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Review
. 2020 Oct 21;12(10):1200.
doi: 10.3390/v12101200.

Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans

Allen Caobi  1 , Madhavan Nair  1 , Andrea D Raymond  1
Affiliations
Review

Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans

Allen Caobi et al. Viruses. .

Abstract

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review's scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.

Keywords: HIV; ZIKA; coronavirus; exosomes; extracellular vesicles (EVs); herpes virus; pathology; retrovirus; therapeutics; viruses.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Size ranges of EVs and characterization. (A) Exosomes released when MVBs fuse with the PM are vesicles that range from 30–120 nm in diameter. Due to the similarity in size to viruses, exosomes are difficult to isolate from virus-infected blood. Microvesicles ranging from 150 nm–1 µm in diameter derive via shedding/budding from the PM surface. Apoptotic vesicles released from apoptotic cells range from 1 µm–5 µm in diameter. (B) Exosomes transport a variety of proteins and genetic material. Lipid raft-derived microdomains form larger domains responsible for inducing budding in an ESCRT-independent pathway of lateral cargo segregation. Exosomes are highly enriched with tetraspanins, which play a critical role in the ESCRT-independent pathway of endosomal sorting and function as exosome-defining surface markers. Depending on the cell of origin, exosomes may contain differing immunoregulatory molecules, such as MHC-I/II. Lastly, exosomes traffic a variety of host cell/viral protein, mRNA, and miRNA.
Figure 2
Figure 2
Comparison of viral and EV biogenesis. Infected cells concurrently release EVs and retroviral particles, possessing shared pathways at the MVB and the PM, whilst incorporating SNARE/SNAP Rab27 and tetraspanins, and ESCRT proteins in both pathways [1]. Depicted here is: sorting and transport of the exosome-specific proteins to the nascent ILVs, and excision from the MVB, Gag-mediated virion assembly at the PM or the MVB, and EV and virion release, [1,3].
Figure 3
Figure 3
EV-mediated anti-ZIKV effects. (A) HPT cell-derived EVs bound with miRNAs with potent anti-viral properties, have been detected. The EVs migrate to non-placental recipient cells conferring anti-ZIKV protection and up-regulating autophagy. (B) ZIKV infection of HPT cells results in an anti-ZIKV host-cell response transported via exosome-trafficking, downregulating miR-21 in uninfected HPTs, reducing TLR7-mediated Neurotoxicity.
Figure 4
Figure 4
HIV-1 infected cell-derived EV-mediated anti-viral and pro-viral effects. Upon infection with HIV-1, cells release EVs which may modulate HIV-1 pathogenesis, either restricting infection or enhancing it. (A) EVs can deliver anti-viral particles, such as A3G, inhibiting HIV-1 replication. (B) EV-mediate dissemination of TLR ligands, including HIV-restriction miRNAs, ISGs, IFNs, and anti-viral factors transfer anti-HIV protection and alert neighboring cells of ongoing infection. (C) EVs derived from bodily fluids such as breast milk, semen, and vaginal fluids can hinder HIV-1 infection by blocking HIV-1 replication after viral entry or competing with HIV-1 for receptor access. Breast milk-derived EVs compete with HIV-1 binding to the DC-SIGN receptor, preventing vertical transmission. Internalization of either semen or vaginal fluid-derived EVs results in deleterious effects upon HIV-1 reverse transcriptase activity leading to a post-entry block of HIV-1 replication. (D) EV-mediated transport of viral particles, such as HIV-1 Nef protein, triggers viral-mediated apoptosis of anti-viral immune cells. (E) Transport of HIV-1 chemokine co-receptors CCR5 or CXCR4 via EVs to cells deficient in these receptors, generates new populations of cells which are now susceptible to HIV-1 infection. HIV-1 infected primary cell-derived EVs carry TAR element RNA, enhancing susceptibility to HIV-1 infection in undifferentiated naïve cells. (F) Lastly, EVs may aggregate upon the HIV-1 virion as a result of exploitation of exosomal surface properties, camouflaging HIV-1 and facilitating viral spread to uninfected innate and adaptive immune cells.
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