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Nature Microbiology Jul 2019Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are... (Review)
Review
Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replication-competent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools.
Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Biological Evolution; Defective Viruses; Genome, Viral; Host-Pathogen Interactions; Humans; RNA Viruses; Virus Replication
PubMed: 31160826
DOI: 10.1038/s41564-019-0465-y -
Viruses Dec 2022Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA... (Review)
Review
Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA viruses, especially in influenza viruses. Evidence indicates that DIPs interfere with the replication and encapsulation of wild-type viruses, namely standard viruses (STVs) that contain full-length viral genomes. DIPs may also activate the innate immune response by stimulating interferon synthesis. In this review, the underlying generation mechanisms and characteristics of influenza virus DIPs are summarized. We also discuss the potential impact of DIPs on the immunogenicity of live attenuated influenza vaccines (LAIVs) and development of influenza vaccines based on NS1 gene-defective DIPs. Finally, we review the antiviral strategies based on influenza virus DIPs that have been used against both influenza virus and SARS-CoV-2. This review provides systematic insights into the theory and application of influenza virus DIPs.
Topics: Humans; Antiviral Agents; Influenza Vaccines; Defective Interfering Viruses; Defective Viruses; COVID-19; SARS-CoV-2; Orthomyxoviridae; Virus Replication
PubMed: 36560777
DOI: 10.3390/v14122773 -
PLoS Pathogens May 2020
Review
Topics: Animals; Defective Viruses; Humans; Influenza, Human; Orthomyxoviridae; Orthomyxoviridae Infections; RNA, Viral; Virion; Virus Replication
PubMed: 32437428
DOI: 10.1371/journal.ppat.1008436 -
Clinical and Vaccine Immunology : CVI Jul 2006
Review
Topics: Adult; Animals; CD4-Positive T-Lymphocytes; Defective Viruses; HIV Infections; HIV-1; Humans; Infant; Lymphocyte Activation
PubMed: 16829607
DOI: 10.1128/CVI.00052-06 -
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 -
Effects of defective interfering viruses on virus replication and pathogenesis in vitro and in vivo.Advances in Virus Research 1991DI viruses and defective viruses generally are widespread in nature. Laboratory studies show that they can sometimes exert powerful disease-modulating effects (either... (Review)
Review
DI viruses and defective viruses generally are widespread in nature. Laboratory studies show that they can sometimes exert powerful disease-modulating effects (either attenuation or intensification of symptoms). Their role in nature remains largely unexplored, despite recent suggestive evidence for their importance in a number of systems.
Topics: Animals; Defective Viruses; Humans; Plants; Virus Physiological Phenomena; Virus Replication; Viruses
PubMed: 1957718
DOI: 10.1016/s0065-3527(08)60279-1 -
Frontiers in Cellular and Infection... 2022Bovine herpesvirus type 1 (BHV-1) is a neurotropic herpesvirus that causes infectious rhinotracheitis and vulvovaginitis in cattle. The virion host shutoff protein...
Bovine herpesvirus type 1 (BHV-1) is a neurotropic herpesvirus that causes infectious rhinotracheitis and vulvovaginitis in cattle. The virion host shutoff protein encoded by the BHV-1 gene is highly conserved in the Alphaherpesvirinae subfamily. This protein can degrade viral and host messenger RNA (mRNA) to interrupt host defense and facilitate the rapid proliferation of BHV-1. However, studies on the BHV-1 gene are limited, and BHV-1 defective virus construction using the CRISPR/Cas9 system is somewhat challenging. In this study, we rapidly constructed a BHV-1 UL41-deficient strain using the CRISPR/Cas9 system in BL primary bovine-derived cells. BHV-1 UL41-defective mutants were screened by Western blot analysis using specific polyclonal antibodies as the primary antibodies. During the isolation and purification of the defective strain, a mixed virus pool edited by an efficient single-guide RNA (sgRNA) showed a plaque number reduction. Viral growth property assessment showed that BHV-1 UL41 was dispensable for replication, but the UL41-defective strain exhibited early and slowed viral replication. Furthermore, the BHV-1 UL41-deficient strain exhibited enhanced sensitivity to temperature and acidic environments. The BHV-1 UL41-deficient strain regulated viral and host mRNA levels to affect viral replication.
