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Bhat, Tara, Amy Cao et John Yin. « Virus-like Particles : Measures and Biological Functions ». Viruses 14, no 2 (14 février 2022) : 383. http://dx.doi.org/10.3390/v14020383.
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Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.
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Marcus, Philip I., John M. Ngunjiri et Margaret J. Sekellick. « Dynamics of Biologically Active Subpopulations of Influenza Virus : Plaque-Forming, Noninfectious Cell-Killing, and Defective Interfering Particles ». Journal of Virology 83, no 16 (3 juin 2009) : 8122–30. http://dx.doi.org/10.1128/jvi.02680-08.
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ABSTRACT The dynamic changes in the temporal appearance and quantity of a new class of influenza virus, noninfectious cell-killing particles (niCKP), were compared to defective interfering particles (DIP). After a single high-multiplicity passage in MDCK cells of an egg-derived stock that lacked detectable niCKP or DIP, both classes of particles appeared in large numbers (>5 × 108/ml), and the plaque-forming particle (PFP) titer dropped ∼60-fold. After two additional serial high-multiplicity passages the DIP remained relatively constant, the DIP/niCKP ratio reached 10:1, and the PFP had declined by about 10,000-fold. Together, the niCKP and DIP subpopulations constituted ca. 20% of the total hemagglutinating particle population in which these noninfectious biologically active particles (niBAP) were subsumed. DIP neither killed cells nor interfered with the cell-killing (apoptosis-inducing) activity of niCKP or PFP (infectious CKP), even though they blocked the replication of PFP. Relative to the UV-target of ∼13,600 nucleotides (nt) for inactivation of PFP, the UV target for niCKP was ∼2,400 nt, consistent with one of the polymerase subunit genes, and that for DIP was ∼350 nt, consistent with the small DI-RNA responsible for DIP-mediated interference. Thus, niCKP and DIP are viewed as distinct particles with a propensity to form during infection at high multiplicities. These conditions are postulated to cause aberrations in the temporally regulated replication of virus and its packaging, leading to the production of niBAP. DIP have been implicated in the virulence of influenza virus, but the role of niCKP is yet unknown.
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Kim, Gyoung Nyoun, et C. Yong Kang. « Utilization of Homotypic and Heterotypic Proteins of Vesicular Stomatitis Virus by Defective Interfering Particle Genomes for RNA Replication and Virion Assembly : Implications for the Mechanism of Homologous Viral Interference ». Journal of Virology 79, no 15 (1 août 2005) : 9588–96. http://dx.doi.org/10.1128/jvi.79.15.9588-9596.2005.
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ABSTRACT Defective interfering (DI) particles of Indiana serotype of vesicular stomatitis virus (VSVInd) are capable of interfering with the replication of both homotypic VSVInd and heterotypic New Jersey serotype (VSVNJ) standard virus. In contrast, DI particles from VSVNJ do not interfere with the replication of VSVInd standard virus but do interfere with VSVNJ replication. The differences in the interfering activities of VSVInd DI particles and VSVNJ DI particles against heterotypic standard virus were investigated. We examined the utilization of homotypic and heterotypic VSV proteins by DI particle genomic RNAs for replication and maturation into infectious DI particles. Here we show that the RNA-nucleocapsid protein (N) complex of one serotype does not utilize the polymerase complex (P and L) of the other serotype for RNA synthesis, while DI particle genomic RNAs of both serotypes can utilize the N, P, and L proteins of either serotype without serotypic restriction but with differing efficiencies as long as all three proteins are derived from the same serotype. The genomic RNAs of VSVInd DI particles assembled and matured into DI particles by using either homotypic or heterotypic viral proteins. In contrast, VSVNJ DI particles could assemble only with homotypic VSVNJ viral proteins, although the genomic RNAs of VSVNJ DI particles could be replicated by using heterotypic VSVInd N, P, and L proteins. Thus, we concluded that both efficient RNA replication and assembly of DI particles are required for the heterotypic interference by VSV DI particles.
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Hein, Marc D., Heike Kollmus, Pavel Marichal-Gallardo, Sebastian Püttker, Dirk Benndorf, Yvonne Genzel, Klaus Schughart, Sascha Y. Kupke et Udo Reichl. « OP7, a novel influenza A virus defective interfering particle : production, purification, and animal experiments demonstrating antiviral potential ». Applied Microbiology and Biotechnology 105, no 1 (4 décembre 2020) : 129–46. http://dx.doi.org/10.1007/s00253-020-11029-5.
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Abstract The novel influenza A virus (IAV) defective interfering particle “OP7” inhibits IAV replication in a co-infection and was previously suggested as a promising antiviral agent. Here, we report a batch-mode cell culture-based production process for OP7. In the present study, a seed virus containing standard virus (STV) and OP7 was used. The yield of OP7 strongly depended on the production multiplicity of infection. To inactivate infectious STV in the OP7 material, which may cause harm in a potential application, UV irradiation was used. The efficacy of OP7 in this material was preserved, as shown by an in vitro interference assay. Next, steric exclusion chromatography was used to purify and to concentrate (~ 13-fold) the UV-treated material. Finally, administration of produced OP7 material in mice did not show any toxic effects. Furthermore, all mice infected with a lethal dose of IAV survived the infection upon OP7 co-treatment. Thus, the feasibility of a production workflow for OP7 and its potential for antiviral treatment was demonstrated. Key points • OP7 efficacy strongly depended on the multiplicity of infection used for production • Purification by steric exclusion chromatography increased OP7 efficacy • OP7-treated mice were protected against a lethal infection with IAV
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Giachetti, C., et J. J. Holland. « Altered replicase specificity is responsible for resistance to defective interfering particle interference of an Sdi- mutant of vesicular stomatitis virus. » Journal of Virology 62, no 10 (1988) : 3614–21. http://dx.doi.org/10.1128/jvi.62.10.3614-3621.1988.
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Poirier, Enzo Z., Bryan C. Mounce, Kathryn Rozen-Gagnon, Peter Jan Hooikaas, Kenneth A. Stapleford, Gonzalo Moratorio et Marco Vignuzzi. « Low-Fidelity Polymerases of Alphaviruses Recombine at Higher Rates To Overproduce Defective Interfering Particles ». Journal of Virology 90, no 5 (16 décembre 2015) : 2446–54. http://dx.doi.org/10.1128/jvi.02921-15.
