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Virus Research Jan 2018Recent studies illustrate that fungi as virus hosts provides a unique platform for hunting viruses and exploring virus/virus and virus/host interactions. Such studies... (Review)
Review
Recent studies illustrate that fungi as virus hosts provides a unique platform for hunting viruses and exploring virus/virus and virus/host interactions. Such studies have revealed a number of as-yet-unreported viruses and virus/virus interactions. Among them is a unique intimate relationship between a (+)ssRNA virus, yado-kari virus (YkV1) and an unrelated dsRNA virus, yado-nushi virus (YnV1). YkV1 dsRNA, a replicated form of YkV1, and RNA-dependent RNA polymerase, are trans-encapsidated by the capsid protein of YnV1. While YnV1 can complete its replication cycle, YkV1 relies on YnV1 for its viability. We previously proposed a model in which YkV1 diverts YnV1 capsids as the replication sites. YkV1 is neither satellite virus nor satellite RNA, because YkV1 appears to encode functional RdRp and enhances YnV1 accumulation. This represents a unique mutualistic virus/virus interplay and similar relations in other virus/host fungus systems are detectable. We propose to establish the family Yadokariviridae that accommodates YkV1 and recently discovered viruses phylogenetically related to YkV1. This article overviews what is known and unknown about the YkV1/YnV1 interactions. Also discussed are the YnV1 Phytoreo_S7 and YkV1 2A-like domains that may have been captured via horizontal transfer during the course of evolution and are conserved across extant diverse RNA viruses. Lastly, evolutionary scenarios are envisioned for YkV1 and YnV1.
Topics: Amino Acid Sequence; Capsid Proteins; Evolution, Molecular; Fungal Viruses; Fungi; Gene Transfer, Horizontal; Microbial Interactions; Phylogeny; RNA Viruses; RNA, Double-Stranded; RNA, Viral; RNA-Dependent RNA Polymerase; Satellite Viruses; Sequence Alignment; Sequence Homology, Amino Acid; Virus Replication
PubMed: 29122644
DOI: 10.1016/j.virusres.2017.11.006 -
Journal of Viral Hepatitis Jan 2024Infection with hepatitis D virus leads to liver disease and cancer most rapidly of all hepatitis viruses. However, knowledge about hepatitis D remains poor and the... (Review)
Review
Infection with hepatitis D virus leads to liver disease and cancer most rapidly of all hepatitis viruses. However, knowledge about hepatitis D remains poor and the burden and impact are underestimated, even though some 12-15 million people mainly in low- and middle-income countries may be affected. Its epidemiology is changing, with increasing migration leading to increased risks of infection and disease. A recent Viral Hepatitis Prevention Board meeting reviewed the current epidemiological status, improvements in diagnostic testing, advances in the development of novel antiviral agents in phase III trials and the need for a greater public health response, such as new guidelines and recommended testing of all people newly identified as infected with hepatitis B virus for hepatitis D virus infection. It identified issues and needs for attention with regard to prevention, diagnosis and treatment.
Topics: Humans; Public Health; Hepatitis D; Antiviral Agents; Hepatitis Delta Virus; Hepatitis B virus
PubMed: 37789715
DOI: 10.1111/jvh.13891 -
The Journal of General Virology Dec 2018The family Sarthroviridae includes a single genus, Macronovirus, which in turn includes a single species, Macrobrachium satellite virus 1. Members of this species, named...
The family Sarthroviridae includes a single genus, Macronovirus, which in turn includes a single species, Macrobrachium satellite virus 1. Members of this species, named extra small virus, are satellite viruses of Macrobrachium rosenbergii nodavirus, an unclassified virus related to members of the family Nodaviridae. Both viruses have isometric, spherical virions, infect giant freshwater prawns and together cause white tail disease, which is responsible for mass mortalities and severe economic losses in hatcheries and farms. Infection is caused by both vertical and horizontal transmission of virus. Aquatic insects act as a carrier to transmit the disease in prawns. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Sarthroviridae, which is available at www.ictv.global/report/sarthroviridae.
Topics: Animals; Disease Transmission, Infectious; Infectious Disease Transmission, Vertical; Insect Vectors; Nodaviridae; Palaemonidae; RNA Virus Infections; RNA Viruses; Satellite Viruses; Virion
PubMed: 30507372
DOI: 10.1099/jgv.0.001158 -
Microbiology Spectrum Dec 2022More than 100 arboviruses, almost all of which have an RNA genome, cause disease in humans. RNA viruses are causing unprecedented health system challenges worldwide,...
