Role of Exosomes in Human Retroviral Mediated Disorders

  • Monique Anderson
  • Fatah Kashanchi
  • Steven Jacobson
INVITED REVIEW

Abstract

Retroviruses comprise an ancient and varied group of viruses with the unique ability to integrate DNA from an RNA transcript into the genome, a subset of which are able to integrate in humans. The timing of these integrations during human history has dictated whether these viruses have remained exogenous and given rise to various human diseases or have become inseparable from the host genome (endogenous retroviruses). Given the ability of retroviruses to integrate into the host and subsequently co-opt host cellular process for viral propagation, retroviruses have been shown to be closely associated with several cellular processes including exosome formation. Exosomes are 30-150 nm unilamellar extracellular vesicles that originate from intraluminal vesicles (ILVs) that form in the endosomal compartment. Exosomes have been shown to be important in intercellular communication and immune cell function. Almost every cell type studied has been shown to produce these types of vesicles, with the cell type dictating the contents, which include proteins, mRNA, and miRNAs. Importantly, recent evidence has shown that infection by viruses, including retroviruses, alter the contents and subsequent function of produced exosomes. In this review, we will discuss the important retroviruses associated with human health and disease. Furthermore, we will delve into the impact of exosome formation and manipulation by integrated retroviruses on human health, survival, and human retroviral disease pathogenesis.

Keywords

Exosomes Intraluminal vesicles (ILV) Transposable element Retroviruses Human endogenous retroviruses (HERV) Provirus Endosomal sorting complexes required fro transport (ESCRT) 

Notes

Compliance with Ethical Standards

Conflict of Interest

Anderson M declares that she has no conflicts of interest. Kashanchi F declares that he has no conflicts of interest. Jacobson S declares that he has no conflicts of interest.

Human and Animal Rights and Informed Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consents were obtained from all individual participants included in the study.