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ABSTRACTLow-fidelity RNA-dependent RNA polymerases for many RNA virus mutators have been shown to confer attenuated phenotypes, presumably due to increased mutation rates. Additionally, for many RNA viruses, replication to high titers results in the production of defective interfering particles (DIs) that also attenuate infection. We hypothesized that fidelity, recombination, and DI production are tightly linked. We show that a Sindbis virus mutator replicating at a high multiplicity of infection manifests an earlier and greater accumulation of DIs than its wild-type counterpart. The isolated DIs interfere with the replication of full-length virus in a dose-dependent manner. Importantly, the ability of the mutator virus to overproduce DIs could be linked to an increased recombination frequency. These data confirm that RNA-dependent RNA polymerase fidelity and recombination are inversely correlated for this mutator. Our findings suggest that defective interference resulting from higher recombination rates may be more detrimental to RNA virus mutators than the increase in mutational burden.IMPORTANCEReplication, adaptation, and evolution of RNA viruses rely in large part on their low-fidelity RNA-dependent RNA polymerase. Viruses artificially modified in their polymerases to decrease fidelity (mutator viruses) are attenuatedin vivo, demonstrating the important role of fidelity in viral fitness. However, attenuation was attributed solely to the modification of the viral mutation rate and the accumulation of detrimental point mutations. In this work, we described an additional phenotype of mutator viruses: an increased recombination rate leading to defective interfering particle (DI) overproduction. Because DIs are known for their inhibitory effect on viral replication, our work suggests that fidelity variants may be attenuatedin vivovia several mechanisms. This has important implications in the development of fidelity variants as live attenuated vaccine strains.
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Mao, Yuntao S., Masaki Yamaga, Xiaohui Zhu, Yongjie Wei, Hui-Qiao Sun, Jing Wang, Mia Yun et al. « Essential and unique roles of PIP5K-γ and -α in Fcγ receptor-mediated phagocytosis ». Journal of Cell Biology 184, no 2 (19 janvier 2009) : 281–96. http://dx.doi.org/10.1083/jcb.200806121.
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The actin cytoskeleton is dynamically remodeled during Fcγ receptor (FcγR)-mediated phagocytosis in a phosphatidylinositol (4,5)-bisphosphate (PIP2)-dependent manner. We investigated the role of type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) γ and α isoforms, which synthesize PIP2, during phagocytosis. PIP5K-γ−/− bone marrow–derived macrophages (BMM) have a highly polymerized actin cytoskeleton and are defective in attachment to IgG-opsonized particles and FcγR clustering. Delivery of exogenous PIP2 rescued these defects. PIP5K-γ knockout BMM also have more RhoA and less Rac1 activation, and pharmacological manipulations establish that they contribute to the abnormal phenotype. Likewise, depletion of PIP5K-γ by RNA interference inhibits particle attachment. In contrast, PIP5K-α knockout or silencing has no effect on attachment but inhibits ingestion by decreasing Wiskott-Aldrich syndrome protein activation, and hence actin polymerization, in the nascent phagocytic cup. In addition, PIP5K-γ but not PIP5K-α is transiently activated by spleen tyrosine kinase–mediated phosphorylation. We propose that PIP5K-γ acts upstream of Rac/Rho and that the differential regulation of PIP5K-γ and -α allows them to work in tandem to modulate the actin cytoskeleton during the attachment and ingestion phases of phagocytosis.
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Ou, Yangli, Shuilong He, Chaofan Hu, Jiading Bao et Wenjie Li. « Research on Rolling Bearing Fault Diagnosis Using Improved Majorization-Minimization-Based Total Variation and Empirical Wavelet Transform ». Shock and Vibration 2020 (15 mai 2020) : 1–11. http://dx.doi.org/10.1155/2020/3218564.
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Bearings are among the most widely used core components in mechanical equipment. Their failure creates the potential for serious accidents and economic losses. Vibration signature analyses are the most common approach to assess the viability of bearings due to its ease of measurement and high correlation with structural dynamics. However, the collected vibration signals of rolling bearings are usually nonstationary and are inevitably accompanied by noise interference. This makes it difficult to extract the feature frequency for the failed bearing and affects the diagnosis accuracy. The majorization-minimization-based total variation (TV-MM) denoising algorithm effectively removes the noise interference from the signal and highlights the related feature information. The value of its main parameter λ determines the quality of the denoising effect. However, manually selecting parameters requires professional experience in a process that it is time-consuming and laborious, while the use of genetic algorithms is cumbersome. Therefore, an improved particle swarm algorithm (IPSO) is used to find the optimal solution of λ. The IPSO utilises the mutation concept in genetic algorithms to reinitialise the particles with a certain probability after each update. In addition, the empirical wavelet transform (EWT) is an adaptive signal processing method suitable for processing nonlinear and nonstationary signals. Therefore, this paper presents an ensemble analysis method that combines the IPSO, TV-MM, and EWT. First, IPSO is used to optimise the denoising parameter λ. The TV-MM under this parameter effectively removes the background noise interference and improves the accuracy of the subsequent modal decomposition. Then, the EWT is used for the adaptive division to produce a set of sequences. Finally, Hilbert envelope demodulation is performed on each component to realise fault diagnosis. The results from simulations and signals received from defective bearings with outer race fault, inner race fault, and rolling element fault demonstrate the effectiveness of the proposed method for fault diagnosis of rolling bearings.
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Rossi, Marika, Marta Vallino, Simona Abbà, Marina Ciuffo, Raffaella Balestrini, Andrea Genre et Massimo Turina. « The Importance of the KR-Rich Region of the Coat Protein of Ourmia melon virus for Host Specificity, Tissue Tropism, and Interference With Antiviral Defense ». Molecular Plant-Microbe Interactions® 28, no 1 (janvier 2015) : 30–41. http://dx.doi.org/10.1094/mpmi-07-14-0197-r.
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The N-terminal region of the Ourmia melon virus (OuMV) coat protein (CP) contains a short lysine/arginine-rich (KR) region. By alanine scanning mutagenesis, we showed that the KR region influences pathogenicity and virulence of OuMV without altering viral particle assembly. A mutant, called OuMV6710, with three basic residue substitutions in the KR region, was impaired in the ability to maintain the initial systemic infection in Nicotiana benthamiana and to infect both cucumber and melon plants systemically. The integrity of this protein region was also crucial for encapsidation of viral genomic RNA; in fact, certain mutations within the KR region partially compromised the RNA encapsidation efficiency of the CP. In Arabidopsis thaliana Col-0, OuMV6710 was impaired in particle accumulation; however, this phenotype was abolished in dcl2/dcl4 and dcl2/dcl3/dcl4 Arabidopsis mutants defective for antiviral silencing. Moreover, in contrast to CPwt, in situ immunolocalization experiments indicated that CP6710 accumulates efficiently in the spongy mesophyll tissue of infected N. benthamiana and A. thaliana leaves but only occasionally infects palisade tissues. These results provided strong evidence of a crucial role for OuMV CP during viral infection and highlighted the relevance of the KR region in determining tissue tropism, host range, pathogenicity, and RNA affinity, which may be all correlated with a possible CP silencing-suppression activity.
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Bauerová, Petra, Adriana Šindelářová, Štěpán Rychlík, Zbyněk Novák et Josef Keder. « Low-Cost Air Quality Sensors : One-Year Field Comparative Measurement of Different Gas Sensors and Particle Counters with Reference Monitors at Tušimice Observatory ». Atmosphere 11, no 5 (11 mai 2020) : 492. http://dx.doi.org/10.3390/atmos11050492.
