Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United States and dependent areas, 2016, vol. 28. 2017.
World Health Organization. HIV Drug Resistance Report 2017. Licence: CC BY-NC-SA 3.0 IGO.
Cihlar T, Fordyce M. Current status and prospects of HIV treatment. Curr Opin Virol. 2016;18:50–6.
Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4):a007161.
Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69–81.
Lindl KA, et al. HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharmacol. 2010;5(3):294–309.
Heaton RK, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17(1):3–16.
Mateen FJ, et al. Neurologic disorders incidence in HIV+ vs HIV− men: Multicenter AIDS Cohort Study, 1996–2011. Neurology. 2012;79(18):1873–80.
Alford K, Vera JH. Cognitive impairment in people living with HIV in the ART era: a review. Brit Med Bull. 2018;127:55–68.
Carvalhal A, et al. Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study. J Neurovirol. 2016;22(3):349–57.
Caniglia EC, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology. 2014;83(2):134–41.
Nightingale S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol. 2014;13(11):1139–51.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–79.
Huotari J, Helenius A. Endosome maturation. EMBO J. 2011;30(17):3481–500.
Edgar JR. Q&A: What are exosomes, exactly? BMC Biol. 2016;14:46.
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.
Johnstone RM. The Jeanne Manery-Fisher Memorial Lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins. Biochem Cell Biol. 1992;70(3–4):179–90.
Harding CV, Heuser JE, Stahl PD. Exosomes: looking back three decades and into the future. J Cell Biol. 2013;200(4):367–71.
Rashed MH, et al. Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci. 2017;18(3):538.
Hurley JH. ESCRTs are everywhere. EMBO J. 2015;34(19):2398–407.
Hurley JH. The ESCRT complexes. Crit Rev Biochem Mol Biol. 2010;45(6):463–87.
Villarroya-Beltri C, et al. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014;28:3–13.
Armstrong D, Wildman DE. Extracellular vesicles and the promise of continuous liquid biopsies. J Pathol Transl Med. 2018;52(1):1–8.
McKelvey KJ, et al. Exosomes: mechanisms of uptake. J Circ Biomark. 2015;4:7.
Shi Y, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507.
Fevrier B, et al. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 2004;101(26):9683–8.
Asai H, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18(11):1584–93.
de Jong OG, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 2012. https://doi.org/10.3402/jev.v1i0.18396.
Momen-Heravi F, et al. Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med. 2015;13:261.
Kreimer S, et al. Mass-spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics. J Proteome Res. 2015;14(6):2367–84.
Masaoutis C, et al. Exosomes in lung cancer diagnosis and treatment. From the translating research into future clinical practice. Biochimie. 2018;151:27–36.
Ensoli B, et al. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature. 1990;345(6270):84–6.
Levy DN, et al. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1994;91(23):10873–7.
Fujii Y, et al. Soluble Nef antigen of HIV-1 is cytotoxic for human CD4+ T cells. FEBS Lett. 1996;393(1):93–6.
Hoshino S, et al. Vpr in plasma of HIV type 1-positive patients is correlated with the HIV type 1 RNA titers. AIDS Res Hum Retrovir. 2007;23(3):391–7.
Mediouni S, et al. Antiretroviral therapy does not block the secretion of the human immunodeficiency virus tat protein. Infect Disord Drug Targets. 2012;12(1):81–6.
Lenassi M, et al. HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic. 2010;11(1):110–22.
Puzar Dominkus P, et al. Nef is secreted in exosomes from Nef.GFP-expressing and HIV-1-infected human astrocytes. J Neurovirol. 2017;23(5):713–24.
McNamara RP, et al. Nef secretion into extracellular vesicles or exosomes is conserved across human and simian immunodeficiency viruses. MBio. 2018;9(1):e02344.
Rahimian P, He JJ. Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein. J Neurovirol. 2016;22(6):774–88.
Park IW, He JJ. HIV-1 is budded from CD4+ T lymphocytes independently of exosomes. Virol J. 2010;7:234.
Arakelyan A, et al. Extracellular vesicles carry HIV Env and facilitate HIV infection of human lymphoid tissue. Sci Rep. 2017;7(1):1695.
Anyanwu SI, et al. Detection of HIV-1 and human proteins in urinary extracellular vesicles from HIV+ patients. Adv Virol. 2018;2018:7863412.
Narayanan A, et al. Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem. 2013;288(27):20014–33.
Klase Z, et al. HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression. Retrovirology. 2009;6:18.
Narayanan A, et al. Analysis of the roles of HIV-derived microRNAs. Expert Opin Biol Ther. 2011;11(1):17–29.
Barclay RA, et al. Exosomes from uninfected cells activate transcription of latent HIV-1. J Biol Chem. 2017;292(28):11682–701.
