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HSVs enter cells in a receptor-dependent [nectin1 or herpesviruses entry mediator (HVEM)] fashion by fusion of the viral envelope with plasma membrane (neutral pH compartment), by endocytosis into neutral or acidic compartments, o...
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HSVs enter cells in a receptor-dependent [nectin1 or herpesviruses entry mediator (HVEM)] fashion by fusion of the viral envelope with plasma membrane (neutral pH compartment), by endocytosis into neutral or acidic compartments, or by macropinocytosis/ phagocytosis. The cellular determinants of the route of entry are unknown. Here, we asked what cellular factors determine the pathway of HSV entry. CHO cells lack β_3-integrin and the respective α-subunits' heterodimers. We report that, in the absence of α_vβ_3-integrin, HSV enters CHO-nectin1 cells through a pathway independent of cholesterol-rich rafts and dynamin2. In the presence of α_vβ_3-integrin, HSV enters CHO-nectin1 cells through a pathway dependent on cholesterol-rich rafts and dynamin2. HSV enters J-nectin1 and 293T cells through a neutral compartment independent of cholesterol-rich rafts and dynamin2. α_vβ_3-integrin overexpres-sion in these cells modifies the route of entry to an acidic compartment dependent on cholesterol-rich rafts and dynamin2, hence similar to that in α_vβ_3-integrin-positive CHO-nectin1 cells. In some cells, the diversion of entry from an integrin- and raft-independent pathway to an acidic compartment requiring cholesterol-rich lipids rafts and dynamin2 is irreversible. Indeed, HSV cannot infect CHO-nectin1-α_vβ_3 cells through any compartment when the α_vβ_3-integrin-dependent pathway is blocked by anti-integrin antibody, anti-dynamin2, or anti-acidification drugs. We conclude that the α_vβ_3-irvtegrin is a determinant in the choice of HSV entry pathway into cells. Because the pathway dictated by α_vβ_3-integrin is through lipid rafts, the platforms for a number of Toll-like receptors, current findings raise the possibility that α_vβ_3-integrin acts as a sentinel of innate immunity.
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Retroviruses enter cells through specific cell-surface receptors and then embark on a journey that ultimately leads to the establishment of the integrated proviral DNA. The steps of the journey include the reverse transcription of...
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Retroviruses enter cells through specific cell-surface receptors and then embark on a journey that ultimately leads to the establishment of the integrated proviral DNA. The steps of the journey include the reverse transcription of the viral RNA into DNA, the trafficking of the viral protein-DNA complex through the cytoplasm, the entry of the complex into the nucleus, and the insertion of the linear viral DNA into the host genome. All these steps are likely to involve specific interactions of viral proteins with host machinery. Our knowledge of the details of these interactions is very limited but is rapidly expanding, and should provide a deeper understanding of the pathways and components used by the different classes of retroviruses. This knowledge in turn should enable the development of better and more efficient retroviral vectors for use in gene therapy protocols in vivo.
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The orthoreoviruses are segmented double strand RNA viruses and are the most abundant viruses in nature. Three main serotypes are known, named 1, 2 and 3. The designation "reovirus" is the acronym for "respiratory enteric orphan v...
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The orthoreoviruses are segmented double strand RNA viruses and are the most abundant viruses in nature. Three main serotypes are known, named 1, 2 and 3. The designation "reovirus" is the acronym for "respiratory enteric orphan virus", expression underlining their respiratory and enteric origin and the fact that they are not associated with well defined clinical disease. Nevertheless. strains of orthoreoviruses have been isolated from several cases of symptomatic diseases in human, namely diseases of the central nervous system such as encephalitis and meningitis sometimes leading to patient death. These different cases show that orthoreoviruses could be pathogenic, causing fatal diseases. Orthoreoviruses infection in animals induces also several diseases. Indeed, according to the inoculation route and the serotype of inoculated strain, encephalitis or hepatitis can be observed. The RNA segments M2 and S1 seem to be involved in this neurovirulence property and are oil the basis of cellular mechanisms, Such its virus entry, virus replication and apoptosis. However, the mechanisms of virulence remain complex.
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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respirat...
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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.
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During cell entry, reovirus particles disassemble to generate ISVPs. ISVPs undergo conformational changes to form ISVP* and this conversion is required for membrane penetration. In tissues where ISVP formation occurs within endoso...
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During cell entry, reovirus particles disassemble to generate ISVPs. ISVPs undergo conformational changes to form ISVP* and this conversion is required for membrane penetration. In tissues where ISVP formation occurs within endosomes, ISVP-to-ISVP* conversion occurs at low pH. In contrast, in tissues where ISVP formation occurs extracellularly, ISVP-to-ISVP* transition occurs at neutral pH. Whether these two distinct pH environments influence the efficiency of cell entry is not known. In this study, we used Ouabain to lower the endosomal pH and determined its effect on reovirus infection. We found that Ouabain treatment blocks reovirus infection. In cells treated with Ouabain, virus attachment, internalization, and ISVP formation were unaffected but the efficiency of ISVP*s formation was diminished. Low pH also diminished the efficiency of ISVP-to-ISVP* conversion in vitro. Thus, the pH of the compartment where ISVP-to-ISVP* conversion takes place may dictate the efficiency of reovirus infection. (C) 2015 Elsevier Inc. All rights reserved.