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With attention increasing regarding the level of air pollution in different metropolitan and industrial areas worldwide, interest in expanding the monitoring networks by low-cost air quality sensors is also increasing. Although the role of these small and affordable sensors is rather supplementary, determination of the measurement uncertainty is one of the main questions of their applicability because there is no certificate for quality assurance of these non-reference technologies. This paper presents the results of almost one-year field testing measurements, when the data from different low-cost sensors (for SO2, NO2, O3, and CO: Cairclip, Envea, FR; for PM1, PM2.5, and PM10: PMS7003, Plantower, CHN, and OPC-N2, Alphasense, UK) were compared with co-located reference monitors used within the Czech national ambient air quality monitoring network. The results showed that in addition to the given reduced measurement accuracy of the sensors, the data quality depends on the early detection of defective units and changes caused by the effect of meteorological conditions (effect of air temperature and humidity on gas sensors and effect of air humidity with condensation conditions on particle counters), or by the interference of different pollutants (especially in gas sensors). Comparative measurement is necessary prior to each sensor’s field applications.
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La Porte, Annalena, Jennifer Cano, Xuhong Wu, Doyel Mitra et Ganjam V. Kalpana. « An Essential Role of INI1/hSNF5 Chromatin Remodeling Protein in HIV-1 Posttranscriptional Events and Gag/Gag-Pol Stability ». Journal of Virology 90, no 21 (24 août 2016) : 9889–904. http://dx.doi.org/10.1128/jvi.00323-16.
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ABSTRACTINI1/hSNF5/SMARCB1/BAF47 is an HIV-specific integrase (IN)-binding protein that influences HIV-1 transcription and particle production. INI1 binds to SAP18 (Sin3a-associated protein, 18 kDa), and both INI1 and SAP18 are incorporated into HIV-1 virions. To determine the significance of INI1 and the INI1-SAP18 interaction during HIV-1 replication, we isolated a panel ofSAP18-interaction-defective (SID)-INI1 mutants using a yeast reverse two-hybrid screen. The SID-INI1 mutants, which retained the ability to bind to IN, cMYC, and INI1 but were impaired for binding to SAP18, were tested for their effects on HIV-1 particle production. SID-INI1 dramatically reduced the intracellular Gag/Gag-Pol protein levels and, in addition, decreased viral particle production. The SID-INI1-mediated effects were less dramatic intranscomplementation assays using IN deletion mutant viruses with Vpr-reverse transcriptase (RT)-IN. SID-INI1 did not inhibit long-terminal-repeat (LTR)-mediated transcription, but it marginally decreased the steady-stategagRNA levels, suggesting a posttranscriptional effect. Pulse-chase analysis indicated that in SID-INI1-expressing cells, the pr55Gag levels decreased rapidly. RNA interference analysis indicated that small hairpin RNA (shRNA)-mediated knockdown ofINI1reduced the intracellular Gag/Gag-Pol levels and further inhibited HIV-1 particle production. These results suggest that SID-INI1 mutants inhibit multiple stages of posttranscriptional events of HIV-1 replication, including intracellular Gag/Gag-Pol RNA and protein levels, which in turn inhibits assembly and particle production. Interfering INI1 leads to a decrease in particle production and Gag/Gag-Pol protein levels. Understanding the role of INI1 and SAP18 in HIV-1 replication is likely to provide novel insight into the stability of Gag/Gag-Pol, which may lead to the development of novel therapeutic strategies to inhibit HIV-1 late events.IMPORTANCESignificant gaps exist in our current understanding of the mechanisms and host factors that influence HIV-1 posttranscriptional events, includinggagRNA levels, Gag/Gag-Pol protein levels, assembly, and particle production. Our previous studies suggested that the IN-binding host factor INI1 plays a role in HIV-1 assembly. An ectopically expressed minimal IN-binding domain of INI1, S6, potently and selectively inhibited HIV-1 Gag/Gag-Pol trafficking and particle production. However, whether or not endogenous INI1 and its interacting partners, such as SAP18, are required for late events was unknown. Here, we report that endogenous INI1 and its interaction with SAP18 are necessary to maintain intracellular levels of Gag/Gag-Pol and for particle production. Interfering INI1 or the INI1-SAP18 interaction leads to the impairment of these processes, suggesting a novel strategy for inhibiting posttranscriptional events of HIV-1 replication.
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Boopalan, Navaamsini, Agileswari K. Ramasamy, Farrukh Nagi et Ammar Ahmed Alkahtani. « Planar Array Failed Element(s) Radiation Pattern Correction : A Comparison ». Applied Sciences 11, no 19 (4 octobre 2021) : 9234. http://dx.doi.org/10.3390/app11199234.
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Phased arrays are widely used in different fields, such as broadcasting, radar, optics, and space communications. The principle of phased arrays is to generate a directed signal from a large number of antennas to be steered at any desired angle. This, however, increases the probability of defective elements in an array. Faulty elements in an array cause asymmetry and result in increased sidelobe levels which rigorously distort the radiation pattern. Increased sidelobe radiation wastes energy and can cause interference by radiating and receiving signals in unintended directions. Therefore, it is necessary to find a method that can provide accuracy in the radiation pattern transmitted or received in the presence of failed element(s) in an array. This paper compares the few available optimization methods, namely, simulated annealing (SA), Genetic Algorithm (GA), Particle Swarm Optimization (PSO), and Pattern Search (PS) methods. For each method, various types of failures were examined, and the most suitable techniques to recover the far-field radiation are recommended. The optimization is then carried out by selecting the optimal weights of the remaining working elements in the planar array. The optimized radiation pattern’s efficiency was evaluated by comparing the Signal to Noise Ratio (SNR) value of the optimized radiation with reference and failed radiation patterns. The PSO method showed a better performance compared to all the other methods in reducing the failed radiation pattern’s SNR value. In various types of failure tests, this method reduced the failed radiation pattern’s SNR from 1 to 10 dB. This method also successfully produced a radiation pattern that closely matches the reference pattern before any failed element(s) are presented in the array. The life cycle of a planar array system with faulty elements can be increased by optimizing the remaining active elements in the array with the PSO method. It also reduces the cost of restoring and replacing the failed elements in an array regularly. This approach also prevents near-field measurement that requires complicated processes using costly equipment.
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Akpinar, Fulya, Bahar Inankur et John Yin. « Spatial-Temporal Patterns of Viral Amplification and Interference Initiated by a Single Infected Cell ». Journal of Virology 90, no 16 (8 juin 2016) : 7552–66. http://dx.doi.org/10.1128/jvi.00807-16.