References

  1. Aiewsakun P, Katzourakis A (2017) Marine origin of retroviruses in the early Palaeozoic era. Nat Commun 8:13954.  https://doi.org/10.1038/ncomms13954 PubMedPubMedCentralGoogle Scholar
  2. Alefantis T, Jain P, Ahuja J, Mostoller K, Wigdahl B (2005) HTLV-1 tax nucleocytoplasmic shuttling, interaction with the secretory pathway, extracellular signaling, and implications for neurologic disease. J Biomed Sci 12:961–974.  https://doi.org/10.1007/s11373-005-9026-x PubMedGoogle Scholar
  3. Alefantis T, Mostoller K, Jain P, Harhaj E, Grant C, Wigdahl B (2005) Secretion of the human T cell leukemia virus type I transactivator protein tax. J Biol Chem 280:17353–17362.  https://doi.org/10.1074/jbc.M409851200 PubMedGoogle Scholar
  4. Alenquer M, Amorim MJ (2015) Exosome biogenesis, regulation, and function in viral infection. Viruses 7:5066–5083.  https://doi.org/10.3390/v7092862 PubMedPubMedCentralGoogle Scholar
  5. Alfahad T, Nath A (2013) Retroviruses and amyotrophic lateral sclerosis. Antivir Res 99:180–187.  https://doi.org/10.1016/j.antiviral.2013.05.006 PubMedPubMedCentralGoogle Scholar
  6. Ali SA, Huang MB, Campbell PE, Roth WW, Campbell T, Khan M, Newman G, Villinger F, Powell MD, Bond VC (2010) Genetic characterization of HIV type 1 Nef-induced vesicle secretion. AIDS Res Hum Retrovir 26:173–192.  https://doi.org/10.1089/aid.2009.0068 PubMedPubMedCentralGoogle Scholar
  7. Anderson MR, Enose-Akahata Y, Massoud R, Ngouth N, Tanaka Y, Oh U, Jacobson S (2014) Epigenetic modification of the FoxP3 TSDR in HAM/TSP decreases the functional suppression of Tregs. J NeuroImmune Pharmacol 9:522–532.  https://doi.org/10.1007/s11481-014-9547-z PubMedPubMedCentralGoogle Scholar
  8. Anderson MR, Kashanchi F, Jacobson S (2016) Exosomes in viral disease. Neurotherapeutics 13:535–546.  https://doi.org/10.1007/s13311-016-0450-6 PubMedPubMedCentralGoogle Scholar
  9. Andreu Z, Yanez-Mo M (2014) Tetraspanins in extracellular vesicle formation and function. Front Immunol 5:442.  https://doi.org/10.3389/fimmu.2014.00442 PubMedPubMedCentralGoogle Scholar
  10. Arenaccio C, Anticoli S, Manfredi F, Chiozzini C, Olivetta E, Federico M (2015) Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1. Retrovirology 12:87.  https://doi.org/10.1186/s12977-015-0216-y PubMedPubMedCentralGoogle Scholar
  11. Arenaccio C, Chiozzini C, Columba-Cabezas S, Manfredi F, Affabris E, Baur A, Federico M (2014) 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 88:11529–11539.  https://doi.org/10.1128/JVI.01712-14 PubMedPubMedCentralGoogle Scholar
  12. Arias M, Fan H (2014) The saga of XMRV: a virus that infects human cells but is not a human virus Emerg Microbes Infect 3:e doi: https://doi.org/10.1038/emi.2014.25
  13. Baglio SR, Pegtel DM, Baldini N (2012) Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 3:359.  https://doi.org/10.3389/fphys.2012.00359 PubMedPubMedCentralGoogle Scholar
  14. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685.  https://doi.org/10.1038/ncb2502 PubMedGoogle Scholar
  15. Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180.  https://doi.org/10.1038/ncomms1180 PubMedPubMedCentralGoogle Scholar
  16. Bangham CRM, Matsuoka M (2017) Human T-cell leukaemia virus type 1: parasitism and pathogenesis. Philos Trans R Soc Lond Ser B Biol Sci 372:20160272.  https://doi.org/10.1098/rstb.2016.0272 Google Scholar
  17. Bannert N, Kurth R (2004) Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci U S A 101(Suppl 2):14572–14579.  https://doi.org/10.1073/pnas.0404838101 PubMedPubMedCentralGoogle Scholar
