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Open AccessArticle

HPV-E7 Delivered by Engineered Exosomes Elicits a Protective CD8⁺ T Cell-Mediated Immune Response

by Paola Di Bonito, Barbara Ridolfi, Sandra Columba-Cabezas, Andrea Giovannelli, Chiara Chiozzini, Francesco Manfredi, Simona Anticoli, Claudia Arenaccio and Maurizio Federico

Viruses 2015, 7(3), 1079-1099; https://0-doi-org.brum.beds.ac.uk/10.3390/v7031079 - 09 Mar 2015

Cited by 44 | Viewed by 7273

Abstract

We developed an innovative strategy to induce a cytotoxic T cell (CTL) immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of [...] Read more.

We developed an innovative strategy to induce a cytotoxic T cell (CTL) immune response against protein antigens of choice. It relies on the production of exosomes, i.e., nanovesicles spontaneously released by all cell types. We engineered the upload of huge amounts of protein antigens upon fusion with an anchoring protein (i.e., HIV-1 Nef^mut), which is an inactive protein incorporating in exosomes at high levels also when fused with foreign proteins. We compared the immunogenicity of engineered exosomes uploading human papillomavirus (HPV)-E7 with that of lentiviral virus-like particles (VLPs) incorporating equivalent amounts of the same antigen. These exosomes, whose limiting membrane was decorated with VSV-G, i.e., an envelope protein inducing pH-dependent endosomal fusion, proved to be as immunogenic as the cognate VLPs. It is noteworthy that the immunogenicity of the engineered exosomes remained unaltered in the absence of VSV-G. Most important, we provide evidence that the inoculation in mouse of exosomes uploading HPV-E7 induces production of anti-HPV E7 CTLs, blocks the growth of syngeneic tumor cells inoculated after immunization, and controls the development of tumor cells inoculated before the exosome challenge. These results represent the proof-of-concept about both feasibility and efficacy of the Nef^mut-based exosome platform for the induction of CD8⁺ T cell immunity. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Review

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Open AccessReview

The Dual Role of Exosomes in Hepatitis A and C Virus Transmission and Viral Immune Activation

by Andrea Longatti

Viruses 2015, 7(12), 6707-6715; https://0-doi-org.brum.beds.ac.uk/10.3390/v7122967 - 17 Dec 2015

Cited by 60 | Viewed by 8719

Abstract

Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus (HAV; [...] Read more.

Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus (HAV; a picornavirus) and Hepatitis C virus (HCV; a flavivirus) two single strand plus-sense RNA viruses, in particular, have been found to use exosomes for viral transmission thus evading antibody-mediated immune responses. Paradoxically, both viral exosomes can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production. This article will review recent findings regarding these two viruses and outline how exosomes are involved in their transmission and immune sensing. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Tegument Assembly and Secondary Envelopment of Alphaherpesviruses

by Danielle J. Owen, Colin M. Crump and Stephen C. Graham

Viruses 2015, 7(9), 5084-5114; https://0-doi-org.brum.beds.ac.uk/10.3390/v7092861 - 18 Sep 2015

Cited by 138 | Viewed by 21693

Abstract

Alphaherpesviruses like herpes simplex virus are large DNA viruses characterized by their ability to establish lifelong latent infection in neurons. As for all herpesviruses, alphaherpesvirus virions contain a protein-rich layer called “tegument” that links the DNA-containing capsid to the glycoprotein-studded membrane envelope. Tegument [...] Read more.

Alphaherpesviruses like herpes simplex virus are large DNA viruses characterized by their ability to establish lifelong latent infection in neurons. As for all herpesviruses, alphaherpesvirus virions contain a protein-rich layer called “tegument” that links the DNA-containing capsid to the glycoprotein-studded membrane envelope. Tegument proteins mediate a diverse range of functions during the virus lifecycle, including modulation of the host-cell environment immediately after entry, transport of virus capsids to the nucleus during infection, and wrapping of cytoplasmic capsids with membranes (secondary envelopment) during virion assembly. Eleven tegument proteins that are conserved across alphaherpesviruses have been implicated in the formation of the tegument layer or in secondary envelopment. Tegument is assembled via a dense network of interactions between tegument proteins, with the redundancy of these interactions making it challenging to determine the precise function of any specific tegument protein. However, recent studies have made great headway in defining the interactions between tegument proteins, conserved across alphaherpesviruses, which facilitate tegument assembly and secondary envelopment. We summarize these recent advances and review what remains to be learned about the molecular interactions required to assemble mature alphaherpesvirus virions following the release of capsids from infected cell nuclei. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Exosome Biogenesis, Regulation, and Function in Viral Infection

by Marta Alenquer and Maria João Amorim

Viruses 2015, 7(9), 5066-5083; https://0-doi-org.brum.beds.ac.uk/10.3390/v7092862 - 17 Sep 2015

Cited by 265 | Viewed by 20082

Abstract

Exosomes are extracellular vesicles released upon fusion of multivesicular bodies(MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) duringthe process of MVB formation. Exosomes were shown to contain selectively sorted functionalproteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing [...] Read more.