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ABSTRACTWhen viruses infect their host cells, they can make defective virus-like particles along with intact virus. Cells coinfected with virus and defective particles often exhibit interference with virus growth caused by the competition for resources by defective genomes. Recent reports of the coexistence and cotransmission of such defective interfering particles (DIPs)in vivo, across epidemiological length and time scales, suggest a role in viral pathogenesis, but it is not known how DIPs impact infection spread, even under controlled culture conditions. Using fluorescence microscopy, we quantified coinfections of vesicular stomatitis virus (VSV) expressing a fluorescent reporter protein and its DIPs on BHK-21 host cell monolayers. We found that viral gene expression was more delayed, infections spread more slowly, and patterns of spread became more “patchy” with higher DIP inputs to the initial cell. To examine how infection spread might depend on the behavior of the initial coinfected cell, we built a computational model, adapting a cellular automaton (CA) approach to incorporate kinetic data on virus growth for the first time. Specifically, changes in observed patterns of infection spread could be directly linked to previous high-throughput single-cell measures of virus-DIP coinfection. The CA model also provided testable hypotheses on the spatial-temporal distribution of the DIPs, which remain governed by their predator-prey interaction. More generally, this work offers a data-driven computational modeling approach for better understanding of how single infected cells impact the multiround spread of virus infections across cell populations.IMPORTANCEDefective interfering particles (DIPs) compete with intact virus, depleting host cell resources that are essential for virus growth and infection spread. However, it is not known how such competition, strong or weak, ultimately affects the way in which infections spread and cause disease. In this study, we address this unmet need by developing an integrated experimental-computational approach, which sheds new light on how infections spread. We anticipate that our approach will also be useful in the development of DIPs as therapeutic agents to manage the spread of viral infections.
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Yuan, Thomas Ta-Tung, Min-Hui Lin, Ding-Shinn Chen et Chiaho Shih. « A Defective Interference-Like Phenomenon of Human Hepatitis B Virus in Chronic Carriers ». Journal of Virology 72, no 1 (1 janvier 1998) : 578–84. http://dx.doi.org/10.1128/jvi.72.1.578-584.1998.
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ABSTRACT Defective interfering (DI) particles have been found in many RNA and DNA viruses of bacteria, plants, and animals since their first discovery in influenza virus. However, this fundamental phenomenon has not been demonstrated in human natural infections. Using a new approach, here we provide the first experimental evidence for the existence of DI-like viruses in human chronic carriers of hepatitis B virus (HBV). Functional characterization of naturally occurring core internal deletion (CID) variants of HBV revealed all of the features of DI particles. When equal amounts of wild-type and CID variant DNAs were cotransfected into a human hepatoma cell line, Huh7, a three- to fivefold enrichment of CID variants was most often observed. The fluctuations of the virus populations between CID variants and helper HBV in three chronic carriers are reminiscent of the cycling phenomenon in other DI viral systems. This finding has important implications for chronic viral hepatitis and other chronic progressive viral diseases.
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Debnath, N. C., R. Tiernery, B. K. Sil, M. R. Wills et A. D. T. Barrett. « In vitro homotypic and heterotypic interference by defective interfering particles of West Nile virus ». Journal of General Virology 72, no 11 (1 novembre 1991) : 2705–11. http://dx.doi.org/10.1099/0022-1317-72-11-2705.
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Bernier, R., et M. Tremblay. « Homologous interference resulting from the presence of defective particles of human immunodeficiency virus type 1. » Journal of virology 69, no 1 (1995) : 291–300. http://dx.doi.org/10.1128/jvi.69.1.291-300.1995.
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Huang, Alice S., Ti-yun Wu, Tilahun Yilma et Gertrude Lanman. « Characterization of virulent isolates of vesicular stomatitis virus in relation to interference by defective particles ». Microbial Pathogenesis 1, no 2 (avril 1986) : 205–15. http://dx.doi.org/10.1016/0882-4010(86)90022-7.
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Salas-Benito, Juan Santiago, et Mónica De Nova-Ocampo. « Viral Interference and Persistence in Mosquito-Borne Flaviviruses ». Journal of Immunology Research 2015 (2015) : 1–14. http://dx.doi.org/10.1155/2015/873404.
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Mosquito-borne flaviviruses are important pathogens for humans, and the detection of two or more flaviviruses cocirculating in the same geographic area has often been reported. However, the epidemiological impact remains to be determined. Mosquito-borne flaviviruses are primarily transmitted throughAedesandCulexmosquitoes; these viruses establish a life-long or persistent infection without apparent pathological effects. This establishment requires a balance between virus replication and the antiviral host response. Viral interference is a phenomenon whereby one virus inhibits the replication of other viruses, and this condition is frequently associated with persistent infections. Viral interference and persistent infection are determined by several factors, such as defective interfering particles, competition for cellular factors required for translation/replication, and the host antiviral response. The interaction between two flaviviruses typically results in viral interference, indicating that these viruses share common features during the replicative cycle in the vector. The potential mechanisms involved in these processes are reviewed here.
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Wu, C. A., L. Harper et T. Ben-Porat. « Molecular basis for interference of defective interfering particles of pseudorabies virus with replication of standard virus. » Journal of Virology 59, no 2 (1986) : 308–17. http://dx.doi.org/10.1128/jvi.59.2.308-317.1986.
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Balzanelli, Mario Giosuè, Pietro Distratis, Gianna Dipalma, Luigi Vimercati, Alessio Danilo Inchingolo, Rita Lazzaro, Sergey Khachatur Aityan et al. « Sars-CoV-2 Virus Infection May Interfere CD34+ Hematopoietic Stem Cells and Megakaryocyte–Erythroid Progenitors Differentiation Contributing to Platelet Defection towards Insurgence of Thrombocytopenia and Thrombophilia ». Microorganisms 9, no 8 (30 juillet 2021) : 1632. http://dx.doi.org/10.3390/microorganisms9081632.
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To date, several cases of thrombosis have been confirmed to be related to Sars-CoV-2 infection. Multiple attempts detected the prolonged occurrence of Sars-CoV-2 viral RNA (long COVID) in whole blood suggesting that virus byproducts may remain within cells and tissues well over the disease has finished. Patients may develop severe thrombocytopenia, acute anemia of inflammation and, systemic thrombosis with the fatal course of disease, which is suggestive of further interferences of Sars-CoV-2 on hematopoietic stem cells (HSCs) within the differentiation process towards erythroid and megakaryocytic cells. Therefore, we speculated whether Sars-CoV-2 propagates in or compartmentalizes with hematopoietic progenitor, erythroid, and megakaryocytic cells as the main cause of thrombotic events in either COVID-19 patients or vaccinated individuals. Results: The Sars-CoV-2 RNA replication, protein translation and infectious particle formation as the spike proteins in hematopoietic cell lines take place via the angiotensin-converting enzyme 2 (ACE2) entry pathway within primary CD34+ HSCs inducing, ex vivo, the formation of defected erythroid and megakaryocytic cells that eventually become targets of humoral and adaptive immune cells. Conclusions: Viral particles from affected CD34+ HSCs or the cellular component of RBC units and eventually platelets, present the greatest risk for sever thrombosis-transmitted Sars-CoV-2 infections.
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Akpinar, Fulya, Andrea Timm et John Yin. « High-Throughput Single-Cell Kinetics of Virus Infections in the Presence of Defective Interfering Particles ». Journal of Virology 90, no 3 (25 novembre 2015) : 1599–612. http://dx.doi.org/10.1128/jvi.02190-15.