  18. Baratella M, Forlani G, Raval GU, Tedeschi A, Gout O, Gessain A, Tosi G, Accolla RS (2017) Cytoplasmic localization of HTLV-1 HBZ protein: a biomarker of HTLV-1-associated myelopathy/tropical spastic Paraparesis (HAM/TSP). PLoS Negl Trop Dis 11:e0005285.  https://doi.org/10.1371/journal.pntd.0005285 PubMedPubMedCentralGoogle Scholar
  19. Barbulescu M, Turner G, Seaman MI, Deinard AS, Kidd KK, Lenz J (1999) Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr Biol 9:861–868PubMedGoogle Scholar
  20. Bashratyan R, Regn D, Rahman MJ, Marquardt K, Fink E, Hu WY, Elder JH, Binley J, Sherman LA, Dai YD (2017) Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice. Eur J Immunol 47:575–584.  https://doi.org/10.1002/eji.201646755 PubMedGoogle Scholar
  21. Bernard MA, Zhao H, Yue SC, Anandaiah A, Koziel H, Tachado SD (2014) Novel HIV-1 miRNAs stimulate TNFalpha release in human macrophages via TLR8 signaling pathway. PLoS One 9:e106006.  https://doi.org/10.1371/journal.pone.0106006 PubMedPubMedCentralGoogle Scholar
  22. Bissig C, Gruenberg J (2014) ALIX and the multivesicular endosome: ALIX in wonderland. Trends Cell Biol 24:19–25.  https://doi.org/10.1016/j.tcb.2013.10.009 PubMedGoogle Scholar
  23. Campbell PE, Isayev O, Ali SA, Roth WW, Huang MB, Powell MD, Leszczynski J, Bond VC (2012) Validation of a novel secretion modification region (SMR) of HIV-1 Nef using cohort sequence analysis and molecular modeling. J Mol Model 18:4603–4613.  https://doi.org/10.1007/s00894-012-1452-x PubMedPubMedCentralGoogle Scholar
  24. Campbell TD, Khan M, Huang MB, Bond VC, Powell MD (2008) HIV-1 Nef protein is secreted into vesicles that can fuse with target cells and virions. Ethnicity & disease 18:S2–14-19Google Scholar
  25. Cloyd MW (1996) Human Retroviruses. In: th, Baron S (eds) Medical Microbiology. Galveston (TX),Google Scholar
  26. Colombo M, Raposo G, Thery C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289.  https://doi.org/10.1146/annurev-cellbio-101512-122326 PubMedGoogle Scholar
  27. Columba Cabezas S, Federico M (2013) Sequences within RNA coding for HIV-1 gag p17 are efficiently targeted to exosomes. Cell Microbiol 15:412–429.  https://doi.org/10.1111/cmi.12046 PubMedGoogle Scholar
  28. Cowan EP, Alexander RK, Daniel S, Kashanchi F, Brady JN (1997) Induction of tumor necrosis factor alpha in human neuronal cells by extracellular human T-cell lymphotropic virus type 1 tax. J Virol 71:6982–6989PubMedPubMedCentralGoogle Scholar
  29. Currer R, van Duyne R, Jaworski E, Guendel I, Sampey G, Das R, Narayanan A, Kashanchi F (2012) HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front Microbiol 3:406.  https://doi.org/10.3389/fmicb.2012.00406 PubMedPubMedCentralGoogle Scholar
  30. Dai YD, Sheng H, Dias P, Jubayer Rahman M, Bashratyan R, Regn D, Marquardt K (2017) Autoimmune responses to exosomes and candidate antigens contribute to type 1 diabetes in non-obese diabetic mice. Curr Diab Rep 17:130.  https://doi.org/10.1007/s11892-017-0962-4 PubMedGoogle Scholar
  31. Das AT, Harwig A, Berkhout B (2011) The HIV-1 tat protein has a versatile role in activating viral transcription. J Virol 85:9506–9516.  https://doi.org/10.1128/JVI.00650-11 PubMedPubMedCentralGoogle Scholar
  32. de Carvalho JV, de Castro RO, da Silva EZM, Silveira PP, da Silva-Januário ME, Arruda E, Jamur MC, Oliver C, Aguiar RS, daSilva LLP (2014) Nef neutralizes the ability of exosomes from CD4+ T cells to act as decoys during HIV-1 infection. PLoS One 9:e113691.  https://doi.org/10.1371/journal.pone.0113691 PubMedPubMedCentralGoogle Scholar