Hladnik A, et al. Trans-activation response element RNA is detectable in the plasma of a subset of Aviremic HIV-1-infected patients. Acta Chim Slov. 2017;64:530–6.
Jaworski E, et al. The use of Nanotrap particles technology in capturing HIV-1 virions and viral proteins from infected cells. PLoS ONE. 2014;9(5):e96778.
Columba Cabezas S, Federico M. Sequences within RNA coding for HIV-1 Gag p17 are efficiently targeted to exosomes. Cell Microbiol. 2013;15(3):412–29.
Sampey GC, et al. Exosomes and their role in CNS viral infections. J Neurovirol. 2014;20(3):199–208.
Anderson MR, Kashanchi F, Jacobson S. Exosomes in viral disease. Neurotherapeutics. 2016;13(3):535–46.
Chahar HS, Bao X, Casola A. Exosomes and their role in the life cycle and pathogenesis of RNA viruses. Viruses. 2015;7(6):3204–25.
Haase AT. Pathogenesis of lentivirus infections. Nature. 1986;322(6075):130–6.
Gould SJ, Booth AM, Hildreth JE. The Trojan exosome hypothesis. Proc Natl Acad Sci U S A. 2003;100(19):10592–7.
Booth AM, et al. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol. 2006;172(6):923–35.
Nguyen DG, et al. Evidence that HIV budding in primary macrophages occurs through the exosome release pathway. J Biol Chem. 2003;278(52):52347–54.
Chertova E, et al. Proteomic and biochemical analysis of purified human immunodeficiency virus type 1 produced from infected monocyte-derived macrophages. J Virol. 2006;80(18):9039–52.
Sherer NM, et al. Visualization of retroviral replication in living cells reveals budding into multivesicular bodies. Traffic. 2003;4(11):785–801.
Pelchen-Matthews A, Raposo G, Marsh M. Endosomes, exosomes and Trojan viruses. Trends Microbiol. 2004;12(7):310–6.
Izquierdo-Useros N, et al. Exosomes and retroviruses: the chicken or the egg? Cell Microbiol. 2011;13(1):10–7.
Welsch S, et al. HIV-1 buds predominantly at the plasma membrane of primary human macrophages. PLoS Pathog. 2007;3(3):e36.
Deneka M, et al. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J Cell Biol. 2007;177(2):329–41.
Grigorov B, et al. A role for CD81 on the late steps of HIV-1 replication in a chronically infected T cell line. Retrovirology. 2009;6:28.
Coren LV, Shatzer T, Ott DE. CD45 immunoaffinity depletion of vesicles from Jurkat T cells demonstrates that exosomes contain CD45: no evidence for a distinct exosome/HIV-1 budding pathway. Retrovirology. 2008;5:64.
Fang Y, et al. Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol. 2007;5(6):e158.
Jolly C, Sattentau QJ. Human immunodeficiency virus type 1 assembly, budding, and cell-cell spread in T cells take place in tetraspanin-enriched plasma membrane domains. J Virol. 2007;81(15):7873–84.
Jager S, et al. Global landscape of HIV-human protein complexes. Nature. 2011;481(7381):365–70.
Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25(6):364–72.
Florin L, Lang T. Tetraspanin assemblies in virus infection. Front Immunol. 2018;9:1140.
Pols MS, Klumperman J. Trafficking and function of the tetraspanin CD63. Exp Cell Res. 2009;315(9):1584–92.
Perez-Hernandez D, et al. The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem. 2013;288(17):11649–61.
Lalonde MS, et al. Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR) RNA. PLoS Pathog. 2011;7(5):e1002038.
Ono A, Freed EO. Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proc Natl Acad Sci U S A. 2001;98(24):13925–30.
Ono A. Relationships between plasma membrane microdomains and HIV-1 assembly. Biol Cell. 2010;102(6):335–50.
Tan SS, et al. Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane. J Extracell Vesicles. 2013. https://doi.org/10.3402/jev.v2i0.22614.
Valapala M, Vishwanatha JK. Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2. J Biol Chem. 2011;286(35):30911–25.
Hogue IB, et al. Gag induces the coalescence of clustered lipid rafts and tetraspanin-enriched microdomains at HIV-1 assembly sites on the plasma membrane. J Virol. 2011;85(19):9749–66.
Sette P, et al. The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif. J Virol. 2010;84(16):8181–92.
Usami Y, et al. The ESCRT pathway and HIV-1 budding. Biochem Soc Trans. 2009;37(Pt 1):181–4.
Chen L, et al. Pathways of production and delivery of hepatocyte exosomes. J Cell Commun Signal. 2018;12(1):343–57.
Mele AR, et al. Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P2 at the epicenter. Traffic. 2018. https://doi.org/10.1111/tra.12578.
