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EMBO J. The influenza B virus nonstructural NS1 protein is essential for efficient viral growth and antagonizes beta interferon induction. Garcia-Sastre A. Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses. Multiple anti-interferon actions of the influenza A virus NS1 protein.
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Protective immunity and susceptibility to infectious diseases: lessons from the influenza pandemic. Nat Immunol. Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res. Human and avian influenza viruses target different cell types in cultures of human airway epithelium.
Replication of avian influenza viruses in humans. Arch Virol. Virulence of avian influenza A viruses for squirrel monkeys. Infect Immun. Human infection with highly pathogenic H5N1 influenza virus. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution.
Genetics of Influenza Viruses. Vienna: Springer-Verlag; Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Viral entry. Curr Top Microbiol Immunol. Stegmann T. Membrane fusion mechanisms: the influenza hemagglutinin paradigm and its implications for intracellular fusion.
Influenza virus M2 protein has ion channel activity. Role of virion M2 protein in influenza virus uncoating: specific reduction in the rate of membrane fusion between virus and liposomes by amantadine. Carter S. Structure, function, and evolution of the Crimean-Congo hemorrhagic fever virus nucleocapsid protein.
Guo Y. Raymond D. Structure of the Rift Valley fever virus nucleocapsid protein reveals another architecture for RNA encapsidation. Phleboviruses encapsidate their genomes by sequestering RNA bases. Ferron F. The hexamer structure of Rift Valley fever virus nucleoprotein suggests a mechanism for its assembly into ribonucleoprotein complexes.
PLoS Pathog. Zhou H. The nucleoprotein of severe fever with thrombocytopenia syndrome virus processes a stable hexameric ring to facilitate RNA encapsidation. Protein Cell. Olal D. Structural insights into RNA encapsidation and helical assembly of the Toscana virus nucleoprotein. Nucleic Acids Res. Le May N. The N terminus of Rift Valley fever virus nucleoprotein is essential for dimerization. Curran J. An N-terminal domain of the Sendai paramyxovirus P protein acts as a chaperone for the NP protein during the nascent chain assembly step of genome replication.
Leyrat C. Structure of the vesicular stomatitis virus N 0 -P complex. Masters P. Complex formation with vesicular stomatitis virus phosphoprotein NS prevents binding of nucleocapsid protein N to nonspecific RNA.
Morin B. Mechanism of RNA synthesis initiation by the vesicular stomatitis virus polymerase. EMBO J. Peluso R. Viral proteins required for the in vitro replication of vesicular stomatitis virus defective interfering particle genome RNA.
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Characterization of RNA aptamers directed against the nucleocapsid protein of Rift Valley fever virus. Reguera J. Segmented negative strand RNA virus nucleoprotein structure. Booth T. Structure and morphogenesis of Dugbe virus Bunyaviridae, Nairovirus studied by immunogold electron microscopy of ultrathin cryosections.
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Harris A. Influenza virus pleiomorphy characterized by cryoelectron tomography. Dicer was shown to be involved in vsRNA1 generation in infected cells. Conversely, blocking vsRNA1 enhanced viral yield and viral protein synthesis.
This viral miRNA is detectable in infected cells and appears to contribute to viral latency. Most of the sequences, with positive polarity These viral siRNAs vsiRNAs were shown to act inhibiting virus replication, since their inhibition using antagomiRs increases virus replication.
Most HIV sRNAs are not supposed to function as miRNAs, because of lack of evolutionary conservation amongst strains, but may still assume a hairpin structure in the regions containing the conserved bases. Presently, viral interactions with cellular miRNAs have been identified, expanding the knowledge of miRNA functions [ 49 ].
One of the first host miRNAs shown to block retrovirus was miR, effectively limiting primate foamy virus type 1 PFV-1 replication [ 50 ]. HIV-1 infection can change the miRNA expression profiles in the circulating blood cells from infected individuals [ 51 ]. In another study, four of these miRNAs were found responsible for differences between monocytes and macrophages in their permissivity to HIV infection [ 59 ]. Therefore, in divergent cells and in varying contexts different miRNAs may selectively regulate HIV-1 infection through direct targeting viral sequences.
Thus, a complex set of miRNA-mediated positive and negative regulatory events is influencing viral replication [ 51 ]. The role of type I-IFNs in increasing host susceptibility could be explained by modulation of components of the immune response involved in controlling the growth of infective agents, such as induction of T cell apoptosis, resulting in greater IL secretion by phagocytic cells, in turn dampening the innate immune response.
A mechanism by which viruses survive inside cells is by inactivating the cellular antiviral machinery, or inactivating the RNA interference response, acting on the dsRNA-activated protein kinase PKR.
Infection thus can escape from the immune response by deregulation of the interferon signaling and the processes forming small RNAs acting in RNA silencing pathways. It was shown that viral life cycle within cells involves hijacking cellular processes and nuclear targeting. This is also at the base of redistribution of translation machinery during the stress response involving the formation of stress granules, processing bodies P-bodies, PB , and perinuclear paraspeckles.