  33. Denner J (2010) Detection of a gammaretrovirus, XMRV, in the human population: open questions and implications for xenotransplantation. Retrovirology 7:16.  https://doi.org/10.1186/1742-4690-7-16 PubMedPubMedCentralGoogle Scholar
  34. Desfarges S, Ciuffi A (2010) Retroviral integration site selection. Viruses 2:111–130.  https://doi.org/10.3390/v2010111 PubMedPubMedCentralGoogle Scholar
  35. Dhib-Jalbut S, Hoffman PM, Yamabe T, Sun D, Xia J, Eisenberg H, Bergey G, Ruscetti FW (1994) Extracellular human T-cell lymphotropic virus type I tax protein induces cytokine production in adult human microglial cells. Ann Neurol 36:787–790.  https://doi.org/10.1002/ana.410360516 PubMedGoogle Scholar
  36. Douville R, Liu J, Rothstein J, Nath A (2011) Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol 69:141–151.  https://doi.org/10.1002/ana.22149 PubMedPubMedCentralGoogle Scholar
  37. Douville RN, Nath A (2014) Human endogenous retroviruses and the nervous system. Handb Clin Neurol 123:465–485.  https://doi.org/10.1016/B978-0-444-53488-0.00022-5 PubMedPubMedCentralGoogle Scholar
  38. Downey RF, Sullivan FJ, Wang-Johanning F, Ambs S, Giles FJ, Glynn SA (2015) Human endogenous retrovirus K and cancer: innocent bystander or tumorigenic accomplice? Int J Cancer 137:1249–1257.  https://doi.org/10.1002/ijc.29003 PubMedGoogle Scholar
  39. Ehrlich M (2009) DNA hypomethylation in cancer cells. Epigenomics 1:239–259.  https://doi.org/10.2217/epi.09.33 PubMedPubMedCentralGoogle Scholar
  40. Escalera-Zamudio M, Greenwood AD (2016) On the classification and evolution of endogenous retrovirus: human endogenous retroviruses may not be 'human' after all. APMIS 124:44–51.  https://doi.org/10.1111/apm.12489 PubMedGoogle Scholar
  41. Fader CM, Sanchez DG, Mestre MB, Colombo MI (2009) TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta 1793:1901–1916.  https://doi.org/10.1016/j.bbamcr.2009.09.011 PubMedGoogle Scholar
  42. Fang Y, Wu N, Gan X, Yan W, Morrell JC, Gould SJ (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158.  https://doi.org/10.1371/journal.pbio.0050158 PubMedPubMedCentralGoogle Scholar
  43. Filipenko NR, MacLeod TJ, Yoon CS, Waisman DM (2004) Annexin A2 is a novel RNA-binding protein. J Biol Chem 279:8723–8731.  https://doi.org/10.1074/jbc.M311951200 PubMedGoogle Scholar
  44. Fisher RD, Chung HY, Zhai Q, Robinson H, Sundquist WI, Hill CP (2007) Structural and biochemical studies of ALIX/AIP1 and its role in retrovirus budding. Cell 128:841–852.  https://doi.org/10.1016/j.cell.2007.01.035 PubMedGoogle Scholar
  45. Garson JA, Tuke PW, Giraud P, Paranhos-Baccala G, Perron H (1998) Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet 351:33PubMedGoogle Scholar
  46. Gimenez J, Montgiraud C, Pichon JP, Bonnaud B, Arsac M, Ruel K, Bouton O, Mallet F (2010) Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucleic Acids Res 38:2229–2246.  https://doi.org/10.1093/nar/gkp1214 PubMedPubMedCentralGoogle Scholar
  47. Gonzalez-Cao M, Iduma P, Karachaliou N, Santarpia M, Blanco J, Rosell R (2016) Human endogenous retroviruses and cancer. Cancer Biol Med 13:483–488.  https://doi.org/10.20892/j.issn.2095-3941.2016.0080 PubMedPubMedCentralGoogle Scholar
  48. Gordon-Alonso M, Yanez-Mo M, Barreiro O, Alvarez S, Munoz-Fernandez MA, Valenzuela-Fernandez A, Sanchez-Madrid F (2006) Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion. J Immunol 177:5129–5137PubMedGoogle Scholar