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ABSTRACTDefective interfering particles (DIPs) are virus mutants that lack essential genes for growth. In coinfections with helper virus, the diversion of viral proteins to the replication and packaging of DIP genomes can interfere with virus production. Mounting cases of DIPs and DIP-like genomes in clinical and natural isolates, as well as growing interest in DIP-based therapies, underscore a need to better elucidate how DIPs work. DIP activity is primarily measured by its inhibition of virus infection yield, an endpoint that masks the dynamic and potentially diverse individual cell behaviors. Using vesicular stomatitis virus (VSV) as a model, we coinfected BHK cells with VSV DIPs and recombinant helper virus carrying a gene encoding a red fluorescent protein (RFP) whose expression correlates with the timing and level of virus release. For single cells within a monolayer, 10 DIPs per cell suppressed the reporter expression in only 1.2% of the cells. In most cells, it slowed and reduced viral gene expression, manifested as a shift in mean latent time from 4 to 6 h and reduced virus yields by 10-fold. For single cells isolated in microwells, DIP effects were more pronounced, reducing virus yields by 100-fold and extending latent times to 12 h, including individual instances above 20 h. Together, these results suggest that direct or indirect cell-cell interactions prevent most coinfected cells from being completely suppressed by DIPs. Finally, a gamma distribution model captures well how the infection kinetics quantitatively depends on the DIP dose. Such models will be useful for advancing a predictive biology of DIP-associated virus growth and infection spread.IMPORTANCEDuring the last century, basic studies in virology have focused on developing a molecular mechanistic understanding of how infectious viruses reproduce in their living host cells. However, over the last 10 years, the advent of deep sequencing and other powerful technologies has revealed in natural and patient infections that viruses do not act alone. Instead, viruses are often accompanied by defective virus-like particles that carry large deletions in their genomes and fail to replicate on their own. Coinfections of viable and defective viruses behave in unpredictable ways, but they often interfere with normal virus growth, potentially enabling infections to evade host immune surveillance. In the current study, controlled levels of defective viruses are coinfected with viable viruses that have been engineered to express a fluorescent reporter protein during infection. Unique profiles of reporter expression acquired from thousands of coinfected cells reveal how interference acts at multiple stages of infection.
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Vashishtha, Govind, et Rajesh Kumar. « Autocorrelation energy and aquila optimizer for MED filtering of sound signal to detect bearing defect in Francis turbine ». Measurement Science and Technology 33, no 1 (20 octobre 2021) : 015006. http://dx.doi.org/10.1088/1361-6501/ac2cf2.
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Abstract This paper presents a method to detect the bearing defects in Francis turbine by minimal entropy deconvolution (MED) filter making use of a sound signal. As the outputs of MED are mainly influenced by the filter length hence its appropriate selection is very necessary to recover a single random pulse in case of a weak faulty signal. The optimal filter length selection is done by Aquila optimizer adaptively which uses the autocorrelation energy as its fitness function. Experimentation done on defective bearings of Francis turbine suggested that the proposed method exposes periodic impulses effectively in case of a weak faulty signal or when the fault signal is embedded within the noise or interferences from other parts of Francis turbine. The proposed fault identification method has been compared with other models of MED such as particle swarm optimization -MED and maximum correlated kurtosis deconvolution. Results obtained reveals that the proposed method is superior in identifying the faulty signal embedded with heavy noise.
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Lancaster, Morag U., Stuart I. Hodgetts, John S. Mackenzie et Nadezda Urosevic. « Characterization of Defective Viral RNA Produced during Persistent Infection of Vero Cells with Murray Valley Encephalitis Virus ». Journal of Virology 72, no 3 (1 mars 1998) : 2474–82. http://dx.doi.org/10.1128/jvi.72.3.2474-2482.1998.
Texte intégralRésumé :
ABSTRACT Defective interfering viral particles are readily produced in cell culture after a high multiplicity of infection with many animal RNA viruses. Due to defects that they carry in their genomes, their life cycle needs to be complemented by the helper functions provided by a parental virus which makes them both dependent on and competitive with the parental virus. In many instances, this may cause the abrogation of a lytic cycle of the parental virus, leading to a persistent infection. In this paper, we describe for the first time the presence of truncated or defective interfering viral RNAs produced in Vero cells persistently infected with the flavivirus Murray Valley encephalitis virus. While these RNAs have not been detected in acutely infected Vero cells, their appearance coincided with the establishment of persistent infection. We also show for the first time that the defective viral RNAs replicate well in both cell culture and cell-free virus replication systems, indicating that they may interfere with the replication of parental virus at the level of viral RNA synthesis. Significantly, structural analyses of these RNA species including nucleotide sequencing have revealed that they carry similar nucleotide deletions encompassing the genes coding for the prM and E proteins and various gene segments coding for the N terminus of the NS1 protein. These deletions are in frame, allowing the synthesis of truncated NS1 proteins to occur in persistently infected cells. This may have further implications for the interference with the parental virus at the level of viral RNA synthesis in addition to a major one at the level of virion assembly and release.
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Jaber, Tareq, Christopher R. Bohl, Gentry L. Lewis, Charles Wood, John T. West et Robert A. Weldon. « Human Ubc9 Contributes to Production of Fully Infectious Human Immunodeficiency Virus Type 1 Virions ». Journal of Virology 83, no 20 (29 juillet 2009) : 10448–59. http://dx.doi.org/10.1128/jvi.00237-09.
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ABSTRACT Ubc9 was identified as a cellular protein that interacts with the Gag protein of Mason-Pfizer monkey virus. We show here that Ubc9 also interacts with the human immunodeficiency virus type 1 (HIV-1) Gag protein and that their interaction is important for virus replication. Gag was found to colocalize with Ubc9 predominantly at perinuclear puncta. While cells in which Ubc9 expression was suppressed with RNA interference produced normal numbers of virions, these particles were 8- to 10-fold less infectious than those produced in the presence of Ubc9. The nature of this defect was assayed for dependence on Ubc9 during viral assembly, trafficking, and Env incorporation. The Gag-mediated assembly of virus particles and protease-mediated processing of Gag and Gag-Pol were unchanged in the absence of Ubc9. However, the stability of the cell-associated Env glycoprotein was decreased and Env incorporation into released virions was altered. Interestingly, overexpression of the Ubc9 trans-dominant-negative mutant C93A, which is a defective E2-SUMO-1 conjugase, suggests that this activity may not be required for interaction with Gag, virion assembly, or infectivity. This finding demonstrates that Ubc9 plays an important role in the production of infectious HIV-1 virions.
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Yerimbetova, Dana, Artem Kozlovskiy, Valeriy Stepanenko et Kassym Zhumadilov. « Application of UV-Vis Optical Spectroscopy and X-ray Diffraction Methods to Describe the Effect of Alpha-Emitting Radionuclides (Radon) When They Are Detected by Solid-State Film Detectors ». Polymers 14, no 13 (4 juillet 2022) : 2731. http://dx.doi.org/10.3390/polym14132731.
