Exosomes from Hepatitis C Infected Patients Transmit HCV Infection and Contain Replication Competent Viral RNA in Complex with Ago2-miR122-HSP90

Bukong, Terence N.; Momen-Heravi, Fatemeh; Kodys, Karen; Bala, Shashi; Szabó, Gyöngyi

doi:10.1371/journal.ppat.1004424

Cited by 368 publications

(392 citation statements)

References 60 publications

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“…Further evidence for virion-independent genome shuttling was provided recently in a study that employed a set of cells with resistance to different antibiotics to distinguish between true EV-mediated RNA transfer and cell-cell fusion (42). Szabo's group, meanwhile, provided an important step toward understanding the in vivo relevance of the phenomenon, finding infectious exosomes in blood of HCV patients (43). Those authors also reported that viral RNA in exosomes was complexed with Argonaute 2 (Ago2) and the replication-enhancing host miR-122 (43).…”

Section: Common Transport Mechanisms Of Evs and Virusesmentioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

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SUMMARYExtracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cellsin vivoand how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors.

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Section: Common Transport Mechanisms Of Evs and Virusesmentioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

View full text Add to dashboard Cite

show abstract

“…In other cases, EVs provide an "envelope" to nonenveloped viruses, e.g., hepatitis A, and these EV-encapsulated viruses can infect cells (5). Similarly, EV released by hepatitis C-infected cells can carry fully infectious viral genomes that in target cells generate new infectious viral particles (6).…”

mentioning

confidence: 99%

Extracellular vesicles and viruses: Are they close relatives?

Hoen

Cremer

Gallo

et al. 2016

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

425

390

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Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell–cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery.

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“…It has been recently shown that HCV hijacks exosomes to incorporate infectious RNA into these structures that are then capable of mediating receptor-independent transmission of the virus (32,39). Here, we describe another model for subversion of exosome-like structures to mediate receptor-independent transmission involving the novel bunyavirus SFTS virus.…”

Section: Discussionmentioning

confidence: 97%

“…It has been previously shown that hepatitis C virus (HCV) hijacks secreted vesicles for receptor independent transmission of viral RNA (32,39). Furthermore, hepatitis A virus (HAV) is released cloaked in host membranes in a release mechanism resembling , and isolation of extracellular microvesicles was performed as depicted in Fig.…”

Section: Sfts Virus Infection Induces the Formation Of Cytoplasmic Stmentioning

confidence: 99%

Extracellular Vesicles Mediate Receptor-Independent Transmission of Novel Tick-Borne Bunyavirus

Silvas

Popov

Paulucci-Holthauzen

et al. 2016

J Virol

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Severe fever with thrombocytopenia syndrome (SFTS) virus is a newly recognized member of the genus Phlebovirus in the family Bunyaviridae. The virus was isolated from patients presenting with hemorrhagic manifestations and an initial case fatality rate of 12 to 30% was reported. Due to the recent emergence of this pathogen, there is limited knowledge on the molecular virology of SFTS virus. Recently, we reported that the SFTS virus NSs protein inhibited the activation of the beta interferon (IFN-␤) promoter. Furthermore, we also found that SFTS virus NSs relocalizes key components of the IFN response into NSs-induced cytoplasmic structures. Due to the important role these structures play during SFTS virus replication, we conducted live cell imaging studies to gain further insight into the role and trafficking of these cytoplasmic structures during virus infection. We found that some of the SFTS virus NSs-positive cytoplasmic structures were secreted to the extracellular space and endocytosed by neighboring cells. We also found that these secreted structures isolated from NSs-expressing cells and SFTS virus-infected cells were positive for the viral protein NSs and the host protein CD63, a protein associated with extracellular vesicles. Electron microscopy studies also revealed that the isolated CD63-immunoprecipitated extracellular vesicles produced during SFTS virus infection contained virions. The virions harbored within these structures were efficiently delivered to uninfected cells and were able to sustain SFTS virus replication. Altogether, these results suggest that SFTS virus exploits extracellular vesicles to mediate virus receptor-independent transmission to host cells and open the avenue for novel therapeutic strategies against SFTS virus and related pathogens. IMPORTANCESFTS virus is novel bunyavirus associated with hemorrhagic fever illness. Currently, limited information is available about SFTS virus. In the present study, we demonstrated that extracellular vesicles produced by SFTS virus-infected cells harbor infectious virions. We sought to determine whether these "infectious" extracellular vesicles can mediate transmission of the virus and confirmed that the SFTS virions were efficiently transported by these secreted structures into uninfected cells and were able to sustain efficient replication of SFTS virus. These results have significant impact on our understanding of how the novel tick-borne phleboviruses hijack cellular machineries to establish infection and point toward a novel mechanism for virus replication among arthropod-borne viruses. The Bunyaviridae family comprises five genera, including Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus. The majority of viruses within this family (with the exception of Hantaviruses) are considered arthropod-borne viruses and are important causes of morbidity and mortality around the world. These viruses are associated with a range of clinical symptoms characterized by febrile illness and in the most severe cases fatal hepa...

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Exosomes from Hepatitis C Infected Patients Transmit HCV Infection and Contain Replication Competent Viral RNA in Complex with Ago2-miR122-HSP90

Cited by 368 publications

References 60 publications

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Extracellular vesicles and viruses: Are they close relatives?

Extracellular Vesicles Mediate Receptor-Independent Transmission of Novel Tick-Borne Bunyavirus

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