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World Journal of Gastroenterology Aug 2015Hepatitis D virus (HDV) is the smallest single stranded RNA virus infecting humans. The hepatitis B surface antigen envelope protein protects the HDV nucleocapsid... (Review)
Review
Hepatitis D virus (HDV) is the smallest single stranded RNA virus infecting humans. The hepatitis B surface antigen envelope protein protects the HDV nucleocapsid antigen and provides a means for the virus to enter and exit the hepatocyte. Hepatitis B and D viruses exploit the human sodium taurocholate co-transporting polypeptide (NTCP), a receptor, for their entry into hepatocytes. Prenylation of the large delta antigen is a critical determinant of HDV particle assembly. Treatment with pegylated interferon results in sustained virological response six months post-treatment in one fourth of the patients. Nucleos(t)ide analogs (NAs) have been widely tested in hepatitis delta, but they appear to be ineffective. Combination treatment of NAs with interferon also proved to be disappointing so there is a need for novel therapeutic options. The receptor function of NTCP is blocked by Myrcludex B, a synthetic N-acylated preS1 lipopeptide that competes with infectious virions for receptor binding. There are already some approved drugs available, including irbesartan, ezetimibe, and ritonavir and cyclosporin A, with documented inhibitory effects on NTCP's metabolic function. These drugs may have a role in HDV treatment. Interference with host-mediated post-translational changes of proteins that are crucial to the HDV life cycle, such as prenylation may become an important tool to control HDV infection and prevent replication. Lonafarnib, a prenylation inhibitor significantly reduces virus levels in hepatitis delta patients. Antisense oligodeoxynucleotides which are complementary to genomic HDV ribozyme self-cleavage site and stem I regions can inhibit genomic HDV ribozyme activity.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepatitis D; Hepatitis Delta Virus; Host-Pathogen Interactions; Humans; Molecular Targeted Therapy; Oligonucleotides, Antisense; Protein Prenylation; Treatment Outcome; Virus Internalization
PubMed: 26327754
DOI: 10.3748/wjg.v21.i32.9461 -
MBio Jan 2020Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the...
Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability in viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex virus-host interplay during influenza virus infection. Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate the disease severity and pathogenicity of an influenza virus infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized virus and host transcriptomes in individual influenza virus-infected cells, including those of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective viral genome species This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.
Topics: A549 Cells; Bronchi; Cells, Cultured; Defective Viruses; Epithelial Cells; Gene Expression Profiling; Genome, Viral; Host Microbial Interactions; Humans; Influenza A virus; RNA, Viral; Sequence Analysis, RNA; Single-Cell Analysis; Virus Replication
PubMed: 31937643
DOI: 10.1128/mBio.02880-19 -
Viruses May 2023RNA viruses may be monopartite (all genes on one strand), multipartite (two or more strands packaged separately) or segmented (two or more strands packaged together). In...
RNA viruses may be monopartite (all genes on one strand), multipartite (two or more strands packaged separately) or segmented (two or more strands packaged together). In this article, we consider competition between a complete monopartite virus, A, and two defective viruses, D and E, that have complementary genes. We use stochastic models that follow gene translation, RNA replication, virus assembly, and transmission between cells. D and E multiply faster than A when stored in the same host as A or when together in the same host, but they cannot multiply alone. D and E strands are packaged as separate particles unless a mechanism evolves that allows assembly of D + E segmented particles. We show that if defective viruses assemble rapidly into separate particles, the formation of segmented particles is selected against. In this case, D and E spread as parasites of A, and the bipartite D + E combination eliminates A if the transmissibility is high. Alternatively, if defective strands do not assemble rapidly into separate particles, then a mechanism for assembly of segmented particles is selected for. In this case, the segmented virus can eliminate A if transmissibility is high. Conditions of excess protein resources favor bipartite viruses, while conditions of excess RNA resources favor segmented viruses. We study the error threshold behavior that arises when deleterious mutations are introduced. Relative to bipartite and segmented viruses, deleterious mutations favor monopartite viruses. A monopartite virus can give rise to either a bipartite or a segmented virus, but it is unlikely that both will originate from the same virus.
Topics: Viruses; RNA Viruses; Virus Assembly
PubMed: 37243221
DOI: 10.3390/v15051135 -
The Journal of General Virology Dec 2018Hepatitis delta virus, the only member of the only species in the genus Deltavirus, is a unique human pathogen. Its ~1.7 kb circular negative-sense RNA genome encodes a...