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This work aims to evaluate the application of optical and X-ray spectroscopy methods to determine the effect of alpha-emitting radionuclides on the properties of solid-state nuclear track detectors (SSNTD) based on nitrocellulose during their detection. The proposed estimation methods are alternative methods to standard technologies, making it possible to determine the concentration of radon and its decay products without the chemical etching of film detectors and subsequent direct counting of the formed latent tracks from interacting particles. During the research, it was found that the use of optical spectroscopy and X-ray diffraction methods makes it possible to qualitatively determine the irradiation effect on changes in the properties of film detectors when α-particles with different energies pass through them. At the same time, a comparison of the data of optical spectroscopy, X-ray diffraction and the visualization of latent tracks after chemical etching made it possible to establish that a part of the registered α-particles in living quarters has an energy of less than 2.5 MeV, which is not enough to pass through the polymer film of the detector, as a result of which well-like tracks are formed. An increase in the intensity of the interference bands in the region above 700 nm and a decrease in the intensity of diffraction reflection characterized the changes in optical transmission. The penetration of the α-particles through the detecting film decreases the film’s transmission capacity, forming an anisotropic change in diffraction reflections associated with a change in the film’s structure and defective fractions distorting the molecular structure.
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Kreger, Jesse, Natalia L. Komarova et Dominik Wodarz. « A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV ». PLOS Computational Biology 17, no 12 (22 décembre 2021) : e1009713. http://dx.doi.org/10.1371/journal.pcbi.1009713.
Texte intégralRésumé :
To study viral evolutionary processes within patients, mathematical models have been instrumental. Yet, the need for stochastic simulations of minority mutant dynamics can pose computational challenges, especially in heterogeneous systems where very large and very small sub-populations coexist. Here, we describe a hybrid stochastic-deterministic algorithm to simulate mutant evolution in large viral populations, such as acute HIV-1 infection, and further include the multiple infection of cells. We demonstrate that the hybrid method can approximate the fully stochastic dynamics with sufficient accuracy at a fraction of the computational time, and quantify evolutionary end points that cannot be expressed by deterministic models, such as the mutant distribution or the probability of mutant existence at a given infected cell population size. We apply this method to study the role of multiple infection and intracellular interactions among different virus strains (such as complementation and interference) for mutant evolution. Multiple infection is predicted to increase the number of mutants at a given infected cell population size, due to a larger number of infection events. We further find that viral complementation can significantly enhance the spread of disadvantageous mutants, but only in select circumstances: it requires the occurrence of direct cell-to-cell transmission through virological synapses, as well as a substantial fitness disadvantage of the mutant, most likely corresponding to defective virus particles. This, however, likely has strong biological consequences because defective viruses can carry genetic diversity that can be incorporated into functional virus genomes via recombination. Through this mechanism, synaptic transmission in HIV might promote virus evolvability.
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Dimmock, Nigel J., et Anthony C. Marriott. « In vivo antiviral activity : defective interfering virus protects better against virulent Influenza A virus than avirulent virus ». Journal of General Virology 87, no 5 (1 mai 2006) : 1259–65. http://dx.doi.org/10.1099/vir.0.81678-0.
Texte intégralRésumé :
A defective interfering (DI) virus differs from the infectious virus from which it originated in having at least one major deletion in its genome. Such DI genomes are replicated only in cells infected in trans with homologous infectious virus and, as their name implies, they interfere with infectious virus replication and reduce the yield of progeny virus. This potent antiviral activity has been abundantly demonstrated in cell culture with many different DI animal viruses, but few in vivo examples have been reported, with the notable exception of DI Influenza A virus. A clue to this general lack of success arose recently when an anomaly was discovered in which DI Influenza A virus solidly protected mice from lethal disease caused by A/PR/8/34 (H1N1) and A/WSN/40 (H1N1) viruses, but protected only marginally from disease caused by A/Japan/305/57 (A/Jap, H2N2). The problem was not any incompatibility between the DI and infectious genomes, as A/Jap replicated the DI RNA in vivo. However, A/Jap required 300-fold more mouse infectious units to cause clinical disease than A/PR8 and it was hypothesized that it was this excess of infectivity that abrogated the protective activity of the DI virus. This conclusion was verified by varying the proportions of DI and challenge virus and showing that increasing the DI virus : infectious virus ratio in infected mice resulted in interference. Thus, counter-intuitively, DI virus is most effective against viruses that cause disease with low numbers of particles, i.e. virulent viruses.
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Opi, Sandrine, Hiroaki Takeuchi, Sandra Kao, Mohammad A. Khan, Eri Miyagi, Ritu Goila-Gaur, Yasumasa Iwatani, Judith G. Levin et Klaus Strebel. « Monomeric APOBEC3G Is Catalytically Active and Has Antiviral Activity ». Journal of Virology 80, no 10 (15 mai 2006) : 4673–82. http://dx.doi.org/10.1128/jvi.80.10.4673-4682.2006.
Texte intégralRésumé :
ABSTRACT APOBEC3G (APO3G) is a cytidine deaminase that restricts replication of vif-defective human immunodeficiency virus type 1 (HIV-1). Like other members of the cellular deaminase family, APO3G has the propensity to form homo-multimers. In the current study, we investigated the functional determinants for multimerization of human APO3G and studied the role of APO3G multimerization for catalytic activity, virus encapsidation, and antiviral activity. We found that human APO3G is capable of forming multimeric complexes in transfected HeLa cells. Interestingly, multimerization of APO3G was exquisitely sensitive to RNase treatment, suggesting that interaction of APO3G subunits is facilitated or stabilized by an RNA bridge. Mutation of a conserved cysteine residue (C97) that is part of an N-terminal zinc-finger motif in APO3G abolished multimerization of APO3G; however, the C97 mutation inhibited neither in vitro deaminase activity nor antiviral function of APO3G. These results suggest that monomeric APO3G is both catalytically active and has antiviral activity. Interference studies employing either catalytically inactive or packaging-incompetent APO3G variants suggest that wild-type APO3G is packaged into HIV-1 particles in monomeric form. These results provide novel insights into the catalytic function and antiviral property of APO3G and demonstrate an important role for C97 in the RNA-dependent multimerization of this protein.
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Jadwin, Joshua A., Victoria Rudd, Paola Sette, Swathi Challa et Fadila Bouamr. « Late Domain-Independent Rescue of a Release-Deficient Moloney Murine Leukemia Virus by the Ubiquitin Ligase Itch ». Journal of Virology 84, no 2 (28 octobre 2009) : 704–15. http://dx.doi.org/10.1128/jvi.01319-09.
