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European Journal of Pharmacology Aug 2017The influenza virus (IV) is a highly contagious virus causing seasonal global outbreaks affecting annually up to 20% of the world's population and leading to... (Review)
Review
The influenza virus (IV) is a highly contagious virus causing seasonal global outbreaks affecting annually up to 20% of the world's population and leading to 250,000-500,000 deaths worldwide. Current vaccines have variable effectiveness, and, in particular during a pandemic outbreak, they are probably not available in the amounts needed to protect the world population. Therefore we need effective small molecule drugs to combat an IV infection and that can be produced, in case of pandemic, rapidly and in large quantities. Unfortunately, natural occurring IV becomes more and more resistant to current anti-IV drugs. And thus, there is an urgent need for development of alternative agents with new mechanisms of action. This review provides an overview of the pharmacology and effectiveness of new anti-IV agents, focusing on inhibition mechanisms directed against virus-host interactions.
Topics: Animals; Antiviral Agents; Drug Interactions; Host-Pathogen Interactions; Humans; Influenza, Human; Orthomyxoviridae
PubMed: 28533172
DOI: 10.1016/j.ejphar.2017.05.038 -
FEMS Microbiology Reviews Sep 2005Influenza virus is a major human pathogen that causes epidemics and pandemics with increased morbidity and, especially in the elderly and those with pre-existing medical... (Review)
Review
Influenza virus is a major human pathogen that causes epidemics and pandemics with increased morbidity and, especially in the elderly and those with pre-existing medical conditions, increased mortality. Influenza is characterised by respiratory symptoms and constitutional symptoms. Whilst knowledge of the mechanisms underlying host and tissue specificity has advanced considerably of late we still know relatively little about other aspects of influenza virus virulence. In this review, we will explore what is known about the role of apoptosis in respiratory epithelial cell damage and the role of cytokines in inflammation and constitutional symptoms with particular emphasis on the link between apoptosis, inflammation, fever and cytokine production.
Topics: Apoptosis; Cytokines; Gene Expression Regulation; Humans; Influenza, Human; Morbidity; Orthomyxoviridae
PubMed: 16102605
DOI: 10.1016/j.femsre.2004.12.003 -
Viruses Apr 2021Hemagglutinin and neuraminidase, which constitute the glycoprotein spikes expressed on the surface of influenza A and B viruses, are the most exposed parts of the virus... (Review)
Review
Hemagglutinin and neuraminidase, which constitute the glycoprotein spikes expressed on the surface of influenza A and B viruses, are the most exposed parts of the virus and play critical roles in the viral lifecycle. As such, they make prominent targets for the immune response and antiviral drugs. Neuraminidase inhibitors, particularly oseltamivir, constitute the most commonly used antivirals against influenza viruses, and they have proved their clinical utility against seasonal and emerging influenza viruses. However, the emergence of resistant strains remains a constant threat and consideration. Antivirals targeting the hemagglutinin protein are relatively new and have yet to gain global use but are proving to be effective additions to the antiviral repertoire, with a relatively high threshold for the emergence of resistance. Here we review antiviral drugs, both approved for clinical use and under investigation, that target the influenza virus hemagglutinin and neuraminidase proteins, focusing on their mechanisms of action and the emergence of resistance to them.
Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Enzyme Inhibitors; Hemagglutinins, Viral; Humans; Influenza, Human; Mice; Neuraminidase; Orthomyxoviridae; Orthomyxoviridae Infections; Oseltamivir; Viral Envelope Proteins
PubMed: 33917376
DOI: 10.3390/v13040624 -
Current Opinion in Virology Oct 2015The emergence of the pandemic influenza virus A(H1N1)pdm09 in 2009 and avian influenza virus A(H7N9) in 2013 provided unique opportunities for assessing genetic... (Review)
Review
The emergence of the pandemic influenza virus A(H1N1)pdm09 in 2009 and avian influenza virus A(H7N9) in 2013 provided unique opportunities for assessing genetic predispositions to severe disease because many patients did not have any underlying risk factor or neutralizing antibody against these agents, in contrast to seasonal influenza viruses. High-throughput screening platforms and large human or animal databases from international collaborations allow rapid selection of potential candidate genes for confirmatory functional studies. In the last 2 years, at least seven new human susceptibility genes have been identified in genetic association studies. Integration of knowledge from genetic and phenotypic studies is essential to identify important gene targets for treatment and prevention of influenza virus infection.
Topics: Genetic Association Studies; Genetic Predisposition to Disease; Host-Pathogen Interactions; Humans; Influenza, Human; Orthomyxoviridae
PubMed: 26079652
DOI: 10.1016/j.coviro.2015.04.010 -
Genetics Jun 2016Methods that bypass analytical evaluations of the likelihood function have become an indispensable tool for statistical inference in many fields of science. These...
Methods that bypass analytical evaluations of the likelihood function have become an indispensable tool for statistical inference in many fields of science. These so-called likelihood-free methods rely on accepting and rejecting simulations based on summary statistics, which limits them to low-dimensional models for which the value of the likelihood is large enough to result in manageable acceptance rates. To get around these issues, we introduce a novel, likelihood-free Markov chain Monte Carlo (MCMC) method combining two key innovations: updating only one parameter per iteration and accepting or rejecting this update based on subsets of statistics approximately sufficient for this parameter. This increases acceptance rates dramatically, rendering this approach suitable even for models of very high dimensionality. We further derive that for linear models, a one-dimensional combination of statistics per parameter is sufficient and can be found empirically with simulations. Finally, we demonstrate that our method readily scales to models of very high dimensionality, using toy models as well as by jointly inferring the effective population size, the distribution of fitness effects (DFE) of segregating mutations, and selection coefficients for each locus from data of a recent experiment on the evolution of drug resistance in influenza.