Sutaria DS, et al. Low active loading of cargo into engineered extracellular vesicles results in inefficient miRNA mimic delivery. J Extracell Vesicles. 2017;6(1):1333882.
Klase Z, et al. HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol. 2007;8:63.
Melo SA, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26(5):707–21.
Janas T, et al. Mechanisms of RNA loading into exosomes. FEBS Lett. 2015;589(13):1391–8.
Roeth JF, Collins KL. Human immunodeficiency virus type 1 Nef: adapting to intracellular trafficking pathways. Microbiol Mol Biol Rev. 2006;70(2):548–63.
Campbell TD, et al. HIV-1 Nef protein is secreted into vesicles that can fuse with target cells and virions. Ethn Dis. 2008;18(2 Suppl 2):S2-14-9.
Witkowski W, Verhasselt B. Contributions of HIV-1 Nef to immune dysregulation in HIV-infected patients: a therapeutic target? Expert Opin Ther Targets. 2013;17(11):1345–56.
Giese SI, et al. Specific and distinct determinants mediate membrane binding and lipid raft incorporation of HIV-1(SF2) Nef. Virology. 2006;355(2):175–91.
Mukerji J, et al. Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation. Retrovirology. 2012;9:33.
Olivetta E, et al. The contribution of extracellular Nef to HIV-induced pathogenesis. Curr Drug Targets. 2016;17(1):46–53.
Ali SA, et al. Genetic characterization of HIV type 1 Nef-induced vesicle secretion. AIDS Res Hum Retrovir. 2010;26(2):173–92.
Shelton MN, et al. Secretion modification region-derived peptide disrupts HIV-1 Nef’s interaction with mortalin and blocks virus and Nef exosome release. J Virol. 2012;86(1):406–19.
Pilzer D, et al. Emission of membrane vesicles: roles in complement resistance, immunity and cancer. Springer Semin Immunopathol. 2005;27(3):375–87.
Muratori C, et al. Massive secretion by T cells is caused by HIV Nef in infected cells and by Nef transfer to bystander cells. Cell Host Microbe. 2009;6(3):218–30.
Arenaccio C, et al. Cell activation and HIV-1 replication in unstimulated CD4+ T lymphocytes ingesting exosomes from cells expressing defective HIV-1. Retrovirology. 2014;11:46.
Arenaccio C, et al. Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license quiescent CD4+ T lymphocytes to replicate HIV-1 through a Nef- and ADAM17-dependent mechanism. J Virol. 2014;88(19):11529–39.
Arenaccio C, et al. Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1. Retrovirology. 2015;12:87.
Sampey GC, et al. Exosomes from HIV-1-infected cells stimulate production of pro-inflammatory cytokines through trans-activating response (TAR) RNA. J Biol Chem. 2016;291(3):1251–66.
Bernard MA, et al. Novel HIV-1 miRNAs stimulate TNFalpha release in human macrophages via TLR8 signaling pathway. PLoS ONE. 2014;9(9):e106006.
Stroud JC, et al. Structural basis of HIV-1 activation by NF-kappaB—a higher-order complex of p50:RelA bound to the HIV-1 LTR. J Mol Biol. 2009;393(1):98–112.
Hiscott J, Kwon H, Genin P. Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest. 2001;107(2):143–51.
Raymond AD, et al. HIV Type 1 Nef is released from infected cells in CD45(+) microvesicles and is present in the plasma of HIV-infected individuals. AIDS Res Hum Retroviru. 2011;27(2):167–78.
Konadu KA, et al. Hallmarks of HIV-1 pathogenesis are modulated by Nef’s secretion modification region. J AIDS Clin Res. 2015. https://doi.org/10.4172/2155-6113.1000476.
Markle TJ, Philip M, Brockman MA. HIV-1 Nef and T-cell activation: a history of contradictions. Future Virol. 2013. https://doi.org/10.2217/fvl.13.20.
Raymond AD, et al. Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides. J Neurovirol. 2016;22(2):129–39.
Felli C, et al. HIV-1 Nef signaling in intestinal mucosa epithelium suggests the existence of an active inter-kingdom crosstalk mediated by exosomes. Front Microbiol. 2017;8:1022.
Atluri VS, et al. Effect of human immunodeficiency virus on blood–brain barrier integrity and function: an update. Front Cell Neurosci. 2015;9:212.
Corasaniti MT, et al. Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G. Biochem Biophys Res Commun. 2000;274(3):664–9.
Alirezaei M, et al. Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci. 2007;27(41):11047–55.
Capone C, et al. A role for spermine oxidase as a mediator of reactive oxygen species production in HIV-Tat-induced neuronal toxicity. Free Radic Biol Med. 2013;63:99–107.
