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Making Sense to Antisense: Viral Antisense Transcripts and Proteins, Therapeutic...
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Making Sense to Antisense: Viral Antisense Transcripts and Proteins, Therapeutic Applications of Antisense Oligonucleotide in Viral Infection

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 8967

Special Issue Editor

Dr. Nathalie Chazal

E-Mail Website
Guest Editor
IRIM, CNRS UMR9004, University Montpellier, Montpellier, France
Interests: HIV-1; coronavirus; AntiSense Protein (ASP); antisense transcripts; assembly and maturation

Special Issue Information

Dear Colleagues,

Viruses are the simplest biological entities and, at the same time, they induce very complex relationships with their cellular host. The genomes of viruses are characterized by a generally small size, which must however provide all the information allowing their replication, and sometimes induce and maintain latency, by hijacking host cell machineries. Viruses have evolved diverse strategies in order to be able to ensure all these processes despite a limited genetic repertoire.

Antisense viral proteins and/or the antisense transcripts play important functions in viral infections, including the control of viral sense transcription and viral latency, but viral antisense actors may be also essential to maintain a latent reservoir and to modulate virulence.

Herpesviruses and retroviruses belong to phylogenetically distant families of viruses, but have open reading frames on both strands of their genome for the former and their provirus for the latter. In herpesviruses, the expression of some transcripts (LATs) allows the passage to the latency phase, while the ICP viral proteins encoded by the ORFs located on the complementary strand act on the viral lytic cycle that leads to cell death. For retroviruses, in the human T-cell leukemia virus type 1 (HTLV-1), which is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), the antisense transcript (HBZ) is responsible for the proliferation of infected cells, while the viral protein (HBZ) is involved in the establishment of viral latency and in the process of oncogenesis. For human immunodeficiency virus type 1 (HIV-1), on the one hand, antisense transcripts may act as bona fide lncRNAs, thereby playing a role in the establishment of viral latency, but HIV-1 antisense transcripts may also contribute to the maintenance of latency through the recruitment of enzymes responsible of the silencing of the 5’ LTR. ASP, on the other hand, can perform different functions according to the stage of the viral cycle. For example, it can promote viral replication at an early stage or, conversely, help maintain viral latency once it is established. Finally, transcripts and antisense-encoded proteins in retroviruses could be more widespread than we know today and allow a more complete understanding of the biology of endogenous retroviruses.

This Special Issue is intended to provide an updated overview of viral transcripts and antisense proteins that have been or could be identified in viruses to enable viral replication, control viral latency, or participate in viral pathogenesis.

Dr. Nathalie Chazal
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • virus
  • herpesviruses
  • retroviruses
  • antisense viral transcript
  • antisense viral protein
  • latency
  • antisense transcription
  • viral pathogenesis
  • endogenous retrovirus

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Published Papers (3 papers)