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Ebola virus (EBOV) is an enveloped filamentous virus that causes severe hemorrhagic fever in humans and nonhuman primates with up to 90% fatality. Accumulating evidence indicates that various viruses, including EBOV, exploit the h...
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Ebola virus (EBOV) is an enveloped filamentous virus that causes severe hemorrhagic fever in humans and nonhuman primates with up to 90% fatality. Accumulating evidence indicates that various viruses, including EBOV, exploit the host apoptotic clearance machinery to enhance their entry into host cells by externalizing phosphatidylserine (PS) in the viral envelope. PS is typically distributed in the inner layer of the plasma membrane (PM) in normal cells. Progeny EBOV virions bud from the PM of infected cells, suggesting that PS is likely flipped to the outer leaflet of the envelope of Ebola virions. Currently, the intracellular dynamics of PS during EBOV infection are poorly understood. This review summarizes recent progress in determining the molecular mechanism of externalization of PS in the envelope of EBOV particles. We also discuss future directions and how viral apoptotic mimicry could be targeted for therapeutics.
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Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to self-assemble, to serve as a protective shell for the viral genome during tra...
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Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to self-assemble, to serve as a protective shell for the viral genome during transfer, and to disassemble when entering a target cell. Disassembly during entry is a complex, multi-step process typically termed uncoating. Uncoating is triggered by multiple host-cell interactions. During cell entry, these interactions occur sequentially in different cellular compartments that the viruses pass through on their way to the site of replication. Here, we highlight the general principles of uncoating for two structurally related virus families, the polyoma- and papillomaviruses. Recent research indicates the use of different compartments and cellular interactions for uncoating despite their structural similarity.
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Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to selfassemble, to serve as a protective shell for the viral genome during tran...
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Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to selfassemble, to serve as a protective shell for the viral genome during transfer, and to disassemble when entering a target cell. Disassembly during entry is a complex, multi-step process typically termed uncoating. Uncoating is triggered by multiple host-cell interactions. During cell entry, these interactions occur sequentially in different cellular compartments that the viruses pass through on their way to the site of replication. Here, we highlight the general principles of uncoating for two structurally related virus families, the polyoma- and papillomaviruses. Recent research indicates the use of different compartments and cellular interactions for uncoating despite their structural similarity.
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The recent development of functional models to analyze the early steps of the hepatitis C virus (HCV) life cycle has highlighted that HCV entry is a slow and complex multistep process involving the presence of several entry factor...
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The recent development of functional models to analyze the early steps of the hepatitis C virus (HCV) life cycle has highlighted that HCV entry is a slow and complex multistep process involving the presence of several entry factors. Initial host cell attachment may involve glycosaminoglycans and the low-density lipoprotein receptor, after which the particle appears to interact sequentially with three entry factors: the scavenger receptor class B type I, the tetraspanin CD81 and the tight-junction protein claudin-1. Several serum components may also modulate HCV entry, while the recently discovered CD81 partner EWI-2wint can block the interaction of the viral particle with CD81, potentially preventing infection in the cell types in which it is expressed. After binding to the host cell, the HCV particle is internalized by clathrin-mediated endocytosis, with fusion likely occuring in early endosomes. This review summarizes our current knowledge on HCV entry.
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Hepatitis C virus (HCV) infection remains a major global health problem, with 130-170 million chronically infected individuals at risk to develop severe liver disease, including hepatocellular carcinoma. Although the development o...
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Hepatitis C virus (HCV) infection remains a major global health problem, with 130-170 million chronically infected individuals at risk to develop severe liver disease, including hepatocellular carcinoma. Although the development of direct-acting antivirals offers cure for a large majority of patients, there are still a number of clinical challenges. These include DAA failure in a significant subset of patients, difficult-to-treat genotypes and limited access to therapy due to high costs. Moreover, recent data indicate that the risk for liver cancer persists in patients with advanced fibrosis. These challenges highlight the need for continued efforts towards novel therapeutic strategies for HCV. Over the past two decades, advances in HCV model systems have enabled a detailed understanding of HCV entry and its clinical impact. Many of the virus-host interactions involved in HCV entry have now been identified and explored as antiviral targets. Furthermore, viral entry is recognized as an important factor for graft reinfection and establishment of persistent infection. HCV entry inhibitors, therefore, offer promising opportunities to address the limitations of DAAs. Here, we summarize recent advances in the field of HCV entry and discuss perspectives towards the prevention and cure of HCV infection and virus-induced liver disease.
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