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HIV-1 release requires a direct interaction between the p6 domain of the Gag protein and Tsg101, a component of the cellular endosomal sorting complex required for transport I (ESCRT-1). Disruption of the binding between Gag and T...
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HIV-1 release requires a direct interaction between the p6 domain of the Gag protein and Tsg101, a component of the cellular endosomal sorting complex required for transport I (ESCRT-1). Disruption of the binding between Gag and Tsg101 is highly detrimental to particle release, making this viral-host cell interaction a potential target for the development of novel anti-HIV-1 agents. An article in this issue reports on the application of a bacterial reverse two-hybrid strategy to identify a cyclic peptide that disrupts Gag-Tsg101 binding and suppresses HIV-1 particle release.
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This paper develops an analytical solution describing propagation of two viral waves in an axon and applies the obtained analytical solution to investigating the dynamics of merging of these two waves as they move retrogradely tow...
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This paper develops an analytical solution describing propagation of two viral waves in an axon and applies the obtained analytical solution to investigating the dynamics of merging of these two waves as they move retrogradely toward the neuron body. The viral diffusivity and viral degradation are accounted for in the model. Computational results are presented for two situations: when all dynein motors move with the same velocity and when dynein motor velocity distribution is characterized by a probability density function (pdf). The effect of various model parameters on the time it takes for the waves to merge is discussed. It is proposed that observing the dynamics of wave merging can be used for determining parameters characterizing viral transport, such as the viral diffusivity. This may contribute toward better understanding of viral transport properties and potentially help in developing novel viral detection techniques.
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Abstract Bartha, the pseudorabies virus (PRV) vaccine strain, is widely used in studies of neuronal circuit-tracing, due to its attenuated virulence and retrograde spreading. However, we know little regarding the molecular mechani...
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Abstract Bartha, the pseudorabies virus (PRV) vaccine strain, is widely used in studies of neuronal circuit-tracing, due to its attenuated virulence and retrograde spreading. However, we know little regarding the molecular mechanisms of PRV infection and spreading between structurally connected neurons. In this study, we systematically analyzed the host brain proteomes after acute infection with PRV, attempting to identified the proteins involved in the processes. Mice were injected with PRV-Bartha and PRV-Becker (PRV-Bartha's wild-type parent strain) in the olfactory system, the proteomes of the brain and synaptosome were analyzed and compared at various infection intervals using mass spectrometry-based proteomics techniques. In all, we identified >100 PRV-infection regulated proteins at the whole-tissue level and the synaptosome level. While at whole-tissue level, bioinformatics analyses mapped most of the regulations to the inflammation pathways, at the synaptosome level, most of those to synaptic transmission, cargo transport and cytoskeleton organization. We established regulated protein networks demonstrating distinct cellular regulation pattern between the global and the synaptosome levels. Moreover, we identified a series of potentially PRV-strain-specific regulated proteins with diverse biological functions. This study may provide new clues for molecular mechanisms for PRV infection and spread. Highlights ? Whole-tissue and synptosome proteome were quantified for virulent and attenuated PRV infection ? >100 regulated proteins at the whole-tissue level and at the synaptosome level were identified. ? PRV infection in olfactory system lead to distinct regulation pattern in global and synaptic level. ? Diverse processes like Cargos transport and cytoskeleton orgnization were regulated at synaptic level. ? Inflammatory regulation was mainly identified at whole-tissue level. ? 44 and 32 PRV-strain-specific regulated proteins were identified at synaptosome and whole-tissue level, respectively.
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A model of retrograde axonal transport of neurotropic viruses is developed. The model accounts for active viral transport by dynein motors as well as for passive transport by diffusion; the destruction of the virus as it propagate...
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A model of retrograde axonal transport of neurotropic viruses is developed. The model accounts for active viral transport by dynein motors as well as for passive transport by diffusion; the destruction of the virus as it propagates toward the neuron soma is modeled utilizing a first-order decay rate process. The effect of a limited time during which the axonal synapse is exposed to the virus is incorporated. An analytical solution is obtained. The obtained solution makes it possible to identify four different regimes of viral transport in the axon that correspond to the following situations: (1) Small viral diffusivity and small rate of viral destruction; (2) Large viral diffusivity and small rate of viral destruction; (3) Small viral diffusivity and large rate of viral destruction; (4) Large viral diffusivity and large rate of viral destruction. Characteristic features of these regimes are discussed.
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Cullin-3 (Cul3) functions as a scaffolding protein in the Bric-a-brac, Tramtrack, Broad-complex (BTB)-Cul3-Rbx1 ubiquitin E3 ligase complex. Here, we report a previously undescribed role for Cul3 complexes in late endosome (LE) ma...