More than 100 arboviruses, almost all of which have an RNA genome, cause disease in humans. RNA viruses are causing unprecedented health system challenges worldwide, many with little or no specific therapies or vaccines available. Certain species of mosquito can carry dengue virus (DENV), Zika virus (ZIKV) and yellow fever virus (YFV), where co-infection of these viruses has occurred. Here, we found that purified synthetic defective interfering particles (DIPs) derived from DENV type 2 (DENV-2) strongly suppressed replication of the aforementioned viruses, respiratory syncytial virus (RSV) and also the novel emerging virus SARS-CoV-2 in human cells. DENV DIPs produced in bioreactors, purified by column chromatography, and concentrated are virus-like particles that are about half the diameter of a typical DENV particle, but with similar ratios of the viral structural proteins envelope and capsid. Overall, DIP-treated cells inhibited DENV, ZIKV, YFV, RSV, and SARS-CoV-2 by at least 98% by mechanisms which included interferon (IFN)-dependent cellular antiviral responses. DIPs are spontaneously derived virus mutants with deletions in genes that block viral replication. DIPs play important roles in modulation of viral disease, innate immune responses, virus persistence and virus evolution. Here, we investigated the antiviral activity of highly purified synthetic DIPs derived from DENV, which were produced in bioreactors. DENV DIPs purified by column chromatography strongly inhibited five different RNA viruses, including DENV, ZIKV, YFV, RSV, and SARS-CoV-2 in human cells. DENV DIPs inhibited virus replication via delivery of a small, noninfectious viral RNA that activated cellular innate immunity, resulting in robust type 1 interferon responses. The work here presents a pathway for DIP production which is adaptable to Good Manufacturing Practice, so that their preclinical testing should be suitable for evaluation in subjects.
Topics: Animals; Humans; Zika Virus; Zika Virus Infection; Yellow Fever; SARS-CoV-2; Defective Interfering Viruses; Antiviral Agents; Dengue Virus; COVID-19; Yellow fever virus; Interferon Type I; Dengue
PubMed: 36445148
DOI: 10.1128/spectrum.03949-22 -
BMC Biology May 2021Infections with influenza A virus (IAV) cause high morbidity and mortality in humans. Additional to vaccination, antiviral drugs are a treatment option. Besides...
BACKGROUND
Infections with influenza A virus (IAV) cause high morbidity and mortality in humans. Additional to vaccination, antiviral drugs are a treatment option. Besides FDA-approved drugs such as oseltamivir or zanamivir, virus-derived defective interfering (DI) particles (DIPs) are considered promising new agents. IAV DIPs typically contain a large internal deletion in one of their eight genomic viral RNA (vRNA) segments. Consequently, DIPs miss the genetic information necessary for replication and can usually only propagate by co-infection with infectious standard virus (STV), compensating for their defect. In such a co-infection scenario, DIPs interfere with and suppress STV replication, which constitutes their antiviral potential.
RESULTS
In the present study, we generated a genetically engineered MDCK suspension cell line for production of a purely clonal DIP preparation that has a large deletion in its segment 1 (DI244) and is not contaminated with infectious STV as egg-derived material. First, the impact of the multiplicity of DIP (MODIP) per cell on DI244 yield was investigated in batch cultivations in shake flasks. Here, the highest interfering efficacy was observed for material produced at a MODIP of 1E-2 using an in vitro interference assay. Results of RT-PCR suggested that DI244 material produced was hardly contaminated with other defective particles. Next, the process was successfully transferred to a stirred tank bioreactor (500 mL working volume) with a yield of 6.0E+8 PFU/mL determined in genetically modified adherent MDCK cells. The produced material was purified and concentrated about 40-fold by membrane-based steric exclusion chromatography (SXC). The DI244 yield was 92.3% with a host cell DNA clearance of 97.1% (99.95% with nuclease digestion prior to SXC) and a total protein reduction of 97.2%. Finally, the DIP material was tested in animal experiments in D2(B6).A2G-Mx1 mice. Mice infected with a lethal dose of IAV and treated with DIP material showed a reduced body weight loss and all animals survived.
CONCLUSION
In summary, experiments not only demonstrated that purely clonal influenza virus DIP preparations can be obtained with high titers from animal cell cultures but confirmed the potential of cell culture-derived DIPs as an antiviral agent.
Topics: Animals; Antiviral Agents; Cell Culture Techniques; Coinfection; Defective Viruses; Felodipine; Influenza A virus; Mice
PubMed: 33941189
DOI: 10.1186/s12915-021-01020-5 -
Communications Biology Oct 2022Defective interfering (DI) particles arise during virus propagation, are conditional on parental virus for replication and packaging, and interfere with viral expansion....
