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The Journal of Infectious Diseases Nov 2023The family Filoviridae consists of several virus members known to cause significant mortality and disease in humans. Among these, Ebola virus (EBOV), Marburg virus...
BACKGROUND
The family Filoviridae consists of several virus members known to cause significant mortality and disease in humans. Among these, Ebola virus (EBOV), Marburg virus (MARV), Sudan virus (SUDV), and Bundibugyo virus (BDBV) are considered the deadliest. The vaccine, Ervebo, was shown to rapidly protect humans against Ebola disease, but is indicated only for EBOV infections with limited cross-protection against other filoviruses. Whether multivalent formulations of similar recombinant vesicular stomatitis virus (rVSV)-based vaccines could likewise confer rapid protection is unclear.
METHODS
Here, we tested the ability of an attenuated, quadrivalent panfilovirus VesiculoVax vaccine (rVSV-Filo) to elicit fast-acting protection against MARV, EBOV, SUDV, and BDBV. Groups of cynomolgus monkeys were vaccinated 7 days before exposure to each of the 4 viral pathogens. All subjects (100%) immunized 1 week earlier survived MARV, SUDV, and BDBV challenge; 80% survived EBOV challenge. Survival correlated with lower viral load, higher glycoprotein-specific immunoglobulin G titers, and the expression of B-cell-, cytotoxic cell-, and antigen presentation-associated transcripts.
CONCLUSIONS
These results demonstrate multivalent VesiculoVax vaccines are suitable for filovirus outbreak management. The highly attenuated nature of the rVSV-Filo vaccine may be preferable to the Ervebo "delta G" platform, which induced adverse events in a subset of recipients.
Topics: Humans; Animals; Ebolavirus; Hemorrhagic Fever, Ebola; Marburgvirus; Vaccines, Attenuated; Macaca fascicularis; Viral Vaccines; Vesiculovirus; Vesicular stomatitis Indiana virus; Antibodies, Viral; Ebola Vaccines
PubMed: 37171813
DOI: 10.1093/infdis/jiad157 -
Expert Review of Vaccines Nov 2010Paramyxoviruses, measles virus (MV), mumps virus (MuV) and Newcastle disease virus (NDV), are well known for causing measles and mumps in humans and Newcastle disease in... (Review)
Review
Paramyxoviruses, measles virus (MV), mumps virus (MuV) and Newcastle disease virus (NDV), are well known for causing measles and mumps in humans and Newcastle disease in birds. These viruses have been tamed (attenuated) and successfully used as vaccines to immunize their hosts. Remarkably, pathogenic MuV and vaccine strains of MuV, MV and NDV efficiently infect and kill cancer cells and are consequently being investigated as novel cancer therapies (oncolytic virotherapy). Phase I/II clinical trials have shown promise but treatment efficacy needs to be enhanced. Technologies being developed to increase treatment efficacy include: virotherapy in combination with immunosuppressive drugs (cyclophosphamide); retargeting of viruses to specific tumor types or tumor vasculature; using infected cell carriers to protect and deliver the virus to tumors; and genetic manipulation of the virus to increase viral spread and/or express transgenes during viral replication. Transgenes have enabled noninvasive imaging or tracking of viral gene expression and enhancement of tumor destruction.
Topics: Clinical Trials as Topic; Humans; Measles virus; Mumps virus; Neoplasms; Newcastle disease virus; Oncolytic Virotherapy; Treatment Outcome
PubMed: 21087107
DOI: 10.1586/erv.10.124 -
Antiviral Research Feb 2018There are no approved medications for the treatment of Marburg or Ebola virus infection. In two previous articles (Martin et al., 2016, Martin et al., 2017), we reviewed... (Review)
Review
There are no approved medications for the treatment of Marburg or Ebola virus infection. In two previous articles (Martin et al., 2016, Martin et al., 2017), we reviewed surface glycoprotein and replication proteins structure/function relationship to decipher the molecular mechanisms of filovirus life cycle and identify antiviral strategies. In the present article, we recapitulate knowledge about the viral proteins involved in filovirus assembly and budding. First we describe the structural data available for viral proteins associated with virus assembly and virion egress and then, we integrate the structural features of these proteins in the functional context of the viral replication cycle. Finally, we summarize recent advances in the development of innovative antiviral strategies to target filovirus assembly and egress. The development of such prophylactic or post-exposure treatments could help controlling future filovirus outbreaks.
