encoding mRNA transcripts use both the proximal polyadenylation sites [(pA)p1 and (pA)p2] and distal polyadenylation sites [(pA)d1 and (pA)dREH] for termination. However, capsid proteins-encoding transcripts only use the distal polyadenylation sites. While the (pA)p1 and (pA)p2 sites were utilized at roughly equal efficiency for proximal polyadenylation of HBoV1 mRNA transcripts, the (pA)d1 site was more preferred for distal polyadenylation. Additionally, small RNA-seq analysis confirmed there is only one viral noncoding RNA (BocaSR) transcribed from nt 5199–5340 of the HBoV1 genome. Thus, our study provides a systematic and unbiased transcription profile, including both mRNA and small RNA transcripts, of HBoV1 in HBoV1-infected HAE-ALI cultures. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessArticle
Human Bocavirus Infection Markers in Peripheral Blood and Stool Samples of Children with Acute Gastroenteritis
Viruses 2018, 10(11), 639; https://doi.org/10.3390/v10110639 - 15 Nov 2018
Cited by 3
Abstract
Human bocaviruses (HBoVs) 1–4 belong to the Parvoviridae family, and they infect the respiratory or gastrointestinal tracts in children. We investigated the prevalence of HBoV1–4 DNAs in the blood and stool samples, and of HBoV1–4 IgG and IgM in the plasma samples, of [...] Read more.
Human bocaviruses (HBoVs) 1–4 belong to the Parvoviridae family, and they infect the respiratory or gastrointestinal tracts in children. We investigated the prevalence of HBoV1–4 DNAs in the blood and stool samples, and of HBoV1–4 IgG and IgM in the plasma samples, of children presenting with acute gastroenteritis (AGE). In addition, we identified HBoV co-infections with the five most frequent gastrointestinal pathogens. A total of 83 paired blood and stool samples were collected from children aged five years or less. Infection markers of HBoV1, 2, or 3 (viral DNA in blood and/or stool and/or antibodies) were detected in 61 out of 83 (73.5%) patients. HBoV1, 2, or 3 DNA as a monoinfection was revealed in 18.1%, 2.4%, and 1.2%, respectively, and 21.7% in total. In 56.1% of the HBoV DNA-positive patients, the presence in stool of another virus—most frequently norovirus or rotavirus—was observed. In conclusion, this study, for the first time, illustrates the prevalence and genetic diversity of HBoVs in Latvian children with gastroenteritis, and shows a widespread distribution of these viruses in the community. HBoV1 and 2 are commonly found as single infectious agents in children with AGE, suggesting that the viruses can be as pathogenic by themselves as other enteric agents are. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available

Review

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Open AccessReview
Advances in the Development of Antiviral Strategies against Parvovirus B19
Viruses 2019, 11(7), 659; https://doi.org/10.3390/v11070659 - 18 Jul 2019
Cited by 6
Abstract
Parvovirus B19 (B19V) is a human pathogenic virus, responsible for an ample range of clinical manifestations. Infections are usually mild, self-limiting, and controlled by the development of a specific immune response, but in many cases clinical situations can be more complex and require [...] Read more.
Parvovirus B19 (B19V) is a human pathogenic virus, responsible for an ample range of clinical manifestations. Infections are usually mild, self-limiting, and controlled by the development of a specific immune response, but in many cases clinical situations can be more complex and require therapy. Presently available treatments are only supportive, symptomatic, or unspecific, such as administration of intravenous immunoglobulins, and often of limited efficacy. The development of antiviral strategies against B19V should be considered of highest relevance for increasing the available options for more specific and effective therapeutic treatments. This field of research has been explored in recent years, registering some achievements as well as interesting future perspectives. In addition to immunoglobulins, some compounds have been shown to possess inhibitory activity against B19V. Hydroxyurea is an antiproliferative drug used in the treatment of sickle-cell disease that also possesses inhibitory activity against B19V. The nucleotide analogues Cidofovir and its lipid conjugate Brincidofovir are broad-range antivirals mostly active against dsDNA viruses, which showed an antiviral activity also against B19V. Newly synthesized coumarin derivatives offer possibilities for the development of molecules with antiviral activity. Identification of some flavonoid molecules, with direct inhibitory activity against the viral non-structural (NS) protein, indicates a possible line of development for direct antiviral agents. Continuing research in the field, leading to better knowledge of the viral lifecycle and a precise understanding of virus–cell interactions, will offer novel opportunities for developing more efficient, targeted antiviral agents, which can be translated into available therapeutic options. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessReview
Systematic Review of PCR Proof of Parvovirus B19 Genomes in Endomyocardial Biopsies of Patients Presenting with Myocarditis or Dilated Cardiomyopathy
Viruses 2019, 11(6), 566; https://doi.org/10.3390/v11060566 - 18 Jun 2019
Cited by 1
Abstract
Background: Diverse viral infections have been associated with myocarditis (MC) and dilated cardiomyopathy (DCM). In this meta-analysis, we summarize the published results on the association of parvovirus B19 (B19V) genomes with human MC/DCM versus controls. Methods: n = 197 publications referring to B19V [...] Read more.
