Membranous Replication Factories Induced by Plus-Strand RNA Viruses

Romero-Brey, Inés; Bartenschlager, Ralf

doi:10.3390/v6072826

Cited by 229 publications

(249 citation statements)

References 161 publications

(256 reference statements)

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“…During viral replication, the capsid proteins appeared spread throughout the entire cytoplasm, in contrast to the intermediate dsRNA species, which were predominantly located close to the nucleus and organized in large structures. This particular intracellular distribution in large clusters suggests that the viral replication occurs in membranous factories, as proposed for other plus-strand RNA viruses, such as the hepatitis C and Dengue virus [25]. …”

Section: Discussionmentioning

confidence: 82%

Cutthroat Trout Virus—Towards a Virus Model to Support Hepatitis E Research

Nordheim

Boinay

Leisi

et al. 2016

Viruses

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Cutthroat trout virus (CTV) is a non-pathogenic fish virus belonging to the Hepeviridae family, and it is distantly related to hepatitis E virus (HEV). Here, we report the development of an efficient cell culture system where CTV can consistently replicate to titers never observed before with a hepevirus. By using the rainbow trout gill (RTGill-W1) cell line, CTV reaches 1010 geq/mL intracellularly and 109 geq/mL extracellularly within 5–6 days in culture. We additionally established a qPCR system to investigate CTV infectivity, and developed a specific antibody directed against the viral capsid protein encoded by ORF2. With these methods, we were able to follow the progressive accumulation of viral RNA and the capsid protein, and their intracellular distribution during virus replication. Virus progeny purified through iodixanol density gradients indicated—that similar to HEV—CTV produced in cell culture is also lipid-associated. The lack of an efficient cell culture system has greatly impeded studies with HEV, a major human pathogen that causes hepatitis worldwide. Although several cell culture systems have recently been established, the replication efficiency of HEV is not robust enough to allow studies on different aspects of the virus replication cycle. Therefore, a surrogate virus that can replicate easily and efficiently in cultured cells would be helpful to boost research studies with hepeviruses. Due to its similarities, but also its key differences to HEV, CTV represents a promising tool to elucidate aspects of the replication cycle of Hepeviridae in general, and HEV in particular.

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Section: Discussionmentioning

confidence: 82%

Cutthroat Trout Virus—Towards a Virus Model to Support Hepatitis E Research

Nordheim

Boinay

Leisi

et al. 2016

Viruses

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“…For instance, hepatitis C virus, brome mosaic virus (BMV) and tobacco mosaic virus replicate in association with endoplasmic reticulum (ER) membranes. In contrast, Flock House virus and carnation Italian ringspot virus replicate in mitochondria, whereas tomato bushy stunt virus replicates in peroxisomes (den Boon et al, 2010;Laliberté and Sanfaçon, 2010;Paul and Bartenschlager, 2013;Romero-Brey and Bartenschlager, 2014). However, the mechanisms by which viruses target their replication proteins to particular membranes for VRC assembly are not well documented.…”

Section: Introductionmentioning

confidence: 99%

An unrecognized function for COPII components in recruiting the viral replication protein BMV 1a to the perinuclear ER

Fuchs

Zhang

et al. 2016

Journal of Cell Science

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Positive-strand RNA viruses invariably assemble their viral replication complexes (VRCs) by remodeling host intracellular membranes. How viral replication proteins are targeted to specific organelle membranes to initiate VRC assembly remains elusive. Brome mosaic virus (BMV), whose replication can be recapitulated in Saccharomyces cerevisiae, assembles its VRCs by invaginating the outer perinuclear endoplasmic reticulum (ER) membrane. Remarkably, BMV replication protein 1a (BMV 1a) is the only viral protein required for such membrane remodeling. We show that ER-vesicle protein of 14 kD (Erv14), a cargo receptor of coat protein complex II (COPII), interacts with BMV 1a. Moreover, the perinuclear ER localization of BMV 1a is disrupted in cells lacking ERV14 or expressing dysfunctional COPII coat components (Sec13, Sec24 or Sec31). The requirement of Erv14 for the localization of BMV 1a is bypassed by addition of a Sec24-recognizable sorting signal to BMV 1a or by overexpressing Sec24, suggesting a coordinated effort by both Erv14 and Sec24 for the proper localization of BMV 1a. The COPII pathway is well known for being involved in protein secretion; our data suggest that a subset of COPII coat proteins have an unrecognized role in targeting proteins to the perinuclear ER membrane.