Defective interfering (DI) particles arise during virus propagation, are conditional on parental virus for replication and packaging, and interfere with viral expansion. There is much interest in developing DIs as anti-viral agents. Here we characterize DI particles that arose following serial passaging of SARS-CoV-2 at high multiplicity of infection. The prominent DIs identified have lost ~84% of the SARS-CoV-2 genome and are capable of attenuating parental viral titers. Synthetic variants of the DI genomes also interfere with infection and can be used as conditional, gene delivery vehicles. In addition, the DI genomes encode an Nsp1-10 fusion protein capable of attenuating viral replication. These results identify naturally selected defective viral genomes that emerged and stably propagated in the presence of parental virus.
Topics: Humans; Defective Viruses; SARS-CoV-2; Defective Interfering Viruses; RNA, Viral; COVID-19
PubMed: 36302891
DOI: 10.1038/s42003-022-04058-5 -
Archives of Virology Jan 2022Ticks are blood-sucking arthropods that transmit many pathogens, including arboviruses. Arboviruses transmitted by ticks are generally referred to as tick-borne viruses...
Ticks are blood-sucking arthropods that transmit many pathogens, including arboviruses. Arboviruses transmitted by ticks are generally referred to as tick-borne viruses (TBVs). TBVs are known to cause diseases in humans, pets, and livestock. There is, however, very limited information on the occurrence and distribution of TBVs in sub-Saharan Africa. This study was designed to determine the presence and distribution of ticks infesting dogs and cattle in Ghana, as well as to identify the tick-borne or tick-associated viruses they harbour. A more diverse population of ticks was found to infest cattle (three genera) relative to those infesting dogs (one genus). Six phleboviruses and an orthonairovirus were detected in tick pools screened by RT-PCR. Subsequent sequence analysis revealed two distinct phleboviruses and the previously reported Odaw virus in ticks collected from dogs and a virus (16GH-T27) most closely related to four unclassified phleboviruses in ticks collected from cattle. The virus 16GH-T27 was considered a strain of Balambala tick virus (BTV) and named BTV strain 16GH-T27. Next-generation sequencing analysis of the BTV-positive tick pool detected only the L and S segments. Phylogenetic analysis revealed that BTV clustered with viruses previously defined as M-segment-deficient phleboviruses. The orthonairovirus detected in ticks collected from cattle was confirmed to be the medically important Dugbe virus. Furthermore, we discuss the importance of understanding the presence and distribution of ticks and TBVs in disease prevention and mitigation and the implications for public health. Our findings contribute to the knowledge pool on TBVs and tick-associated viruses.
Topics: Animals; Cattle; Dogs; Ghana; Phlebovirus; Phylogeny; Satellite Viruses; Tick-Borne Diseases; Ticks
PubMed: 34757503
DOI: 10.1007/s00705-021-05296-4 -
Liver International : Official Journal... Jun 2023HDV is a defective virus that uses the HBV surface antigen to enter hepatocytes. It is associated with an accelerated course of liver fibrosis progression and an... (Review)
Review
HDV is a defective virus that uses the HBV surface antigen to enter hepatocytes. It is associated with an accelerated course of liver fibrosis progression and an increased risk of hepatocellular carcinoma. Negative HDV RNA 24 weeks after the end of therapy has been proposed as an endpoint but late relapses make this endpoint suboptimal, hence HBsAg loss appears to be more appropriate. Current HBV antiviral agents have poor activity against HDV hence the search for improved therapy. Drugs only active against HDV, such as lonafarnib, have shown efficacy in combination with nucleoside analogues and peginterferon, but do not lead to HBsAg loss. HBsAg loss sustained 24 weeks after the end of therapy with negative HBV DNA is termed functional cure. Agents that are being investigated for functional cure include those that inhibit replication such as entry inhibitors, polymerase inhibitors and capsid assembly modulators but seldom lead to functional cure. Agents that reduce HBV antigen load such as RNA interference and inhibitors of HBsAg secretion are promising. Immunomodulators on their own seldom achieve functional cure, hence these agents in combination to assess the optimal combination are being investigated. Consequently, agents leading to functional cure of HBV are ideal for both HBV and HDV.
Topics: Humans; Hepatitis B Surface Antigens; Hepatitis B virus; Antiviral Agents; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis Delta Virus
PubMed: 35946084
DOI: 10.1111/liv.15387 -
Proceedings of the National Academy of... Jan 2021Hepatitis delta virus (HDV) is an unusual RNA agent that replicates using host machinery but exploits hepatitis B virus (HBV) to mobilize its spread within and between...