  49. Gould SJ, Booth AM, Hildreth JE (2003) The Trojan exosome hypothesis. Proc Natl Acad Sci U S A 100:10592–10597.  https://doi.org/10.1073/pnas.1831413100 PubMedPubMedCentralGoogle Scholar
  50. Grant C, Oh U, Yao K, Yamano Y, Jacobson S (2008) Dysregulation of TGF-beta signaling and regulatory and effector T-cell function in virus-induced neuroinflammatory disease. Blood 111:5601–5609.  https://doi.org/10.1182/blood-2007-11-123430 PubMedPubMedCentralGoogle Scholar
  51. Griffiths DJ (2001) Endogenous retroviruses in the human genome sequence Genome Biol 2:REVIEWS1017Google Scholar
  52. Hagiwara K, Katsuda T, Gailhouste L, Kosaka N, Ochiya T (2015) Commitment of Annexin A2 in recruitment of microRNAs into extracellular vesicles. FEBS Lett 589:4071–4078.  https://doi.org/10.1016/j.febslet.2015.11.036 PubMedGoogle Scholar
  53. Han SP, Friend LR, Carson JH, Korza G, Barbarese E, Maggipinto M, Hatfield JT, Rothnagel JA, Smith R (2010) Differential subcellular distributions and trafficking functions of hnRNP A2/B1 spliceoforms. Traffic 11:886–898.  https://doi.org/10.1111/j.1600-0854.2010.01072.x PubMedPubMedCentralGoogle Scholar
  54. Helwa I, Cai J, Drewry MD, Zimmerman A, Dinkins MB, Khaled ML, Seremwe M, Dismuke WM, Bieberich E, Stamer WD, Hamrick MW, Liu Y (2017) A comparative study of serum exosome isolation using differential ultracentrifugation and three commercial reagents. PLoS One 12:e0170628.  https://doi.org/10.1371/journal.pone.0170628 PubMedPubMedCentralGoogle Scholar
  55. Henne WM, Buchkovich NJ, Emr SD (2011) The ESCRT pathway. Dev Cell 21:77–91.  https://doi.org/10.1016/j.devcel.2011.05.015 PubMedGoogle Scholar
  56. Holder BS, Tower CL, Abrahams VM, Aplin JD (2012) Syncytin 1 in the human placenta. Placenta 33:460–466.  https://doi.org/10.1016/j.placenta.2012.02.012 PubMedGoogle Scholar
  57. Hughes JF, Coffin JM (2005) Human endogenous retroviral elements as indicators of ectopic recombination events in the primate genome. Genetics 171:1183–1194.  https://doi.org/10.1534/genetics.105.043976 PubMedPubMedCentralGoogle Scholar
  58. Irish BP, Khan ZK, Jain P, Nonnemacher MR, Pirrone V, Rahman S, Rajagopalan N, Suchitra JB, Mostoller K, Wigdahl B (2009) Molecular mechanisms of neurodegenerative diseases induced by human retroviruses: a review. Am J Infect Dis 5:231–258PubMedPubMedCentralGoogle Scholar
  59. Izquierdo-Useros N, Puertas MC, Borras FE, Blanco J, Martinez-Picado J (2011) Exosomes and retroviruses: the chicken or the egg? Cell Microbiol 13:10–17.  https://doi.org/10.1111/j.1462-5822.2010.01542.x PubMedGoogle Scholar
  60. Jarrin I, Sellier P, Lopes A, Morgand M, Makovec T, Delcey V, Champion K, Simoneau G, Green A, Mouly S, Bergmann JF, Lloret-Linares C (2016) Etiologies and Management of Aseptic Meningitis in patients admitted to an internal medicine department. Medicine (Baltimore) 95:e2372.  https://doi.org/10.1097/MD.0000000000002372 Google Scholar
  61. Jaworski E, Narayanan A, van Duyne R, Shabbeer-Meyering S, Iordanskiy S, Saifuddin M, Das R, Afonso PV, Sampey GC, Chung M, Popratiloff A, Shrestha B, Sehgal M, Jain P, Vertes A, Mahieux R, Kashanchi F (2014) Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain tax protein. J Biol Chem 289:22284–22305.  https://doi.org/10.1074/jbc.M114.549659 PubMedPubMedCentralGoogle Scholar