Exosomes are extracellular vesicles released upon fusion of multivesicular bodies(MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) duringthe process of MVB formation. Exosomes were shown to contain selectively sorted functionalproteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in thephysiology of the healthy and diseased organism. Challenges in the field include the identificationof mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles andthe understanding of the underlying processes directing MVBs for degradation or fusion with theplasma membrane. The investigation into the formation and roles of exosomes in viral infection is inits early years. Although still controversial, exosomes can, in principle, incorporate any functionalfactor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation.This review initially focuses on the composition and biogenesis of exosomes. It then explores theregulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system,which is tightly regulated and able to respond to several stimuli that lead to alterations in thecomposition of its sub-compartments. We discuss the current knowledge of how these changesaffect exosomal release. We then summarize how different viruses exploit specific proteins ofendocytic sub-compartments and speculate that it could interfere with exosome function, althoughno direct link between viral usage of the endocytic system and exosome release has yet beenreported. Many recent reports have ascribed functions to exosomes released from cells infectedwith a variety of animal viruses, including viral spread, host immunity, and manipulation of themicroenvironment, which are discussed. Given the ever-growing roles and importance of exosomesin viral infections, understanding what regulates their composition and levels, and defining theirfunctions will ultimately provide additional insights into the virulence and persistence of infections. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Cloak and Dagger: Alternative Immune Evasion and Modulation Strategies of Poxviruses

by Susanna R. Bidgood and Jason Mercer

Viruses 2015, 7(8), 4800-4825; https://0-doi-org.brum.beds.ac.uk/10.3390/v7082844 - 21 Aug 2015

Cited by 29 | Viewed by 11382

Abstract

As all viruses rely on cellular factors throughout their replication cycle, to be successful they must evolve strategies to evade and/or manipulate the defence mechanisms employed by the host cell. In addition to their expression of a wide array of host modulatory factors, [...] Read more.

As all viruses rely on cellular factors throughout their replication cycle, to be successful they must evolve strategies to evade and/or manipulate the defence mechanisms employed by the host cell. In addition to their expression of a wide array of host modulatory factors, several recent studies have suggested that poxviruses may have evolved unique mechanisms to shunt or evade host detection. These potential mechanisms include mimicry of apoptotic bodies by mature virions (MVs), the use of viral sub-structures termed lateral bodies for the packaging and delivery of host modulators, and the formation of a second, “cloaked” form of infectious extracellular virus (EVs). Here we discuss these various strategies and how they may facilitate poxvirus immune evasion. Finally we propose a model for the exploitation of the cellular exosome pathway for the formation of EVs. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Regulation of the Host Antiviral State by Intercellular Communications

by Sonia Assil, Brian Webster and Marlène Dreux

Viruses 2015, 7(8), 4707-4733; https://0-doi-org.brum.beds.ac.uk/10.3390/v7082840 - 19 Aug 2015

Cited by 24 | Viewed by 11092

Abstract

Viruses usually induce a profound remodeling of host cells, including the usurpation of host machinery to support their replication and production of virions to invade new cells. Nonetheless, recognition of viruses by the host often triggers innate immune signaling, preventing viral spread and [...] Read more.

Viruses usually induce a profound remodeling of host cells, including the usurpation of host machinery to support their replication and production of virions to invade new cells. Nonetheless, recognition of viruses by the host often triggers innate immune signaling, preventing viral spread and modulating the function of immune cells. It conventionally occurs through production of antiviral factors and cytokines by infected cells. Virtually all viruses have evolved mechanisms to blunt such responses. Importantly, it is becoming increasingly recognized that infected cells also transmit signals to regulate innate immunity in uninfected neighboring cells. These alternative pathways are notably mediated by vesicular secretion of various virus- and host-derived products (miRNAs, RNAs, and proteins) and non-infectious viral particles. In this review, we focus on these newly-described modes of cell-to-cell communications and their impact on neighboring cell functions. The reception of these signals can have anti- and pro-viral impacts, as well as more complex effects in the host such as oncogenesis and inflammation. Therefore, these “broadcasting” functions, which might be tuned by an arms race involving selective evolution driven by either the host or the virus, constitute novel and original regulations of viral infection, either highly localized or systemic. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Exosomes: Implications in HIV-1 Pathogenesis

by Marisa N. Madison and Chioma M. Okeoma

Viruses 2015, 7(7), 4093-4118; https://0-doi-org.brum.beds.ac.uk/10.3390/v7072810 - 20 Jul 2015

Cited by 136 | Viewed by 14785

Abstract

Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by [...] Read more.

Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. The role of exosomes in viral pathogenesis, especially human immunodeficiency virus type 1 [HIV-1] is beginning to unravel. Recent research reports suggest that exosomes from various sources play important but different roles in the pathogenesis of HIV-1. From these reports, it appears that the source of exosomes is the defining factor for the exosomal effect on HIV-1. In this review, we will describe how HIV-1 infection is modulated by exosomes and in turn how exosomes are targeted by HIV-1 factors. Finally, we will discuss potentially emerging therapeutic options based on exosomal cargos that may have promise in preventing HIV-1 transmission. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Early Events in Chikungunya Virus Infection—From Virus CellBinding to Membrane Fusion

by Mareike K. S. Van Duijl-Richter, Tabitha E. Hoornweg, Izabela A. Rodenhuis-Zybert and Jolanda M. Smit

Viruses 2015, 7(7), 3647-3674; https://0-doi-org.brum.beds.ac.uk/10.3390/v7072792 - 07 Jul 2015

Cited by 90 | Viewed by 12554

Abstract

Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne alphavirus causing millions of infections in the tropical and subtropical regions of the world. CHIKV infection often leads to an acute self-limited febrile illness with debilitating myalgia and arthralgia. A potential long-term complication of CHIKV [...] Read more.

Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne alphavirus causing millions of infections in the tropical and subtropical regions of the world. CHIKV infection often leads to an acute self-limited febrile illness with debilitating myalgia and arthralgia. A potential long-term complication of CHIKV infection is severe joint pain, which can last for months to years. There are no vaccines or specific therapeutics available to prevent or treat infection. This review describes the critical steps in CHIKV cell entry. We summarize the latest studies on the virus-cell tropism, virus-receptor binding, internalization, membrane fusion and review the molecules and compounds that have been described to interfere with virus cell entry. The aim of the review is to give the reader a state-of-the-art overview on CHIKV cell entry and to provide an outlook on potential new avenues in CHIKV research. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Exosomes and Their Role in the Life Cycle and Pathogenesis of RNA Viruses

by Harendra Singh Chahar, Xiaoyong Bao and Antonella Casola

Viruses 2015, 7(6), 3204-3225; https://0-doi-org.brum.beds.ac.uk/10.3390/v7062770 - 19 Jun 2015

Cited by 177 | Viewed by 20110

Abstract

Exosomes are membrane-enclosed vesicles actively released into the extracellular space, whose content reflect the physiological/pathological state of the cells they originate from. These vesicles participate in cell-to-cell communication and transfer of biologically active proteins, lipids, and RNAs. Their role in viral infections is [...] Read more.

Exosomes are membrane-enclosed vesicles actively released into the extracellular space, whose content reflect the physiological/pathological state of the cells they originate from. These vesicles participate in cell-to-cell communication and transfer of biologically active proteins, lipids, and RNAs. Their role in viral infections is just beginning to be appreciated. RNA viruses are an important class of pathogens and affect millions of people worldwide. Recent studies on Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), human T-cell lymphotropic virus (HTLV), and Dengue Virus (DENV) have demonstrated that exosomes released from infected cells harbor and deliver many regulatory factors including viral RNA and proteins, viral and cellular miRNA, and other host functional genetic elements to neighboring cells, helping to establish productive infections and modulating cellular responses. Exosomes can either spread or limit an infection depending on the type of pathogen and target cells, and can be exploited as candidates for development of antiviral or vaccine treatments. This review summarizes recent progress made in understanding the role of exosomes in RNA virus infections with an emphasis on their potential contribution to pathogenesis. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessReview

Dynamics of Virus-Receptor Interactions in Virus Binding, Signaling, and Endocytosis

by Steeve Boulant, Megan Stanifer and Pierre-Yves Lozach

Viruses 2015, 7(6), 2794-2815; https://0-doi-org.brum.beds.ac.uk/10.3390/v7062747 - 02 Jun 2015

Cited by 129 | Viewed by 20736

Abstract

During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host [...] Read more.

During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host cell membrane surface, binding to receptors, signaling, internalization, and delivery of the genetic information. The focus of this review is on the very initial steps of virus entry, from receptor binding to particle uptake into the host cell. We will discuss how viruses find their receptor, move to sub-membranous regions permissive for entry, and how they hijack the receptor-mediated signaling pathway to promote their internalization. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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