Topics: Antiviral Agents; Drug Discovery; Filoviridae; Genome, Viral; Genomics; Humans; Structure-Activity Relationship; Viral Proteins; Virus Assembly; Virus Release
PubMed: 29305306
DOI: 10.1016/j.antiviral.2017.12.022 -
Philosophical Transactions of the Royal... Sep 2013Bornaviruses are the only animal RNA viruses that establish a persistent infection in their host cell nucleus. Studies of bornaviruses have provided unique information... (Review)
Review
Bornaviruses are the only animal RNA viruses that establish a persistent infection in their host cell nucleus. Studies of bornaviruses have provided unique information about viral replication strategies and virus-host interactions. Although bornaviruses do not integrate into the host genome during their replication cycle, we and others have recently reported that there are DNA sequences derived from the mRNAs of ancient bornaviruses in the genomes of vertebrates, including humans, and these have been designated endogenous borna-like (EBL) elements. Therefore, bornaviruses have been interacting with their hosts as driving forces in the evolution of host genomes in a previously unexpected way. Studies of EBL elements have provided new models for virology, evolutionary biology and general cell biology. In this review, we summarize the data on EBL elements including what we have newly identified in eukaryotes genomes, and discuss the biological significance of EBL elements, with a focus on EBL nucleoprotein elements in mammalian genomes. Surprisingly, EBL elements were detected in the genomes of invertebrates, suggesting that the host range of bornaviruses may be much wider than previously thought. We also review our new data on non-retroviral integration of Borna disease virus.
Topics: Animals; Biological Evolution; Bornaviridae; Eukaryota; Genome; Humans; Mononegavirales Infections; Nucleoproteins; Virus Replication
PubMed: 23938751
DOI: 10.1098/rstb.2012.0499 -
Journal of Biosciences Dec 2011Rhabdoviridae, characterized by bullet-shaped viruses, is known for its diverse host range, which includes plants, arthropods, fishes and humans. Understanding the... (Review)
Review
Rhabdoviridae, characterized by bullet-shaped viruses, is known for its diverse host range, which includes plants, arthropods, fishes and humans. Understanding the viral-host interactions of this family can prove beneficial in developing effective therapeutic strategies. The host proteins interacting with animal rhabdoviruses have been reviewed in this report. Several important host proteins commonly interacting with animal rhabdoviruses are being reported, some of which, interestingly, have molecular features, which can serve as potential antiviral targets. This review not only provides the generalized importance of the functions of animal rhabdovirus-associated host proteins for the first time but also compares them among the two most studied viruses, i.e. Rabies virus (RV) and Vesicular Stomatitis virus (VSV). The comparative data can be used for studying emerging viruses such as Chandipura virus (CHPV) and the lesser studied viruses such as Piry virus (PIRYV) and Isfahan virus (ISFV) of the Rhabdoviridae family.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Host-Pathogen Interactions; Humans; Molecular Sequence Data; Protein Binding; Rabies virus; Vesiculovirus; Viral Proteins
PubMed: 22116291
DOI: 10.1007/s12038-011-9164-4 -
Current Opinion in Genetics &... Dec 1994RNA genomes evolve largely on the basis of single point mutations introduced by imprecise RNA polymerases, or by recombination. Clusters of certain transitions (biased... (Review)
Review
RNA genomes evolve largely on the basis of single point mutations introduced by imprecise RNA polymerases, or by recombination. Clusters of certain transitions (biased hypermutations) were detected first in the genomes of persistent viruses, and in the past year have also been found in the genomes of lytic RNA viruses. A cellular RNA-modifying enzyme probably introduces the clustered transitions and thus contributes to the evolution of RNA viruses.