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Cullin-3 (Cul3) functions as a scaffolding protein in the Bric-a-brac, Tramtrack, Broad-complex (BTB)-Cul3-Rbx1 ubiquitin E3 ligase complex. Here, we report a previously undescribed role for Cul3 complexes in late endosome (LE) maturation. RNAi-mediated depletion of Cul3 results in a trafficking defect of two cargoes of the endoly-sosomal pathway, influenza A virus (IAV) and epidermal growth factor receptor (EGFR). IAV is able to reach an acidic endosomal compartment, coinciding with LE/lysosome (LY) markers. However, it remains trapped or the capsid is unable to uncoat after penetration into the cytosol. Similarly, activation and subsequent ubiquitination of EGFR appear normal, whereas downstream EGFR degradation is delayed and its ligand EGF accumulates in LE/LYs. Indeed, Cul3-de-pleted cells display severe morphological defects in LEs that could account for these trafficking defects; they accumulate acidic LE/LYs, and some cells become highly vacuolated, with enlarged Rab7-pos-itive endosomes. Together, these results suggest a crucial role of Cul3 in regulating late steps in the endolysosomal trafficking pathway.
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An analytical solution representing a wave of viral concentration as it propagates from the axon synapse toward the neuron soma is obtained. The obtained solution is based on a model of molecular motor-assisted retrograde transpor...
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An analytical solution representing a wave of viral concentration as it propagates from the axon synapse toward the neuron soma is obtained. The obtained solution is based on a model of molecular motor-assisted retrograde transport of a neurotropic virus in an axon of a peripheral nervous system. It is established that the velocity of the viral concentration wave is almost independent of the rate of viral destruction in the axon, but depends on viral diffusivity, especially right after viral uptake at the synapse, when viral concentration gradient is large. As time progresses, the velocity of the viral concentration wave approaches that of a dynein motor, which indicates that for a large time viral transport in an axon is almost exclusively motor-driven.
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Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in infected cells, including RNA viruses such as the flavivirus Dengu...
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Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in infected cells, including RNA viruses such as the flavivirus Dengue virus (DENV). DENV non-structural protein 5 (NS5) traffics into and out of the host cell nucleus/nucleolus, being observed in the nucleus, although to differing extents, very early in infection in the case of all 4 DENV serotypes; with results from both reverse genetics and inhibitor studies indicating that this trafficking is critical to DENV infection. Knowledge of the transporters and targeting signals responsible for nuclear trafficking of NS5 has enabled inhibitors of DENV NS5 nuclear import to be identified using a novel screening/counterscreen approach. N-(4-hydroxyphenyl) retinamide (4-HPR) is of particular interest as a specific, non-toxic inhibitor able to protect against infection by all four serotypes of DENV, as well as the severe, antibody-enhanced form of DENV infection, in a lethal mouse model. Since 4-HPR can also inhibit DENV-related flaviviruses of medical significance such as West Nile Virus and Zika virus, it is of great interest for future commercialisation. Targeting nucleocytoplasmic trafficking of flavivirus proteins promises to be a powerful strategy to counter flaviviruses, for which the development of protective vaccines has thus far proven problematic.
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Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to...
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Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellulartransport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAPI and MAP2 families, and microtubule plus-end tracking proteins (+TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on non-motile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.
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Rabies virus (RABV), an enveloped virus with a single-stranded and negative-sense RNA genome, is the type species of the Lyssavirus Genus within the Rhabdoviridae family. As the causative agent of rabies with a nearly 100% fatalit...
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Rabies virus (RABV), an enveloped virus with a single-stranded and negative-sense RNA genome, is the type species of the Lyssavirus Genus within the Rhabdoviridae family. As the causative agent of rabies with a nearly 100% fatality, the neurotropic RABV pose a serious threat to the global public health. Though a great effort has been made toward understanding the molecular mechanism underlying virus infection cycle, there are still many aspects need to be elucidated, especially on the early events during virus replication cycle. With the application of the multiple advanced technologies, much progress has been made on these aspects. To date, multiple receptors, such as nAChR, NCAM, p75NTR, mGluR2, carbohydrates, and gangliosides, have been identified. Following initial attachment, RABV internalization occurs through clathrin-mediated endocytosis (CME) with the help of actin. After viral entry, intracellular trafficking occurs. Two retrograde trafficking models, stating that either whole virions are parceled into vesicles or only the viral capsids are transported, have been proposed. Moreover, complete enveloped virions or G-containing vesicle-associated ribonucleoproteins (RNPs) may be formed during anterograde transport, which remains poorly characterized but is important for viral budding. Combining the data elucidating the molecular mechanisms of RABV attachment, entry, and intracellular trafficking, this review provides an integrated view of the early events in the viral life cycle.
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BK Polyomavirus (BKPyV) is a ubiquitous nonenveloped human virus that can cause severe disease in immunocompromised populations. After internalization into renal proximal tubule epithelial cells, BKPyV traffics through the ER and ...
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BK Polyomavirus (BKPyV) is a ubiquitous nonenveloped human virus that can cause severe disease in immunocompromised populations. After internalization into renal proximal tubule epithelial cells, BKPyV traffics through the ER and enters the cytosol. However, it is unclear how the virus enters the nucleus. In this study, we elucidate a role for the nuclear localization signal located on the minor capsid proteins VP2 and VP3 during infection. Site-directed mutagenesis of a single lysine in the basic region of the C-terminus of the minor capsid proteins abrogated their nuclear localization, and the analogous genomic mutation reduced infectivity. Additionally, through use of the inhibitor ivermectin and knockdown of importin beta 1, we found that the importin alpha/beta pathway is involved during infection. Overall these data are the first to show the significance of the NLS of the BKPyV minor capsid proteins during infection in a natural host cell. (C) 2014 Elsevier Inc. All rights reserved.
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