Topics: Animals; CRISPR-Cas Systems; Cattle; Defective Viruses; RNA, Messenger; Viral Proteins; Virus Replication
PubMed: 35873151
DOI: 10.3389/fcimb.2022.942987 -
Journal of Virology Nov 2018Dengue virus (DENV) is the most prevalent mosquito-transmitted viral pathogen in humans. The recently licensed dengue vaccine has major weaknesses. Therefore, there is...
Dengue virus (DENV) is the most prevalent mosquito-transmitted viral pathogen in humans. The recently licensed dengue vaccine has major weaknesses. Therefore, there is an urgent need to develop improved dengue vaccines. Here, we report a virion assembly-defective DENV as a vaccine platform. DENV containing an amino acid deletion (K188) in nonstructural protein 2A (NS2A) is fully competent in viral RNA replication but is completely defective in virion assembly. When -complemented with wild-type NS2A protein, the virion assembly defect could be rescued, generating pseudoinfectious virus (PIV) that could initiate single-round infection. The -complementation efficiency could be significantly improved through selection for adaptive mutations, leading to high-yield PIV production, with titers of >10 infectious-focus units (IFU)/ml. Mice immunized with a single dose of PIV elicited strong T cell immune responses and neutralization antibodies and were protected from wild-type-virus challenge. Collectively, the results proved the concept of using assembly-defective virus as a vaccine approach. The study also solved the technical bottleneck in producing high yields of PIV vaccine. The technology could be applicable to vaccine development for other viral pathogens. Many flaviviruses are significant human pathogens that pose global threats to public health. Although licensed vaccines are available for yellow fever, Japanese encephalitis, tick-borne encephalitis, and dengue viruses, new approaches are needed to develop improved vaccines. Using dengue virus as a model, we developed a vaccine platform using a virion assembly-defective virus. We show that such an assembly-defective virus could be rescued to higher titers and infect cells for a single round. Mice immunized with the assembly-defective virus were protected from wild-type-virus infection. This vaccine approach could be applicable to other viral pathogens.
Topics: Animals; Antibodies, Neutralizing; Defective Viruses; Dengue; Dengue Vaccines; Dengue Virus; Female; Humans; Male; Mice; Mutation; RNA, Viral; Viral Nonstructural Proteins; Virus Assembly; Virus Replication
PubMed: 30111567
DOI: 10.1128/JVI.01002-18 -
Viruses Jul 2015Defective interfering (DI) genomes are characterised by their ability to interfere with the replication of the virus from which they were derived, and other genetically... (Review)
Review
Defective interfering (DI) genomes are characterised by their ability to interfere with the replication of the virus from which they were derived, and other genetically compatible viruses. DI genomes are synthesized by nearly all known viruses and represent a vast natural reservoir of antivirals that can potentially be exploited for use in the clinic. This review describes the application of DI virus to protect from virus-associated diseases in vivo using as an example a highly active cloned influenza A DI genome and virus that protects broadly in preclinical trials against different subtypes of influenza A and against non-influenza A respiratory viruses. This influenza A-derived DI genome protects by two totally different mechanisms: molecular interference with influenza A replication and by stimulating innate immunity that acts against non-influenza A viruses. The review considers what is needed to develop DI genomes to the point of entry into clinical trials.
Topics: Animals; Cloning, Molecular; Defective Viruses; Humans; Influenza A virus; Influenza, Human; RNA, Viral
PubMed: 26184282
DOI: 10.3390/v7072796 -
Trends in Microbiology Oct 1993Almost all viruses produce replication-defective mutants that have complex effects on the growth and evolution of the virus in culture. These effects can be explained... (Review)
Review
Almost all viruses produce replication-defective mutants that have complex effects on the growth and evolution of the virus in culture. These effects can be explained qualitatively by a simple mathematical model. However, the model shows that the quantitative effects of these mutants are intrinsically unpredictable.
Topics: Biological Evolution; Defective Viruses; Virus Replication
PubMed: 8162406
DOI: 10.1016/0966-842x(93)90048-v