Topics: Drug Resistance, Viral; Genetic Fitness; Genetic Loci; Models, Genetic; Mutation; Orthomyxoviridae; Probability; Selection, Genetic
PubMed: 27052569
DOI: 10.1534/genetics.116.187567 -
Cold Spring Harbor Perspectives in... Jan 2021Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling... (Review)
Review
Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strategies of antiviral intervention. Here, we will summarize the current knowledge of activation and function of influenza virus-induced signaling pathways with a focus on nuclear factor (NF)-κB signaling, mitogen-activated protein kinase cascades, and the phosphatidylinositol-3-kinase pathway. We will discuss the opportunities and drawbacks of targeting these signaling pathways for antiviral intervention.
Topics: Animals; Antiviral Agents; Apoptosis; Humans; Mitogen-Activated Protein Kinases; NF-kappa B; Orthomyxoviridae; Signal Transduction; Viral Nonstructural Proteins; Virus Replication
PubMed: 31871235
DOI: 10.1101/cshperspect.a038513 -
Advances in Virus Research 1988It is an accepted concept that the pathogenicity of a virus is of polygenic nature. Because of their segmented genome, influenza viruses provide a suitable system to... (Review)
Review
It is an accepted concept that the pathogenicity of a virus is of polygenic nature. Because of their segmented genome, influenza viruses provide a suitable system to prove this concept. The studies employing virus mutants and reassortants have indicated that the pathogenicity depends on the functional integrity of each gene and on a gene constellation optimal for the infection of a given host. As a consequence, virtually every gene product of influenza virus has been reported to contribute to pathogenicity, but evidence is steadily growing that a key role has to be assigned to hemagglutinin. As the initiator of infection, hemagglutinin has a double function: (1) promotion of adsorption of the virus to the cell surface, and (2) penetration of the viral genome through a fusion process among viral and cellular membranes. Adsorption is based on the binding to neuraminic acid-containing receptors, and different virus strains display a distinct preference for specific oligosaccharides. Fusion capacity depends on proteolytic cleavage by host proteases, and variations in amino acid sequence at the cleavage site determine whether hemagglutinin is activated in a given cell. Differences in cleavability and presumably also in receptor specificity are important determinants for host tropism, spread of infection, and pathogenicity. The concept that proteolytic activation is a determinant for pathogenicity was originally derived from studies on avian influenza viruses, but there is now evidence that it may also be relevant for the disease in humans because bacterial proteases have been found to promote the development of influenza pneumonia in mammals.
Topics: Animals; Genes, Viral; Hemagglutinins, Viral; Humans; Orthomyxoviridae; Viral Proteins
PubMed: 3046255
DOI: 10.1016/s0065-3527(08)60520-5 -
MBio 2011Novel pandemic influenza viruses enter the human population with some regularity and can cause disease that is severe and widespread. The emergence of novel viruses,... (Review)
Review
Novel pandemic influenza viruses enter the human population with some regularity and can cause disease that is severe and widespread. The emergence of novel viruses, historically, has often been coupled with the disappearance of existing seasonal virus strains. Here, we propose that the elimination of seasonal strains during virus pandemics is a process mediated, at the population level, by humoral immunity. Specifically, we suggest that infection with a novel virus strain, in people previously exposed to influenza viruses, can elicit a memory B cell response against conserved hemagglutinin stalk epitopes and/or neuraminidase epitopes. The anti-stalk and/or anti-neuraminidase antibodies then act to diminish the clinical severity of disease caused by novel influenza viruses and to eliminate seasonal virus strains.
Topics: Antibodies, Viral; Biological Evolution; Extinction, Biological; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza, Human; Orthomyxoviridae; Selection, Genetic
PubMed: 21878571
DOI: 10.1128/mBio.00150-11 -
Medicinal Research Reviews Jan 2008Annual epidemics of influenza virus infection are responsible for considerable morbidity and mortality, and pandemics are much more devastating. Considerable knowledge... (Review)
Review
Annual epidemics of influenza virus infection are responsible for considerable morbidity and mortality, and pandemics are much more devastating. Considerable knowledge of viral infectivity and replication has been acquired, but many details still have to be elucidated and the virus remains a challenging target for drug design and development. This review provides an overview of the antiviral drugs targeting the influenza viral replicative cycle. Included are a brief description of their chemical syntheses and biological activities. For other reviews, see References1-9.
Topics: Animals; Antiviral Agents; Cell Line; Humans; Orthomyxoviridae; Virus Replication
PubMed: 17160999
DOI: 10.1002/med.20096 -
Journal of Virology Sep 2004
Review
Topics: Animals; Antiviral Agents; Birds; Humans; Influenza Vaccines; Influenza, Human; Orthomyxoviridae; Swine
PubMed: 15308692
DOI: 10.1128/JVI.78.17.8951-8959.2004