These stress granules, containing the RNA to be translated, have a role in spatial and temporal inhibition of mRNAs, until resolving the stress for processing the mRNAs, or degrading it in case of non recovery from the stress.
Different viruses exploit the binding to protein scaffolds to avoid SG formation or to assemble their RNA into SGs devoid of cellular RNA, thus exploiting the transcriptional machinery for their own means [ 64 ]. HIV-1 blocks SG assembly in vitro and ex vivo in patient samples.
Downstream to this event, measles protein C is required for alleviation of SG translation inhibition, while A-to-C mutation events dependent on ADAR modify the virus genome.
In picornaviruses, such as enteroviruses, proteinases have been shown involved in disassembly of SG, while in kobuviruses other factors, such as a small leader peptide, are important in SG inhibition. The viral accessory protein Vpr is a component of the PIC.
Vpr belongs to the RADlike family of proteins, similarly to Vpx [ 66 ]. Several studies showed the potentiality of Vpr to interact with many E2 and E3 enzymes [ 70 ]. Vpr has been shown to affect, either directly or indirectly, the modification of proteins, such as ubiquitinylation, phosphorylation and neddylation. In this way, Vpr influences and regulates the levels of many proteins [ 71 ].
Vpr also can regulate several proteins and host factors, some of them can affect RNA replication. Zahoor et al. These findings enhance the current understanding of HIV-1 replication and pathogenesis in human macrophages. Vpr, together with other HIV factors, recruits cellular adaptors to facilitate immune evasion [ 81 ]. Clearly the cell is not a passive participant in virus replication.
The first one, identified in retrovirus infected cells, was Fv1 which restricts ecotropic murine leukemia viruses. Following this finding, other similar factors restricting HIV were identified. Because of their potential importance in novel antiviral approaches, they have been extensively investigated in recent years. As an adaptive response, viruses develop the ability to interact and deactivate these defences, a mechanism named pathogen mimicry.
Among several mechanisms, there are: a the development of proteins and molecules that act interfering with cellular processes; b virus miRNA analogs of host miRNAs, exploiting the presence of a network of cell effectors and antiapoptotic factors; c incorporating protein-protein interaction domains or association modules in their genome; d through increased mutation rates evolving the recognition domains of proteins targeted by cellular defences.
Infective agents and bacteria when entering inside the cells activate several mechanisms to avoid immune detection [ 84 ]. Many viruses entering inside the cells are able to derail the cellular machinery, including the epigenetic control.
A large set of host proteins required for HIV infection have been identified through a functional genomic screen [ 88 ]. The HIV-1 transcriptional activator Tat has evolved mechanisms to resolve the transcription block.
Tat is associated with histone acetyl transferase HAT proteins whose activities remodel nucleosomes to allow transcriptional access. Recently, Tat has also been found to bind a histone chaperone protein, hNAP-1, which acts with ATP-dependent chromatin remodeling complexes to facilitate transcription. Tat expression down regulates HDAC-1 to remove the transcription repression.
In this review we highlighted the importance of cellular and viral RNAs in the cell response to RNA viruses, especially to retroviruses and endogenous L1 remnants of viral DNA integration. In addition, we reviewed several pathways involving small RNAs and short interfering RNAs deregulated in various states, from active infection to virus-associated cancers and defective immune signaling.
A special role has been assigned to the deregulation of interferon response and the inhibition of protein complexes in stress granules and P-bodies, RNA binding proteins, RISC components and the RNA silencing machinery. We thank Dr. Concetta Ambrosino and Dr. Giuseppe Fiume for the critical reading of the manuscript. The author s confirm that this article content has no conflict of interest. National Center for Biotechnology Information , U. Journal List Curr Genomics v.
Curr Genomics. Published online Oct. Author information Article notes Copyright and License information Disclaimer. This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4. This article has been cited by other articles in PMC.
RNA Pseudoknots, Hairpins and Secondary Structures RNA can both store information in its linear sequence and take on critical structural and catalytic roles in the cell, such as during the translation of messenger RNA into proteins [ 15 ]. Subversion of IFN Responses The role of type I-IFNs in increasing host susceptibility could be explained by modulation of components of the immune response involved in controlling the growth of infective agents, such as induction of T cell apoptosis, resulting in greater IL secretion by phagocytic cells, in turn dampening the innate immune response.
Virus Deregulation of Stress Granule Function It was shown that viral life cycle within cells involves hijacking cellular processes and nuclear targeting.
Resetting of Epigenetic Marks Infective agents and bacteria when entering inside the cells activate several mechanisms to avoid immune detection [ 84 ]. Villarreal L. Rethinking quasispecies theory: From fittest type to cooperative consortia.
World J. It has been shown that the efficiency of Hantavirus replication is inversely proportional to the ability of infected cells to activate MxA expression Kanerva et al. Generally, IRF-3 is present in the cytoplasm of the cell in a dormant state Reich, It has been shown that IRF-3 nuclear translocation can occur as early as 24 after Hantavirus infection Khaiboullina et al.