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Research

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18 pages, 997 KiB  
Article
Extending the Coding Potential of Viral Genomes with Overlapping Antisense ORFs: A Case for the De Novo Creation of the Gene Encoding the Antisense Protein ASP of HIV-1
by Angelo Pavesi and Fabio Romerio
Viruses 2022, 14(1), 146; https://doi.org/10.3390/v14010146 - 14 Jan 2022
Cited by 3 | Viewed by 2216
Abstract
Gene overprinting occurs when point mutations within a genomic region with an existing coding sequence create a new one in another reading frame. This process is quite frequent in viral genomes either to maximize the amount of information that they encode or in [...] Read more.
Gene overprinting occurs when point mutations within a genomic region with an existing coding sequence create a new one in another reading frame. This process is quite frequent in viral genomes either to maximize the amount of information that they encode or in response to strong selective pressure. The most frequent scenario involves two different reading frames in the same DNA strand (sense overlap). Much less frequent are cases of overlapping genes that are encoded on opposite DNA strands (antisense overlap). One such example is the antisense ORF, asp in the minus strand of the HIV-1 genome overlapping the env gene. The asp gene is highly conserved in pandemic HIV-1 strains of group M, and it is absent in non-pandemic HIV-1 groups, HIV-2, and lentiviruses infecting non-human primates, suggesting that the ~190-amino acid protein that is expressed from this gene (ASP) may play a role in virus spread. While the function of ASP in the virus life cycle remains to be elucidated, mounting evidence from several research groups indicates that ASP is expressed in vivo. There are two alternative hypotheses that could be envisioned to explain the origin of the asp ORF. On one hand, asp may have originally been present in the ancestor of contemporary lentiviruses, and subsequently lost in all descendants except for most HIV-1 strains of group M due to selective advantage. Alternatively, the asp ORF may have originated very recently with the emergence of group M HIV-1 strains from SIVcpz. Here, we used a combination of computational and statistical approaches to study the genomic region of env in primate lentiviruses to shed light on the origin, structure, and sequence evolution of the asp ORF. The results emerging from our studies support the hypothesis of a recent de novo addition of the antisense ORF to the HIV-1 genome through a process that entailed progressive removal of existing internal stop codons from SIV strains to HIV-1 strains of group M, and fine tuning of the codon sequence in env that reduced the chances of new stop codons occurring in asp. Altogether, the study supports the notion that the HIV-1 asp gene encodes an accessory protein, providing a selective advantage to the virus. Full article
(This article belongs to the Special Issue Making Sense to Antisense: Viral Antisense Transcripts and Proteins, Therapeutic Applications of Antisense Oligonucleotide in Viral Infection)
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17 pages, 1762 KiB  
Article
Viral Decoys: The Only Two Herpesviruses Infecting Invertebrates Evolved Different Transcriptional Strategies to Deflect Post-Transcriptional Editing
by Chang-Ming Bai, Umberto Rosani, Xiang Zhang, Lu-Sheng Xin, Enrico Bortoletto, K. Mathias Wegner and Chong-Ming Wang
Viruses 2021, 13(10), 1971; https://doi.org/10.3390/v13101971 - 30 Sep 2021
Cited by 8 | Viewed by 2748
Abstract
The highly versatile group of Herpesviruses cause disease in a wide range of hosts. In invertebrates, only two herpesviruses are known: the malacoherpesviruses HaHV-1 and OsHV-1 infecting gastropods and bivalves, respectively. To understand viral transcript architecture and diversity we first reconstructed full-length viral [...] Read more.
The highly versatile group of Herpesviruses cause disease in a wide range of hosts. In invertebrates, only two herpesviruses are known: the malacoherpesviruses HaHV-1 and OsHV-1 infecting gastropods and bivalves, respectively. To understand viral transcript architecture and diversity we first reconstructed full-length viral genomes of HaHV-1 infecting Haliotis diversicolor supertexta and OsHV-1 infecting Scapharca broughtonii by DNA-seq. We then used RNA-seq over the time-course of experimental infections to establish viral transcriptional dynamics, followed by PacBio long-read sequencing of full-length transcripts to untangle viral transcript architectures at two selected time points. Despite similarities in genome structure, in the number of genes and in the diverse transcriptomic architectures, we measured a ten-fold higher transcript variability in HaHV-1, with more extended antisense gene transcription. Transcriptional dynamics also appeared different, both in timing and expression trends. Both viruses were heavily affected by post-transcriptional modifications performed by ADAR1 affecting sense-antisense gene pairs forming dsRNAs. However, OsHV-1 concentrated these modifications in a few genomic hotspots, whereas HaHV-1 diluted ADAR1 impact by elongated and polycistronic transcripts distributed over its whole genome. These transcriptional strategies might thus provide alternative potential roles for sense-antisense transcription in viral transcriptomes to evade the host’s immune response in different virus–host combinations. Full article
(This article belongs to the Special Issue Making Sense to Antisense: Viral Antisense Transcripts and Proteins, Therapeutic Applications of Antisense Oligonucleotide in Viral Infection)
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Review

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17 pages, 944 KiB  
Review
Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?
by Roger H. Miller, Alexis Zimmer, Gilles Moutot, Jean-Michel Mesnard and Nathalie Chazal
Viruses 2021, 13(11), 2221; https://doi.org/10.3390/v13112221 - 4 Nov 2021
Cited by 5 | Viewed by 2901
Abstract
Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious [...] Read more.
Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies. Full article
(This article belongs to the Special Issue Making Sense to Antisense: Viral Antisense Transcripts and Proteins, Therapeutic Applications of Antisense Oligonucleotide in Viral Infection)
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