Ferrucci A, Nonnemacher MR, Wigdahl B. Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis. Adv Virus Res. 2011;81:165–99.
Malik S, Eugenin EA. Mechanisms of HIV Neuropathogenesis: role of Cellular Communication Systems. Curr HIV Res. 2016;14(5):400–11.
James T, et al. Defining the roles for Vpr in HIV-1-associated neuropathogenesis. J Neurovirol. 2016;22(4):403–15.
Singh IN, et al. Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. Neuroscience. 2005;135(3):781–90.
Khan MB, et al. Nef exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Abeta(1-42) secretion in SH-SY5Y neural cells. J Neurovirol. 2016;22(2):179–90.
Ortega M, Ances BM. Role of HIV in amyloid metabolism. J Neuroimmune Pharmacol. 2014;9(4):483–91.
Andras IE, et al. Extracellular vesicles of the blood–brain barrier: role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci. 2017;79:12–22.
Lee JH, et al. HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Mol Cell. 2013;49(4):668–79.
Kosaka N, et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285(23):17442–52.
Dinkins MB, et al. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging. 2014;35(8):1792–800.
Essandoh K, et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015;1852(11):2362–71.
Fleshner M, Crane CR. Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol. 2017;38(10):768–76.
Huang MB, et al. Secretion modification region-derived peptide blocks exosome release and mediates cell cycle arrest in breast cancer cells. Oncotarget. 2017;8(7):11302–15.
Levy S. Function of the tetraspanin molecule CD81 in B and T cells. Immunol Res. 2014;58(2–3):179–85.
Ji C, et al. Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody. Hepatology. 2015;61(4):1136–44.
Liu X, et al. Synthesized peptide 710-725 from HCV subtype 1a E2 glycoprotein blocks HCV infection through competitive binding of CD81. Int J Mol Med. 2016;37(3):836–42.
Cui HK, et al. Stapled peptide-based membrane fusion inhibitors of hepatitis C virus. Bioorg Med Chem. 2013;21(12):3547–54.
Scarborough RJ, Gatignol A. RNA interference therapies for an HIV-1 functional cure. Viruses. 2017. https://doi.org/10.3390/v10010008.
Bobbin ML, Burnett JC, Rossi JJ. RNA interference approaches for treatment of HIV-1 infection. Genome Med. 2015;7(1):50.
Leonard JN, et al. HIV evades RNA interference directed at TAR by an indirect compensatory mechanism. Cell Host Microbe. 2008;4(5):484–94.
Mousseau G, Valente S. Strategies to block HIV transcription: focus on small molecule tat inhibitors. Biology (Basel). 2012;1(3):668–97.
Bohjanen PR, Liu Y, Garcia-Blanco MA. TAR RNA decoys inhibit tat-activated HIV-1 transcription after preinitiation complex formation. Nucleic Acids Res. 1997;25(22):4481–6.
Mousseau G, et al. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe. 2012;12(1):97–108.
Hayashi T, et al. Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription. Antivir Res. 2017;146:76–85.
Kessing CF, et al. In vivo suppression of HIV rebound by didehydro-cortistatin A, a “block-and-lock” strategy for HIV-1 treatment. Cell Rep. 2017;21(3):600–11.
Blazek D, et al. The CD8+ cell non-cytotoxic antiviral response affects RNA polymerase II-mediated human immunodeficiency virus transcription in infected CD4+ cells. J Gen Virol. 2016;97(1):220–4.
Tumne A, et al. Noncytotoxic suppression of human immunodeficiency virus type 1 transcription by exosomes secreted from CD8+ T cells. J Virol. 2009;83(9):4354–64.
Madison MN, Okeoma CM. Exosomes: implications in HIV-1 pathogenesis. Viruses. 2015;7(7):4093–118.
Madison MN, Roller RJ, Okeoma CM. Human semen contains exosomes with potent anti-HIV-1 activity. Retrovirology. 2014;11:102.
Welch JL, et al. Semen exosomes promote transcriptional silencing of HIV-1 by disrupting NF-kB/Sp1/Tat circuitry. J Virol. 2018. https://doi.org/10.1128/JVI.00731-18.
Medapalli RK, He JC, Klotman PE. HIV-associated nephropathy: pathogenesis. Curr Opin Nephrol Hypertens. 2011;20(3):306–11.
Kim Y, Anderson JL, Lewin SR. Getting the “kill” into “shock and kill”: strategies to eliminate latent HIV. Cell Host Microbe. 2018;23(1):14–26.
Darcis G, Das AT, Berkhout B. Tackling HIV persistence: pharmacological versus CRISPR-based shock strategies. Viruses. 2018. https://doi.org/10.3390/v10040157.
Kadiu I, et al. Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol. 2012;189(2):744–54.