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Review
. 2015 Jul 20;7(7):4093-118.
doi: 10.3390/v7072810.

Exosomes: Implications in HIV-1 Pathogenesis

Marisa N Madison  1 , Chioma M Okeoma  2   3
Affiliations
Review

Exosomes: Implications in HIV-1 Pathogenesis

Marisa N Madison et al. Viruses. .

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 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.

Keywords: HIV-1; exosome; extracellular vesicle; murine AIDS; nanoparticle; semen; seminal plasma.

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Figures

Figure 1
Figure 1
Cell culture derived exosomes modulate HIV-1 infection: (1) Cell-free HIV-1 virions bind host cells via viral envelope (Env) to (2) CD4 on target cell plasma membrane followed by binding to a viral co-receptor, CXCR4 or CCR5; (3) Co-receptor binding initiates viral fusion, whereupon viral contents including (4) single stranded viral genomic RNA (gRNA); reverse transcriptase (RT) and integrase (IN] are emptied into the cellular cytoplasm. Viral gRNA is (5) reverse transcribed by HIV-1 reverse transcriptase (RT) into (6) double stranded viral copy DNA (HIV-1 DNA), which is incorporated by (7) viral IN enzyme as (8) proviral DNA within human genomic DNA (gDNA). The provirus is transcribed by host cellular machinery into (9) nascent viral RNA, which is translated by host cellular machinery into (10) HIV-1 proteins, including Nef. Viral proteins are assembled with nascent viral RNA including HIV TAR RNA sequences (vmiRTAR) into (11) budding progeny virions. During the budding process viral protease initiates cleavage of viral proteins in budding progeny. Budding progeny break free from the cell as (12) immature progeny within the extracellular milieu, which undergo maturation with the completion of viral protease-mediated processing into (13) mature progeny capable of propagating productive HIV-1 infection in neighboring and distal cells; (14) Inward budding of the cellular plasma membrane during endocytosis generates endosomes; (15) Inward budding of the endosome membrane generates exosomes with cellular cytosol derived proteins and nucleotides sequestered within the exosome lumen, including HIV Nef and vmiRTAR; (16) Back fusion of the endosome containing exosomes (multivesicular body) to the cellular plasma membrane releases exosomes into the extracellular milieu. Exosomes derived from HIV-1 infected cell cultures may enhance infection through the following mechanisms: (17) transferring viral binding and entry receptors to HIV-1 susceptible cells, thereby increasing the expression of viral binding sites on the surface of the host cellular plasma membrane. (18) Nef-mediated internalization and degradation of CD4 molecules and Nef-mediated reduction of CD4 expression on the surface of exosomes and (19) suppression of Bim and Cdk9 expression and apoptosis by viral miRNA generated from vmiRTAR. The protective roles of cell culture derived exosomes from uninfected cells may be mediated by: (20) Apobec3G enwrapped within exosomes and (21) exosomal CD4 binding to HIV-1 Env.
Figure 2
Figure 2
Model of biofluid exosome antiviral functions within the HIV-1 life cycle: (1–13) HIV-1 life cycle as defined in Figure 1 legend. Biofluid exosomes may interact with free HIV-1 and (14) sequester free viral particles within exosome aggregates thereby inhibiting HIV-1 infection by preventing virus from binding to target cells. Biofluid exosomes that present CD4 molecules on the exosome surface may (15) compete for viral Env binding to CD4 on the host cell plasma membrane, thereby inhibiting HIV-1 infection by preventing virus from binding to target cells. Competition may also occur via binding of exosome ligands/receptors to other receptors/ligands on the viral envelope (e.g., phosphatidylserine/annexin interaction). Exosomes are taken up by cells via direct fusion with the plasma membrane or by endocytosis into endosomes that may subsequently fuse with lysosomes. Exosomal interaction with HIV-1 may lead to entry of the virus into the cell via endocytosis, leading to (16) exosomal delivery of virus into lysosomes for degradation, subsequently inhibiting HIV-1 infection. (17) HIV-1 gRNA may be degraded or otherwise rendered non-functional by exosomal antiviral proteins including Apobec3g, or following translation of exosomal antiviral mRNA into antiviral proteins including Apobec3g, or by antiviral exosomal miRNA. Exosomal antiviral protein, mRNA or miRNA may (18) inhibit viral RT and reverse transcription processes by blocking RT activity, blocking RT binding to RNA or facilitating degradation of RT. In the event that exosomes fuse with the cellular plasma membrane, they may enrich the cell surface with proteins that may function to (19) tether budding progeny virions to the plasma membrane (e.g., BST-2/tetherin, PS/Annexin), preventing them from diffusing into the extracellular milieu and subsequently preventing HIV-1 propagation.
Figure 3
Figure 3
Biofluid derived exosomes modulate HIV-1 infection: (1–6) HIV-1 life cycle as defined in Figure 1 legend. Exosomes derived from human semen inhibit direct, trans and cell-to-cell transmission of HIV in human PBL, T cells and monocytes by (7) mediating deleterious effects on HIV reverse transcriptase and reverse transcription processes. Exosomes derived from human blood plasma or blood serum have no effect on HIV infectivity. Exosomes derived from human breast milk inhibit cell-to-cell transmission of HIV from monocyte-derived dendritic cells (MDDC) to CD4+ T cells by (8) competing for binding of HIV to DC-SIGN on MDDC. Biofluid derived exosomes may also inhibit HIV infectivity by (9) exosomal donation or transfer of antiviral cargo to recipient cells; (10) inhibition of cellular signaling or molecules required for HIV replication or (11) induction of cellular signaling or donation of exosomal factors resulting in enhancement of expression of molecules responsible for host protection against HIV.
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References

    1. Harding C., Heuser J., Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 1983;97:329–339. doi: 10.1083/jcb.97.2.329. - DOI - PMC - PubMed
    1. Pan B.T., Teng K., Wu C., Adam M., Johnstone R.M. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J. Cell Biol. 1985;101:942–948. doi: 10.1083/jcb.101.3.942. - DOI - PMC - PubMed
    1. Johnstone R.M., Adam M., Hammond J.R., Orr L., Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes) J. Biol. Chem. 1987;262:9412–9420. - PubMed
    1. Raposo G., Nijman H.W., Stoorvogel W., Liejendekker R., Harding C.V., Melief C.J., Geuze H.J. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 1996;183:1161–1172. doi: 10.1084/jem.183.3.1161. - DOI - PMC - PubMed
    1. Valadi H., Ekstrom K., Bossios A., Sjostrand M., Lee J.J., Lotvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007;9:654–659. doi: 10.1038/ncb1596. - DOI - PubMed