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  • Review Article
  • Published:

Viral effects on the content and function of extracellular vesicles

Nature Reviews Microbiology volume 15, pages 559–572 (2017)Cite this article

Subjects

Key Points

  • The transfer of extracellular vesicles (EVs) from one cell to another is thought to be an important mechanism for cell–cell communication, and EVs that are produced by virus-infected cells may modulate uninfected cells.

  • Viruses have specific receptors and therefore usually have a more restricted cellular tropism. By contrast, the uptake of EVs is almost universal and can occur through several cellular endocytic mechanisms in addition to direct fusion, a property that enables systemic delivery of their content.

  • The differences between viral and EV receptor usage can be used to separate and purify EVs. This enables the identification of specific EV-mediated effects and enables compounds that potentially inhibit the delivery and function of extracellular vesicles to be tested.

  • Viruses that establish chronic and persistent infections in a host probably use EVs to enhance the establishment and maintenance of infection. The EVs that are produced from virus-infected cells (and may therefore differ in content) may also restrict virus infection and enable continued host viability and persistent viral infection.

  • The incorporation of virions into EVs could prevent the recognition of viral proteins by the immune system and facilitate spread in the host.

Abstract

The release of membrane-bound vesicles from cells is being increasingly recognized as a mechanism of intercellular communication. Extracellular vesicles (EVs) or exosomes are produced by virus-infected cells and are thought to be involved in intercellular communication between infected and uninfected cells. Viruses, in particular oncogenic viruses and viruses that establish chronic infections, have been shown to modulate the production and content of EVs. Viral microRNAs, proteins and even entire virions can be incorporated into EVs, which can affect the immune recognition of viruses or modulate neighbouring cells. In this Review, we discuss the roles that EVs have during viral infection to either promote or restrict viral replication in target cells. We will also discuss our current understanding of the molecular mechanisms that underlie these roles, the potential consequences for the infected host and possible future diagnostic applications.

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Figure 1: Modulation of the EV biogenesis pathway during viral infection.
Figure 2: Interactions between viruses and EVs.
Figure 3: Isolation of EVs and virions.
Figure 4: Local and systemic spread of viruses and EVs.

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Acknowledgements

Work in the authors' laboratories is supported by public health service grants (DA040394 and CA019014) and the University Cancer Research Fund (UCRF). The authors thank their colleagues R. McNamara, P. Chugh and B. Damania for insightful discussions.

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Authors and Affiliations

  1. UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, CB# 7295, Chapel Hill, 27599-7295, North Carolina, USA

    Nancy Raab-Traub & Dirk P. Dittmer

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 125 Mason Farm Road, Chapel Hill, 27599-7290, North Carolina, USA

    Nancy Raab-Traub & Dirk P. Dittmer

Authors
  1. Nancy Raab-Traub
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  2. Dirk P. Dittmer
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Correspondence to Nancy Raab-Traub or Dirk P. Dittmer.

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Competing interests

D.P.D. has received early access and beta testing reagents related to extracellular vesicles and miRNA diagnostics from JSR Micro, Life Sciences Inc. and Aclea Inc. This did not influence the opinions expressed in this Review.

PowerPoint slides

Glossary

Multivesicular bodies

(MVBs). Structures below the plasma membrane that function as the central hub for the sorting of molecules into other specialized compartments, into and out of cells.

Biomarker

A protein, mRNA or other small molecule that can be measured and is associated with disease outcome, either independent of treatment (prognostic) or in relation to treatment (predictive).

Crowding agents

Chemicals, such as polyethylene glycol or acetone that change the availability of free solvent for proteins and other macromolecular structures, which results in aggregation.

Nanotubes

Membranous protrusions that connect adjacent cells over extended distances (up to 100 μM) and can transfer cellular components and viruses.

Cross-priming

The transfer of antigens from one cell to another cell, often to a professional antigen-presenting cell, that does not make the antigen; the phrase was originally coined to explain counterintuitive aspects of T cell responses.

Latent infections

The long-term presence of viral genomes (DNA or RNA) in a cell without any evidence of virion production.

Capsid

Proteins that encapsulate viral genomes. Capsids are rigid, highly structured and are similar to crystals with a defined symmetry. The size, shape and symmetry of the capsid can be determined by electron microscopy and is sometimes used to classify viruses into taxa.

Endosomal sorting complex required for transport machinery

(ESCRT machinery). A multiprotein complex that is involved in the biogenesis of membrane vesicles. Viruses use the ESCRT machinery to assemble virions and bud.

RGD motif

The tripeptide Arg-Gly-Asp (RGD) is recognized by many integrins, either as part of a short peptide (blocking peptide) or as repeat region in extracellular matrix proteins.

Angiogenesis

The formation of new vessels that carry either blood or lymph, which involves the migration, growth and differentiation of endothelial cells.

Hyperimmune serum

Serum obtained from one, or many, infected convalescent animals that contains high levels of blocking antibodies to a target virus.

Cytopathic effect

Changes in host cells that are caused by virus infection.

Interstitial spaces

Small, narrow spaces between tissues that are typically filled with interstitial liquid.

Principal component analysis

A statistical method used to uncover relationships defined by 10–1,000 or more correlated variables, which identifies the factors that contribute to variability. Typically, the first 3–5 principal components are composed of the variables that have the greatest explanatory power.

Spectral counting

A method that determines the relative presence or absence of a peptide in a pair of samples analysed by mass spectroscopy.

Primary effusion lymphoma

A diffuse large B cell lymphoma that is caused by Kaposi sarcoma-associated herpesvirus.

Paracrine

Affecting the physiology of neighbouring cells without cell-to-cell contact, typically through cytokines or growth factors. If the growth factors act on the same cell type from which they originate the process is called an autocrine loop.

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Raab-Traub, N., Dittmer, D. Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 15, 559–572 (2017). https://doi.org/10.1038/nrmicro.2017.60

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