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Naked viruses can escape host cells before the induction of lysis via release in extracellular vesicles (EVs). These nanosized EVs cloak the secreted virus particles in a host-derived membrane, which alters virus-host interactions that affect infection efficiency and antiviral immunity. Currently, little is known about the viral and host factors regulating this form of virus release. Here, we assessed the role of the encephalomyocarditis virus (EMCV) Leader protein, a 'viral security protein' that subverts the host antiviral response. EV release upon infection with wildtype virus or a Leader-deficient mutant was characterized at the single particle level using high-resolution flow cytometry. Inactivation of the Leader abolished EV induction during infection and strongly reduced EV-enclosed virus release. We demonstrate that the Leader promotes the release of virions within EVs by stimulating a secretory arm of autophagy. This newly discovered role of the EMCV Leader adds to the variety of mechanisms via which this protein affects virus-host interactions. Moreover, these data provide first evidence for a crucial role of a non-structural viral protein in the non-lytic release of picornaviruses via packaging in EVs. Picornaviruses can escape infected cells via packaging in extracellular vesicles (EVs). Here, van der Grein et al. show that the non-structural Leader protein of encephalomyocarditis virus (EMCV) promotes the release of EV-enclosed virus particles and provide evidence for a role of secretory autophagy in this process. [ABSTRACT FROM AUTHOR]

The release and uptake of nano-sized extracellular vesicles (EV) is a highly conserved means of intercellular communication. The molecular composition of EV, and thereby their signaling function to target cells, is regulated by cellular activation and differentiation stimuli. EV are regarded as snapshots of cells and are, therefore, in the limelight as biomarkers for disease. Although research on EV-associated RNA has predominantly focused on microRNAs, the transcriptome of EV consists of multiple classes of small non-coding RNAs with potential gene-regulatory functions. It is not known whether environmental cues imposed on cells induce specific changes in a broad range of EV-associated RNA classes. Here, we investigated whether immune-activating or -suppressing stimuli imposed on primary dendritic cells affected the release of various small non-coding RNAs via EV. The small RNA transcriptomes of highly pure EV populations free from ribonucleoprotein particles were analyzed by RNA sequencing and RT-qPCR. Immune stimulus-specific changes were found in the miRNA, snoRNA, and Y-RNA content of EV from dendritic cells, whereas tRNA and snRNA levels were much less affected. Only part of the changes in EV-RNA content reflected changes in cellular RNA, which urges caution in interpreting EV as snapshots of cells. By comprehensive analysis of RNA obtained from highly purified EV, we demonstrate that multiple RNA classes contribute to genetic messages conveyed via EV. The identification of multiple RNA classes that display cell stimulation-dependent association with EV is the prelude to unraveling the function and biomarker potential of these EV-RNAs. [ABSTRACT FROM AUTHOR]

It is a long-standing paradigm in the field of virology that naked viruses cause lysis of infected cells to release progeny virus. However, recent data indicate that naked virus types of the Picornaviridae and Hepeviridae families can also leave cells via an alternative route involving enclosure in fully host-derived lipid bilayers. The resulting particles resemble extracellular vesicles (EV), which are 50 nm-1 μm vesicles released by all cells. These EV contain lipids, proteins, and RNA, and generally serve as vehicles for intercellular communication in various (patho)physiological processes. EV can act as carriers of naked viruses and as invisibility cloaks to evade immune attacks. However, the exact combination of virions and host-derived molecules determines how these virus-containing EV affect spread of infection and/or triggering of antiviral immune responses. An underexposed aspect in this research area is that infected cells likely release multiple types of virus-induced and constitutively released EV with unique molecular composition and function. In this review, we identify virus-, cell-, and environment-specific factors that shape the EV population released by naked virus-infected cells. In addition, current findings on the formation and molecular composition of EV induced by different virus types will be compared and placed in the context of the widely proven heterogeneity of EV populations and biases caused by different EV isolation methodologies. Close interactions between the fields of EV biology and virology will help to further delineate the intricate relationship between EV and naked viruses and its relevance for viral life cycles and outcomes of viral infections. [ABSTRACT FROM AUTHOR]