MxA activation has been shown to vary in different cell types Khaiboullina et al. Further studies have shown that Hantavirus replication efficacy is inversely proportional to the ability of infected cells to activate expression of MxA protein Kanerva et al. These data suggest that variations in Hantavirus replication may partially depend on ability of the particular cell types to activate MxA protein.
Thus, it is very likely that in the case of hantaviruses the mechanism of MxA inhibition is similar. Increased microvascular permeability is characteristic for hantavirus infections Zhang et al.
However, permeability of endothelial cell monolayer did not change after Hantavirus infection in vitro Khaiboullina et al. Hantavirus infection is not cytopathic, therefore, it has been suggested that an increased microvascular leakage is most likely associated with cell response to infection, rather than related to virus replication.
A DNA microarray conducted to determine changes in cell responses in Hantavirus infected cells showed that non-pathogenic PHV and pathogenic SNV hantaviruses have different effects on transcriptional activity in infected cells Khaiboullina et al. In particular, it has been shown that PHV infection activates approximately five times less genes than the SNV infection does 36 genes were up-regulated in PHV-infected cells in comparison to genes in SNV-infected cells.
As infection progressed, more changes in transcriptional activation were detected. Activation of nuclear and transcriptional factors was shown to vary in cells infected with pathogenic versus non-pathogenic hantaviruses 17 vs. Although no changes in transcriptional activity of IRF3 were noted, nuclear translocation of this factor in Hantavirus infected cells has been shown by immunohistochemistry Khaiboullina et al.
Nuclear translocation is essential for IRF3 activity which includes activation of IFN inducible genes as well as activation of cytokines. DNA Array data have shown upregulation of several genes controlling processes of apoptosis, growth and proliferation. Also, Hantavirus infected cells are characterized by transcriptional activation of vascular endothelial growth factor VEGF , a survival factor for endothelial cells, which prevents apoptosis by inducing Bcl-2 expression.
Therefore, it could be suggested that activation of Bcl2 and VEGF can explain absence of apoptosis in Hantavirus infected cells. It has been suggested that cytokines play important role in pathogenesis of the vascular leakage in Hantavirus infected microvascular beds Zaki et al. Also, data presented by Geimonen et al. It is known that CCL5 plays a role in regulation of immune effectors migration to the site of infection Schall et al. Interestingly, mononuclear leukocyte accumulation is a histological hallmark of Hantavirus infection Zaki et al.
One could suggest that increased traffic of immune effectors through the endothelial monolayer may lead to its damage and, thereby, making it more permeable Schall et al. However, it has been suggested that, this alone may not be sufficient to make them virulent and some other virulence factors may play role Matthys et al.
It has been demonstrated that the Hantavirus N protein prevents PKR phosphorylation, which is essential for its enzymatic activity. PKR inhibits virus replication and is essential for establishing antiviral state Goodbourn et al. Therefore, it could be suggested that the glycoproteins and the N protein may interfere with antiviral activity in infected cells, thus promoting viral replication.
The mortality rate may vary from 0. The Hantavirus genome is composed of a three negative sense single stranded RNA segments coding for the N protein, G1 and G2 glycoproteins and viral polymerase. Genetic reassortment between different hantaviruses has been documented both in nature and in vitro. Emerging evidence suggests that the Hantavirus N protein plays a major role not only in virus replication, transcription and virus assembly, but also in establishing favorable environment for virus replication within the host cell.
Pathogenic hantaviruses cause more pronounced changes in transcriptional activity of various cellular genes as compared to non-pathogenic strains. Activation of CCL5 may contribute to Hantavirus-induced leukocyte accumulation in infected tissue and, potentially, to pathogenesis of vascular permeability.
The Hantavirus N protein interacts with host proteins interfering with activation of the antiviral pathways in infected cells. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was supported by Russian Science Foundation grant The work is performed according to the Russian Government Program of Competitive Growth of Kazan Federal University and subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities.
National Center for Biotechnology Information , U. Front Microbiol. Published online Nov Musalwa Muyangwa , 1 Ekaterina V. Martynova , 1 Svetlana F. Khaiboullina , 1, 2 Sergey P. Morzunov , 3 and Albert A. Ekaterina V. Svetlana F. Sergey P. Albert A. Author information Article notes Copyright and License information Disclaimer.
Rizvanov, ur. This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology. Received Jun 2; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Hantaviruses are the members of the family Bunyaviridae that are naturally maintained in the populations of small mammals, mostly rodents. Keywords: Hantavirus, nucleocapsid protein, glycoprotein, reassortment, MxA protein.
Introduction Hantaviruses comprise genus Hantavirus within family Bunyaviridae Elliott, Table 1 Representative hantaviruses and their rodent hosts. Open in a separate window. Hantavirus Genome Structure And Life Cycle Hantavirus virions have spherical shape with size varying between 80 and nm.
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