Hepatitis delta virus (HDV) is an unusual RNA agent that replicates using host machinery but exploits hepatitis B virus (HBV) to mobilize its spread within and between hosts. In doing so, HDV enhances the virulence of HBV. How this seemingly improbable hyperparasitic lifestyle emerged is unknown, but it underpins the likelihood that HDV and related deltaviruses may alter other host-virus interactions. Here, we show that deltaviruses diversify by transmitting between mammalian species. Among 96,695 RNA sequence datasets, deltaviruses infected bats, rodents, and an artiodactyl from the Americas but were absent from geographically overrepresented Old World representatives of each mammalian order, suggesting a relatively recent diversification within the Americas. Consistent with diversification by host shifting, both bat and rodent-infecting deltaviruses were paraphyletic, and coevolutionary modeling rejected cospeciation with mammalian hosts. In addition, a 2-y field study showed common vampire bats in Peru were infected by two divergent deltaviruses, indicating multiple introductions to a single host species. One vampire bat-associated deltavirus was detected in the saliva of up to 35% of individuals, formed phylogeographically compartmentalized clades, and infected a sympatric bat, illustrating horizontal transmission within and between species on ecological timescales. Consistent absence of HBV-like viruses in two deltavirus-infected bat species indicated acquisitions of novel viral associations during the divergence of bat and human-infecting deltaviruses. Our analyses support an American zoonotic origin of HDV and reveal prospects for future cross-species emergence of deltaviruses. Given their peculiar life history, deltavirus host shifts will have different constraints and disease outcomes compared to ordinary animal pathogens.
Topics: Animals; Chiroptera; Disease Transmission, Infectious; Genetic Variation; Genome, Viral; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Host Specificity; Host-Pathogen Interactions; Humans; Mammals; Phylogeny; Rodentia; Satellite Viruses
PubMed: 33397804
DOI: 10.1073/pnas.2019907118 -
Journal of Hepatology Oct 2022Besides HBV-dependent de novo infection, cell division-mediated spread contributes to HDV persistence and dampens the effect of antivirals that abrogate de novo...
BACKGROUND & AIMS
Besides HBV-dependent de novo infection, cell division-mediated spread contributes to HDV persistence and dampens the effect of antivirals that abrogate de novo infection. Nonetheless, the combination of these antivirals with interferons (IFNs) showed strong synergism in recent clinical trials, implying a complementary mode-of-action of IFNs. Therefore, we investigated the effect of IFN response on cell division-mediated HDV spread.
METHODS
Cells infected with HDV were passaged to undergo cell division. The effect of the IFN response was evaluated by blocking HDV-induced IFN activation, by applying different IFN treatment regimens, and by adjusting HDV infection doses.
RESULTS
Cell division-mediated HDV spread was highly efficient following infection of HuH7 cells (defective in IFN production), but profoundly restricted in infected IFN-competent HepaRG cells. Treatment with IFN-α/-λ1 inhibited HDV spread in dividing HuH7 cells, but exhibited a marginal effect on HDV replication in resting cells. Blocking the HDV-induced IFN response with the JAK1/2 inhibitor ruxolitinib or knocking down MDA5 augmented HDV spread in dividing HepaRG cells. The virus-induced IFN response also destabilized HDV RNA in dividing cells. Moreover, the effect of exogenous IFNs on cell division-mediated HDV spread was more pronounced at low multiplicities of infection with weak virus-induced IFN responses.
CONCLUSIONS
Both HDV-induced IFN response and exogenous IFN treatment suppress cell division-mediated HDV spread, presumably through acceleration of HDV RNA decay. Our findings demonstrate a novel mode-of-action of IFN, explain the more pronounced effect of IFN therapy in patients with lower HDV serum RNA levels, and provide insights for the development of combination therapies.
LAY SUMMARY
Chronic hepatitis D is a major health problem. The causative pathogen hepatitis D virus (HDV) can propagate through viral particle-mediated infection and the division of infected cells. Although viral particle-dependent infection can be blocked by recently developed drugs, therapies addressing the cell division route have not been reported. Taking advantage of relevant cell culture models, we demonstrate that the widely used immune modulator interferon can efficiently suppress HDV spread through cell division. This work unveils a new function of interferon and sheds light on potentially curative combination therapies.
Topics: Antiviral Agents; Cell Division; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Interferons; RNA; Virus Replication
PubMed: 35636579
DOI: 10.1016/j.jhep.2022.05.023