Topics: Adenosine; Adenosine Deaminase; Animals; Biological Evolution; Deamination; Genome, Viral; Humans; Inosine; Mononegavirales; Point Mutation; RNA Editing; RNA Viruses; RNA, Double-Stranded; RNA, Viral; RNA-Binding Proteins
PubMed: 7888761
DOI: 10.1016/0959-437x(94)90076-0 -
Viruses Oct 2016Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying... (Comparative Study)
Comparative Study Review
Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the (CDV) causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the (MeV) and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development.
Topics: Animals; Disease Models, Animal; Distemper Virus, Canine; Dogs; Ferrets; Humans; Immune Evasion; Immune Tolerance; Measles virus; Viral Tropism
PubMed: 27727184
DOI: 10.3390/v8100274 -
PloS One 2012Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral...
Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11-16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Binding Sites; Computational Biology; Conserved Sequence; Humans; Models, Molecular; Molecular Sequence Data; Mononegavirales; Phosphoproteins; Sequence Homology, Amino Acid; Viral Proteins
PubMed: 22403617
DOI: 10.1371/journal.pone.0031719 -
Antiviral Research Feb 2019Filoviruses, which include Ebola virus (EBOV) and Marburg virus, are negative-sense RNA viruses associated with sporadic outbreaks of severe viral hemorrhagic fever... (Review)
Review
Filoviruses, which include Ebola virus (EBOV) and Marburg virus, are negative-sense RNA viruses associated with sporadic outbreaks of severe viral hemorrhagic fever characterized by uncontrolled virus replication. The extreme virulence and emerging nature of these zoonotic pathogens make them a significant threat to human health. Replication of the filovirus genome and production of viral RNAs require the function of a complex of four viral proteins, the nucleoprotein (NP), viral protein 35 (VP35), viral protein 30 (VP30) and large protein (L). The latter performs the enzymatic activities required for production of viral RNAs and capping of viral mRNAs. Although it has been recognized that interactions between the virus-encoded components of the EBOV RNA polymerase complex are required for viral RNA synthesis reactions, specific molecular details have, until recently, been lacking. New efforts have combined structural biology and molecular virology to reveal in great detail the molecular basis for critical protein-protein interactions (PPIs) necessary for viral RNA synthesis. These efforts include recent studies that have identified a range of interacting host factors and in some instances demonstrated unique mechanisms by which they act. For a select number of these interactions, combined use of mutagenesis, over-expressing of peptides corresponding to PPI interfaces and identification of small molecules that disrupt PPIs have demonstrated the functional significance of virus-virus and virus-host PPIs and suggest several as potential targets for therapeutic intervention.
Topics: Animals; Ebolavirus; Filoviridae; Host Microbial Interactions; Humans; Marburgvirus; Protein Binding; RNA, Viral; Viral Proteins; Virus Diseases; Virus Replication
PubMed: 30550800
DOI: 10.1016/j.antiviral.2018.12.006 -
Antiviral Research Nov 2016This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the... (Review)
Review
This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the surface glycoprotein GP and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and Δ-peptide. Then, we compare filovirus surface GP proteins in terms of structure, synthesis and function. As they bear potential in drug-design, the discovery of small organic compounds inhibiting filovirus entry is a currently very active field. Although it is at an early stage, the development of antiviral drugs against Ebola and Marburg virus entry might prove essential to reduce outbreak-associated fatality rates through post-exposure treatment of both suspected and confirmed cases.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; Drug Discovery; Ebolavirus; Filoviridae; Filoviridae Infections; Glycoproteins; Humans; Marburgvirus; Mice; Viral Envelope Proteins; Virus Internalization
PubMed: 27640102
DOI: 10.1016/j.antiviral.2016.09.001