Hepatitis delta virus, the only member of the only species in the genus Deltavirus, is a unique human pathogen. Its ~1.7 kb circular negative-sense RNA genome encodes a protein, hepatitis delta antigen, which occurs in two forms, small and large, both with unique functions. Hepatitis delta virus uses host RNA polymerase II to replicate via double rolling circle RNA synthesis. Newly synthesized linear RNAs are circularized after autocatalytic cleavage and ligation. Hepatitis delta virus requires the envelope of the helper virus, hepatitis B virus (family Hepadnaviridae), to produce infectious particles. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Deltavirus which is available at www.ictv.global/report/deltavirus.
Topics: Genome, Viral; Helper Viruses; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Host-Pathogen Interactions; Humans; RNA; RNA Polymerase II; RNA, Circular; RNA, Viral; Viral Envelope Proteins; Virus Replication
PubMed: 30311870
DOI: 10.1099/jgv.0.001150 -
PLoS Pathogens Sep 2021During replication, RNA viruses accumulate genome alterations, such as mutations and deletions. The interactions between individual variants can determine the fitness of...
During replication, RNA viruses accumulate genome alterations, such as mutations and deletions. The interactions between individual variants can determine the fitness of the virus population and, thus, the outcome of infection. To investigate the effects of defective interfering genomes (DI) on wild-type (WT) poliovirus replication, we developed an ordinary differential equation model, which enables exploring the parameter space of the WT and DI competition. We also experimentally examined virus and DI replication kinetics during co-infection, and used these data to infer model parameters. Our model identifies, and our experimental measurements confirm, that the efficiencies of DI genome replication and encapsidation are two most critical parameters determining the outcome of WT replication. However, an equilibrium can be established which enables WT to replicate, albeit to reduced levels.
Topics: Coinfection; Defective Viruses; Humans; Models, Theoretical; Poliovirus; Virus Replication
PubMed: 34570820
DOI: 10.1371/journal.ppat.1009277 -
Antiviral Research Jan 2023Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), possesses the smallest viral genome known to infect animals. HDV needs HBV surface protein for... (Review)
Review
Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), possesses the smallest viral genome known to infect animals. HDV needs HBV surface protein for secretion and entry into target liver cells. However, HBV is dispensable for HDV genome amplification, as it relies almost exclusively on cellular host factors for replication. HBV/HDV co-infections affect over 12 million people worldwide and constitute the most severe form of viral hepatitis. Co-infected individuals are at higher risk of developing liver cirrhosis and hepatocellular carcinoma compared to HBV mono-infected patients. Bulevirtide, an entry inhibitor, was conditionally approved in July 2020 in the European Union for adult patients with chronic hepatitis delta (CHD) and compensated liver disease. There are several drugs in development, including lonafarnib and interferon lambda, with different modes of action. In this review, we detail our current fundamental knowledge of HDV lifecycle and review antiviral treatments under development against this virus, outlining their respective mechanisms-of-action. Finally, we describe the antiviral effect these compounds are showing in ongoing clinical trials, discussing their promise and potential pitfalls for managing HDV infected patients.
Topics: Animals; Hepatitis Delta Virus; Hepatitis D; Antiviral Agents; Hepatitis B; Hepatitis B virus
PubMed: 36396025
DOI: 10.1016/j.antiviral.2022.105461 -
Current Opinion in Virology Apr 2016The viroids of plants are the simplest known infectious genetic elements. They have RNA genomes of up to 400 nucleotides in length and no protein encoding capacity.... (Review)
Review
The viroids of plants are the simplest known infectious genetic elements. They have RNA genomes of up to 400 nucleotides in length and no protein encoding capacity. Hepatitis delta virus (HDV), an infectious agent found only in humans co-infected with hepatitis B virus (HBV), is just slightly more complex, with an RNA genome of about 1700 nucleotides, and the ability to express just one small protein. Viroid and HDV RNAs share several features that include circular structure, compact folding, and replication via a rolling-circle mechanism. Both agents were detected because of their obvious pathogenic effects. Their simplicity demands a greater need than conventional RNA or DNA viruses to redirect host components for facilitating their infectious cycle, a need that directly and indirectly incites pathogenic effects. The mechanisms by which these pathogenic effects are produced are the topic of this review. In this context, RNA silencing mediates certain aspects of viroid pathogenesis.