Background: Diverse viral infections have been associated with myocarditis (MC) and dilated cardiomyopathy (DCM). In this meta-analysis, we summarize the published results on the association of parvovirus B19 (B19V) genomes with human MC/DCM versus controls. Methods: n = 197 publications referring to B19V and MC or DCM were retrieved using multiple PubMed search modes. Out of these, n = 29 publications met the inclusion criteria with data from prospective analyses on >10 unselected patients presenting with MC or DCM (dataset: MA01). Data retrieved simultaneously from both controls and MC/DCM patients were available from n = 8 from these publications (dataset: MA02). Results: In the dataset MA01 B19V genomes were detected in 42.6% of the endomyocardial biopsies (EMB) in this cohort by PCR. In the dataset MA02 comprising n = 638 subjects, there was no statistically significant different rate of B19V positivity in myocardial tissues comparing controls (mean: 38.8 + 24.1%) versus the MC/DCM-patients (45.5 + 24.3%; p = 0.58). There was also no statistical difference between the positivity rate of B19V genomes in myocardial tissues of MA01 (46.0 + 19.5%) and the two patient groups of MA02 (p > 0.05). Conclusions: This systematic review reveals that the mean rate of PCR detected B19V genomes in patients presenting with MC/DCM does not differ significantly from the findings in control myocardial tissues. These data imply pathogenetically insignificant latency of B19V genomes in a proportion of myocardial tissues, both in MC-/DCM-patients and in controls. More information (i.e., replicative status, viral protein expression) is pertinent to achieve a comprehensive workup of myocardial B19V infection. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessReview
H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future
Viruses 2019, 11(6), 562; https://doi.org/10.3390/v11060562 - 18 Jun 2019
Cited by 5
Abstract
The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers [...] Read more.
The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers anticancer immune responses. The safety and tolerability of H-1PV treatment has been demonstrated in early clinical studies in glioma and pancreatic carcinoma patients. Virus treatment was associated with surrogate signs of efficacy including immune conversion of tumor microenvironment, effective virus distribution into the tumor bed even after systemic administration, and improved patient overall survival compared with historical control. However, monotherapeutic use of the virus was unable to eradicate tumors. Thus, further studies are needed to improve H-1PV’s anticancer profile. In this review, we describe H-1PV’s anticancer properties and discuss recent efforts to improve the efficacy of H-1PV and, thereby, the clinical outcome of H-1PV-based therapies. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessReview
Immune System Stimulation by Oncolytic Rodent Protoparvoviruses
Viruses 2019, 11(5), 415; https://doi.org/10.3390/v11050415 - 04 May 2019
Cited by 3
Abstract
Rodent protoparvoviruses (PVs), parvovirus H-1 (H-1PV) in particular, are naturally endowed with oncolytic properties. While being historically described as agents that selectively replicate in and kill cancer cells, recent yet growing evidence demonstrates that these viruses are able to reverse tumor-driven immune suppression [...] Read more.
Rodent protoparvoviruses (PVs), parvovirus H-1 (H-1PV) in particular, are naturally endowed with oncolytic properties. While being historically described as agents that selectively replicate in and kill cancer cells, recent yet growing evidence demonstrates that these viruses are able to reverse tumor-driven immune suppression through induction of immunogenic tumor cell death, and the establishment of antitumorigenic, proinflammatory milieu within the tumor microenvironment. This review summarizes the most important preclinical proofs of the interplay and the cooperation between PVs and the host immune system. The molecular mechanisms of PV-induced immunostimulation are also discussed. Furthermore, initial encouraging in-human observations from clinical trials and compassionate virus uses are presented, and speak in favor of further H-1PV clinical development as partner drug in combined immunotherapeutic protocols. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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Open AccessReview
Twenty-Five Years of Structural Parvovirology
Viruses 2019, 11(4), 362; https://doi.org/10.3390/v11040362 - 20 Apr 2019
Cited by 18
Abstract
Parvoviruses, infecting vertebrates and invertebrates, are a family of single-stranded DNA viruses with small, non-enveloped capsids with T = 1 icosahedral symmetry. A quarter of a century after the first parvovirus capsid structure was published, approximately 100 additional structures have been analyzed. This [...] Read more.
Parvoviruses, infecting vertebrates and invertebrates, are a family of single-stranded DNA viruses with small, non-enveloped capsids with T = 1 icosahedral symmetry. A quarter of a century after the first parvovirus capsid structure was published, approximately 100 additional structures have been analyzed. This first structure was that of Canine Parvovirus, and it initiated the practice of structure-to-function correlation for the family. Despite high diversity in the capsid viral protein (VP) sequence, the structural topologies of all parvoviral capsids are conserved. However, surface loops inserted between the core secondary structure elements vary in conformation that enables the assembly of unique capsid surface morphologies within individual genera. These variations enable each virus to establish host niches by allowing host receptor attachment, specific tissue tropism, and antigenic diversity. This review focuses on the diversity among the parvoviruses with respect to the transcriptional strategy of the encoded VPs, the advances in capsid structure-function annotation, and therapeutic developments facilitated by the available structures. Full article
(This article belongs to the Special Issue New Insights into Parvovirus Research) Printed Edition available
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