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ABSTRACT Moloney murine leukemia virus (MoMLV) Gag utilizes its late (L) domain motif PPPY to bind members of the Nedd4-like ubiquitin ligase family. These interactions recruit components of the cell's budding machinery that are critical for virus release. MoMLV Gag contains two additional L domains, PSAP and LYPAL, that are believed to drive residual MoMLV release via interactions with cellular proteins Tsg101 and Alix, respectively. We found that overexpression of Tsg101 or Alix failed to rescue the release of PPPY-deficient MoMLV via these other L domains. However, low-level expression of the ubiquitin ligase Itch potently rescued the release and infectivity of MoMLV lacking PPPY function. In contrast, other ubiquitin ligases such as WWP1, Nedd4.1, Nedd4.2, and Nedd4.2s did not rescue this release-deficient virus. Efficient rescue required the ubiquitin ligase activity of Itch and an intact C2 domain but not presence of the endophilin-binding site. Additionally, we found Itch to immunoprecipitate with MoMLV Gag lacking the PPPY motif and to be incorporated into rescued MoMLV particles. The PSAP and LYPAL motifs were dispensable for Itch-mediated virus rescue, and their absence did not affect the incorporation of Itch into the rescued particles. Itch-mediated rescue of release-defective MoMLV was sensitive to inhibition by dominant-negative versions of ESCRT-III components and the VPS4 AAA ATPase, indicating that Itch-mediated correction of MoMLV release defects requires the integrity of the host vacuolar sorting protein pathway. RNA interference knockdown of Itch suppressed the residual release of the MoMLV lacking the PPPY motif. Interestingly, Itch stimulation of the PPPY-deficient MoMLV release was accompanied by the enhancement of Gag ubiquitination and the appearance of new ubiquitinated Gag proteins in virions. Together, these results suggest that Itch can facilitate MoMLV release in an L domain-independent manner via a mechanism that requires the host budding machinery and involves Gag ubiquitination.
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Olivetta, Eleonora, Katherina Pugliese, Roberta Bona, Paola D'Aloja, Flavia Ferrantelli, Anna Claudia Santarcangelo, Gianfranco Mattia, Paola Verani et Maurizio Federico. « cis Expression of the F12 Human Immunodeficiency Virus (HIV) Nef Allele Transforms the Highly Productive NL4-3 HIV Type 1 to a Replication-Defective Strain : Involvement of both Env gp41 and CD4 Intracytoplasmic Tails ». Journal of Virology 74, no 1 (1 janvier 2000) : 483–92. http://dx.doi.org/10.1128/jvi.74.1.483-492.2000.
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ABSTRACT F12 human immunodeficiency virus type 1 (HIV-1) nef is a naturally occurring nef mutant cloned from the provirus of a nonproductive, nondefective, and interfering HIV-1 variant (F12-HIV). We have already shown that cells stably transfected with a vector expressing the F12-HIV nef allele do not downregulate CD4 receptors and, more peculiarly, become resistant to the replication of wild type (wt) HIV. In order to investigate the mechanism of action of such an HIV inhibition, the F12-HIVnef gene was expressed in the context of the NL4-3 HIV-1 infectious molecular clone by replacing the wt nef gene (NL4-3/chi). Through this experimental approach we established the following. First, NL4-3/chi and nef-defective (Δnef) NL4-3 viral particles behave very similarly in terms of viral entry and HIV protein production during the first replicative cycle. Second, no viral particles were produced from cells infected with NL4-3/chi virions, whatever the multiplicity of infection used. The viral inhibition apparently occurs at level of viral assembling and/or release. Third, this block could not be relieved by in-trans expression of wt nef. Finally, NL4-3/chi reverts to a producer HIV strain when F12-HIV Nef is deprived of its myristoyl residue. Through a CD4 downregulation competition assay, we demonstrated that F12-HIV Nef protein potently inhibits the CD4 downregulation induced by wt Nef. Moreover, we observed a redistribution of CD4 receptors at the cell margin induced by F12-HIV Nef. These observations strongly suggest that F12-HIV Nef maintains the ability to interact with the intracytoplasmic tail of the CD4 receptor molecule. Remarkably, we distinguished the intracytoplasmic tails of Env gp41 and CD4 as, respectively, viral and cellular targets of the F12-HIV Nef-induced viral retention. For the first time, the inhibition of the viral life cycle by means of in-cis expression of a Nef mutant is here reported. Delineation of the F12-HIV Nef mechanism of action may offer additional approaches to interference with the propagation of HIV infection.
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Noble, Beth, Paolo Abada, Juan Nunez-Iglesias et Paula M. Cannon. « Recruitment of the Adaptor Protein 2 Complex by the Human Immunodeficiency Virus Type 2 Envelope Protein Is Necessary for High Levels of Virus Release ». Journal of Virology 80, no 6 (15 mars 2006) : 2924–32. http://dx.doi.org/10.1128/jvi.80.6.2924-2932.2006.
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ABSTRACT The envelope (Env) protein of human immunodeficiency virus type 2 (HIV-2) and the HIV-1 Vpu protein stimulate the release of retroviral particles from human cells that restrict virus production, an activity that we call the enhancement of virus release (EVR). We have previously shown that two separate domains in the HIV-2 envelope protein are required for this activity: a glycine-tyrosine-x-x-hydrophobic (GYxxθ) motif in the cytoplasmic tail and an unmapped region in the ectodomain of the protein. We here report that the cellular partner of the GYxxθ motif is the adaptor protein complex AP-2. The mutation of this motif or the depletion of AP-2 by RNA interference abrogated EVR activity and changed the cellular distribution of the Env from a predominantly punctate pattern to a more diffuse distribution. Since the L domain of equine infectious anemia virus (EIAV) contains a Yxxθ motif that interacts with AP-2, we used both wild-type and L domain-defective particles of HIV-1 and EIAV to examine whether the HIV-2 Env EVR function was analogous to L domain activity. We observed that the production of all particles was stimulated by HIV-2 Env or Vpu, suggesting that the L domain and EVR activities play independent roles in the release of retroviruses. Interestingly, we found that the cytoplasmic tail of the murine leukemia virus (MLV) Env could functionally substitute for the HIV-2 Env tail, but it did so in a manner that did not require a Yxxθ motif or AP-2. The cellular distribution of the chimeric HIV-2/MLV Env was significantly less punctate than the wild-type Env, although confocal analysis revealed an overlap in the steady-state locations of the two proteins. Taken together, these data suggest that the essential GYxxθ motif in the HIV-2 Env tail recruits AP-2 in order to direct Env to a cellular pathway or location that is necessary for its ability to enhance virus release but that an alternate mechanism provided by the MLV Env tail can functionally substitute.
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Mokry, Rebekah L., Megan L. Schumacher, Neil Hogg et Scott S. Terhune. « Nitric Oxide Circumvents Virus-Mediated Metabolic Regulation during Human Cytomegalovirus Infection ». mBio 11, no 6 (15 décembre 2020) : e02630-20. http://dx.doi.org/10.1128/mbio.02630-20.