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“…Hepatitis C virus is known to induce accumulations of vesicles forming a membranous web (MW) (26), consisting of mainly double membrane vesicles (DMVs) that are thought to be the site of viral RNA replication within the infected liver (27,28). To examine whether MWs are formed in vivo within the liver of NPHV + horses, we performed electron microscopy (EM)-based studies on liver biopsies of an infected horse, and in various cells, we observed numerous vesicles (Ve), which could not be detected in an uninfected horse ( Fig.…”

Section: Horses Can Be Experimentally Infected With Nphv and Display mentioning

confidence: 99%

Immune protection against reinfection with nonprimate hepacivirus

Pfaender

Wälter

Grabski

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus (HCV) displays a restricted host species tropism and only humans and chimpanzees are susceptible to infection. A robust immunocompetent animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control, and prophylactic vaccine development. The closest homolog of HCV is the equine nonprimate hepacivirus (NPHV), which shares similar features with HCV and thus represents an animal model to study hepacivirus infections in their natural hosts. We aimed to dissect equine immune responses after experimental NPHV infection and conducted challenge experiments to investigate immune protection against secondary NPHV infections. Horses were i.v. injected with NPHV containing plasma. Flow cytometric analysis was used to monitor immune cell frequencies and activation status. All infected horses became viremic after 1 or 2 wk and viremia could be detected in two horses for several weeks followed by a delayed seroconversion and viral clearance. Histopathological examinations of liver biopsies revealed mild, periportally accentuated infiltrations of lymphocytes, macrophages, and plasma cells with some horses displaying subclinical signs of hepatitis. Following viral challenge, an activation of equine immune responses was observed. Importantly, after a primary NPHV infection, horses were protected against rechallenge with the homologous as well as a distinct isolate with only minute amounts of circulating virus being detectable.hepatitis C virus | nonprimate hepacivirus | infection | immune protection | rechallenge H epatitis C virus (HCV) infections constitute a major global health problem with ∼130 million people being chronically infected (1). Once infected, 70-90% of individuals progress to chronicity, rendering HCV the leading cause of liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (2). HCV is a blood-borne, positive-stranded RNA virus classified to the family of Flaviviridae within the genus Hepacivirus. Seven different HCV genotypes and numerous subtypes have been described, which differ on the nucleotide level by ∼30-35% between different genotypes and maximally 30% between subtypes (3). Furthermore, within infected individuals the virus circulates as a population of closely related but distinct genomes (4). Recently, significant progress has been made regarding the treatment of HCV with the implementation of direct-acting antiviral (DAA) drugs, which can be administered as all-oral IFN-free therapeutics and should help to reduce the global burden of HCV infections (5). However, there are still many caveats, including high treatment costs and the risk of reinfection after successful therapy, which is a problem especially in patient populations with frequent exposure to HCV. Furthermore, the inadequacy of current HCV screening programs often results in late diagnosis of chronic HCV infection and subsequent proceeding to end-stage liver diseases (6). All of these challenges highlight the necessity for a prophylactic vaccine against HCV, ...

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Membranous Replication Factories Induced by Plus-Strand RNA Viruses

Cited by 229 publications

References 161 publications

Cutthroat Trout Virus—Towards a Virus Model to Support Hepatitis E Research

Cutthroat Trout Virus—Towards a Virus Model to Support Hepatitis E Research

An unrecognized function for COPII components in recruiting the viral replication protein BMV 1a to the perinuclear ER

Immune protection against reinfection with nonprimate hepacivirus

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