Topics: Animals; Coinfection; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Host-Pathogen Interactions; Humans; Plant Diseases; Plants; Primates; RNA Interference; RNA, Viral; Viroids; Virus Replication
PubMed: 26897654
DOI: 10.1016/j.coviro.2016.01.022 -
Current Opinion in Virology Aug 2015Hepatitis B virus (HBV) infections are a global health problem afflicting approximately 360 million patients. Of these individuals, 15-20 million are co-infected with... (Review)
Review
Hepatitis B virus (HBV) infections are a global health problem afflicting approximately 360 million patients. Of these individuals, 15-20 million are co-infected with hepatitis delta virus (HDV). Progress toward curative therapies has been impeded by the highly restricted host tropism of HBV, which is limited to productive infections in humans and chimpanzees. Here, we will discuss different approaches that have been taken to study HBV and HDV infections in vivo. The development of transgenic and humanized mice has lead to deeper insights into HBV pathogenesis. An improved understanding of the determinants governing HBV and HDV species tropism will aid in the construction of a small animal model with inheritable susceptible to HBV/HDV.
Topics: Animals; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Viral Tropism
PubMed: 26164658
DOI: 10.1016/j.coviro.2015.06.004 -
Journal of Virology Oct 2021Here, we examine the infection dynamics and interactions of two Zika virus (ZIKV) genomes: one is the full-length ZIKV genome (wild type [WT]), and the other is one of...
Here, we examine the infection dynamics and interactions of two Zika virus (ZIKV) genomes: one is the full-length ZIKV genome (wild type [WT]), and the other is one of the naturally occurring defective viral genomes (DVGs), which can replicate in the presence of the WT genome, appears under high-MOI (multiplicity of infection) passaging conditions, and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODEs) were used to simulate the infection of cells by virus particles and the intracellular replication of the WT and DVG genomes that produce these particles. For each virus passage in Vero and C6/36 cell cultures, the rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately as well as the sensitivity of the model's parameters. We also determined which simulated processes of virus evolution are the most important for the adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in the majority of passages, the rates of DVG production are higher inC6/36 cells than in Vero cells, which might result in tolerance and therefore drive the persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed a slower accumulation of infected cells under higher activation of the DVG-associated processes, which indicates a potential role of DVGs in virus attenuation. One of the ideas for lessening Zika pathogenicity is the addition of its natural or engineered defective virus genomes (DVGs) (have no pathogenicity) to the infection pool: a DVG is redirecting the wild-type (WT)-associated virus development resources toward its own maturation. The mathematical model presented here, attuned to the data from interplays between WT Zika viruses and their natural DVGs in mammalian and mosquito cells, provides evidence that the loss of uninfected cells is attenuated by the DVG development processes. This model enabled us to estimate the rates of virus development processes in the WT/DVG interplay, determine the key processes, and show that the key processes are faster in mosquito cells than in mammalian ones. In general, the presented model and its detailed study suggest in what important virus development processes the therapeutically efficient DVG might compete with the WT; this may help in assembling engineered DVGs for ZIKV and other flaviviruses.
Topics: Aedes; Animals; Chlorocebus aethiops; Defective Viruses; Host Microbial Interactions; Vero Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 34468175
DOI: 10.1128/JVI.00977-21 -
Viruses Jun 2024Begomoviruses have emerged as destructive pathogens of crops, particularly in the tropics and subtropics, causing enormous economic losses and threatening food security.... (Review)
Review
Begomoviruses have emerged as destructive pathogens of crops, particularly in the tropics and subtropics, causing enormous economic losses and threatening food security. Epidemics caused by begomoviruses have even spread in regions and crops that were previously free from these viruses. The most seriously affected crops include cassava; cotton; grain legumes; and cucurbitaceous, malvaceous, and solanaceous vegetables. Alphasatellites, betasatellites, and deltasatellites are associated with the diseases caused by begomoviruses, but begomovirus-betasatellite complexes have played significant roles in the evolution of begomoviruses, causing widespread epidemics in many economically important crops throughout the world. This article provides an overview of the evolution, distribution, and approaches used by betasatellites in the suppression of host plant defense responses and increasing disease severity.
Topics: Begomovirus; Plant Diseases; Crops, Agricultural; Satellite Viruses; Evolution, Molecular; DNA, Satellite; Phylogeny
PubMed: 38932261
DOI: 10.3390/v16060970