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ABSTRACTNitric oxide is a versatile and critical effector molecule that can modulate many cellular functions. Although recognized as a regulator of infections, the inhibitory mechanism of nitric oxide against human cytomegalovirus (HCMV) replication remains elusive. We demonstrate that nitric oxide attenuates viral replication by interfering with HCMV-mediated modulation of several cellular processes. Nitric oxide exposure reduced HCMV genome synthesis and infectious viral progeny with cell-type-dependent differences observed. Mitochondrial respiration was severely reduced in both uninfected and HCMV-infected cells during exposure with little impact on ATP levels indicating changes in cellular metabolism. Metabolomics identified significantly altered small molecules in multiple pathways during nitric oxide exposure including nucleotide biosynthesis, tricarboxylic acid (TCA) cycle, and glutamine metabolism. Glutathione metabolites were increased coinciding with a reduction in the glutathione precursor glutamine. This shift was accompanied by increased antioxidant enzymes. Glutamine deprivation mimicked defects in HCMV replication and mitochondrial respiration observed during nitric oxide exposure. These data suggest that nitric oxide limits glutaminolysis by shuttling glutamine to glutathione synthesis. In addition, lipid intermediates were severely altered, which likely contributes to the observed increase in defective viral particles. Nitric oxide disrupts multiple cellular processes, and we had limited success in rescuing replication defects by supplementing with metabolic intermediates. Our studies indicate that nitric oxide attenuation of HCMV is multifactorial with interference in viral manipulation of cellular metabolism playing a central role.IMPORTANCE Human cytomegalovirus is a prevalent pathogen that can cause serious disease in patients with compromised immune systems, including transplant patients and during congenital infection. HCMV lytic replication likely occurs in localized sites of infection with immune cells infiltrating and releasing nitric oxide with other effector molecules. This nonspecific immune response results in both uninfected and infected cells exposed to high levels of nitric oxide. The absence of nitric oxide synthase has been associated with lethal HCMV infection. We demonstrate that nitric oxide inhibition of HCMV replication is multifactorial and cell type dependent. Our results indicate that nitric oxide controls replication by interfering with viral modulation of cellular metabolism while also affecting proliferation and mitochondrial respiration of neighboring uninfected cells. These studies identify the mechanism and contribution of nitric oxide during immune control of HCMV infection and provide insight into its role in other viral infections.
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Xie, Maorong, Baoqin Xuan, Jiaoyu Shan, Deng Pan, Yamei Sun, Zhao Shan, Jinping Zhang, Dong Yu, Bin Li et Zhikang Qian. « Human Cytomegalovirus Exploits Interferon-Induced Transmembrane Proteins To Facilitate Morphogenesis of the Virion Assembly Compartment ». Journal of Virology 89, no 6 (31 décembre 2014) : 3049–61. http://dx.doi.org/10.1128/jvi.03416-14.
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ABSTRACTRecently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication.IMPORTANCEHCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we identified a new function of IFITMs during the very late stage of virus replication, i.e., virion assembly. Virus entry and assembly both involve vesicle transport and membrane fusion; thus, a common biochemical activity of IFITMs is likely to be involved. Therefore, our findings may provide a new platform for dissecting the molecular mechanism of action of IFITMs during the blocking or enhancement of virus infection, which are under intense investigation in this field.
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Kupke, Sascha Young, Dietmar Riedel, Timo Frensing, Pawel Zmora et Udo Reichl. « A Novel Type of Influenza A Virus-Derived Defective Interfering Particle with Nucleotide Substitutions in Its Genome ». Journal of Virology 93, no 4 (21 novembre 2018). http://dx.doi.org/10.1128/jvi.01786-18.
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ABSTRACTDefective interfering particles (DIPs) replicate at the expense of coinfecting, fully infectious homologous virus. Typically, they contain a highly deleted form of the viral genome. Utilizing single-cell analysis, here we report the discovery of a yet-unknown DIP type, derived from influenza A viruses (IAVs), termed OP7 virus. Instead of deletions, the genomic viral RNA (vRNA) of segment 7 (S7) carried 37 point mutations compared to the reference sequence, affecting promoter regions, encoded proteins, and genome packaging signals. Coinfection experiments demonstrated strong interference of OP7 virus with IAV replication, manifested by a dramatic decrease in the infectivity of released virions. Moreover, an overproportional quantity of S7 in relation to other genome segments was observed, both intracellularly and in the released virus population. Concurrently, OP7 virions lacked a large fraction of other vRNA segments, which appears to constitute its defect in virus replication. OP7 virus might serve as a promising candidate for antiviral therapy. Furthermore, this novel form of DIP may also be present in other IAV preparations.IMPORTANCEDefective interfering particles (DIPs) typically contain a highly deleted form of the viral genome, rendering them defective in virus replication. Yet upon complementation through coinfection with fully infectious standard virus (STV), interference with the viral life cycle can be observed, leading to suppressed STV replication and the release of mainly noninfectious DIPs. Interestingly, recent research indicates that DIPs may serve as an antiviral agent. Here we report the discovery of a yet-unknown type of influenza A virus-derived DIP (termed “OP7” virus) that contains numerous point mutations instead of large deletions in its genome. Furthermore, the underlying principles that render OP7 virions interfering and apparently defective seem to differ from those of conventional DIPs. In conclusion, we believe that OP7 virus might be a promising candidate for antiviral therapy. Moreover, it exerts strong effects, both on virus replication and on the host cell response, and may have been overlooked in other IAV preparations.
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Hein, Marc D., Prerna Arora, Pavel Marichal-Gallardo, Michael Winkler, Yvonne Genzel, Stefan Pöhlmann, Klaus Schughart, Sascha Y. Kupke et Udo Reichl. « Cell culture-based production and in vivo characterization of purely clonal defective interfering influenza virus particles ». BMC Biology 19, no 1 (3 mai 2021). http://dx.doi.org/10.1186/s12915-021-01020-5.
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Abstract 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-Mx1r/r 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.
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Jiang, Jun, Anna Erickson, Wenjie Qiao, Emilyn E. Matsumura et Bryce W. Falk. « Flock house virus as a vehicle for aphid Virus-induced gene silencing and a model for aphid biocontrol approaches ». Journal of Pest Science, 8 avril 2022. http://dx.doi.org/10.1007/s10340-022-01499-z.
Texte intégralRésumé :
AbstractDue to their high specificity and efficacy, RNA interference (RNAi)-based strategies have been used for fundamental functional genomics studies in a number of insects. However, its potential for translational applications in pest management is also of great interest. The lack of suitable RNAi triggering approaches, however, so far has largely precluded the implementation of RNAi-based approaches to target aphids. In this work, we first demonstrate that Flock House virus (FHV), an insect virus, can infect multiple aphid species, including the green peach aphid, Myzus persicae (M. persicae), the corn leaf aphid, Rhopalosiphum maidis (R. maidis), and the bird cherry-oat aphid, Rhopalosiphum padi (R. padi), by both microinjection and oral feeding. Using green fluorescent protein (GFP) as an indicator, we showed that the defective interfering RNA (DI-634) of FHV RNA2, which is generated autonomously during wild-type (WT) virus replication, can carry foreign sequences, and further for their functional expression. More importantly, the engineered DI-634 was incorporated into virus particles in co-infections with WT FHV. Using FHV virions containing genetically modified DI-634, the accumulation levels of the M. persicae mRNAs for Cathepsin L (CatL) and Sugar Transporter 4 (ST4), were decreased by ~ 35% and ~ 30–50%, respectively when virions were injected intrathoracically into aphids. Finally, and of more practical relevance, oral acquisition of these engineered FHV virions caused lethality of M. persicae. In summary, as a proof-of-concept, our work demonstrates that FHV can be a valuable RNAi tool for fundamental research, and suggests opportunities for using engineered insect viruses as biological agents for aphid pest control.