  62. Jaworski E, Saifuddin M, Sampey G, Shafagati N, van Duyne R, Iordanskiy S, Kehn-Hall K, Liotta L, Petricoin E, Young M, Lepene B, Kashanchi F (2014) The use of Nanotrap particles technology in capturing HIV-1 virions and viral proteins from infected cells. PLoS One 9:e96778.  https://doi.org/10.1371/journal.pone.0096778 PubMedPubMedCentralGoogle Scholar
  63. Jesus da Costa L, Lopes dos Santos A, Mandic R, Shaw K, Santana de Aguiar R, Tanuri A, Luciw PA, Peterlin BM (2009) Interactions between SIVNef, SIVGagPol and Alix correlate with viral replication and progression to AIDS in rhesus macaques. Virology 394:47–56.  https://doi.org/10.1016/j.virol.2009.08.024 PubMedGoogle Scholar
  64. Kannian P, Green PL (2010) Human T Lymphotropic virus type 1 (HTLV-1): molecular biology and oncogenesis. Viruses 2:2037–2077.  https://doi.org/10.3390/v2092037 PubMedPubMedCentralGoogle Scholar
  65. Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T, Kumagai H (2003) Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol 31:1007–1014PubMedGoogle Scholar
  66. Krementsov DN, Weng J, Lambele M, Roy NH, Thali M (2009) Tetraspanins regulate cell-to-cell transmission of HIV-1. Retrovirology 6:64.  https://doi.org/10.1186/1742-4690-6-64 PubMedPubMedCentralGoogle Scholar
  67. Kubota R, Nagai M, Kawanishi T, Osame M, Jacobson S (2000) Increased HTLV type 1 tax specific CD8+ cells in HTLV type 1-asociated myelopathy/tropical spastic paraparesis: correlation with HTLV type 1 proviral load. AIDS Res Hum Retrovir 16:1705–1709.  https://doi.org/10.1089/08892220050193182 PubMedGoogle Scholar
  68. Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, Le Pecq JB (2002) Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods 270:211–226PubMedGoogle Scholar
  69. Lenassi M, Cagney G, Liao M, Vaupotič T, Bartholomeeusen K, Cheng Y, Krogan NJ, Plemenitaš A, Peterlin BM (2010) HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic 11:110–122.  https://doi.org/10.1111/j.1600-0854.2009.01006.x PubMedPubMedCentralGoogle Scholar
  70. Lepoutre V, Jain P, Quann K, Wigdahl B, Khan ZK (2009) Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease. Front Biosci 14:1152–1168Google Scholar
  71. Levin MC, Lee SM, Morcos Y, Brady J, Stuart J (2002) Cross-reactivity between immunodominant human T lymphotropic virus type I tax and neurons: implications for molecular mimicry. J Infect Dis 186:1514–1517.  https://doi.org/10.1086/344734 PubMedGoogle Scholar
  72. Lezin A, Olindo S, Olière S, Varrin-Doyer M, Marlin R, Cabre P, Smadja D, Cesaire R (2005) Human T lymphotropic virus type I (HTLV-I) proviral load in cerebrospinal fluid: a new criterion for the diagnosis of HTLV-I-associated myelopathy/tropical spastic paraparesis? J Infect Dis 191:1830–1834.  https://doi.org/10.1086/429962 PubMedGoogle Scholar
  73. Li HC, Fujiyoshi T, Lou H, Yashiki S, Sonoda S, Cartier L, Nunez L, Munoz I, Horai S, Tajima K (1999) The presence of ancient human T-cell lymphotropic virus type I provirus DNA in an Andean mummy. Nat Med 5:1428–1432.  https://doi.org/10.1038/71006 PubMedGoogle Scholar
  74. Li M, Kesic M, Yin H, Yu L, Green PL (2009) Kinetic analysis of human T-cell leukemia virus type 1 gene expression in cell culture and infected animals. J Virol 83:3788–3797.  https://doi.org/10.1128/JVI.02315-08 PubMedPubMedCentralGoogle Scholar
  75. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF, Wang XZ (2015) Exosomes: novel biomarkers for clinical diagnosis. Sci World J 2015:657086.  https://doi.org/10.1155/2015/657086 Google Scholar
  76. Lokossou AG, Toudic C, Barbeau B (2014) Implication of human endogenous retrovirus envelope proteins in placental functions. Viruses 6:4609–4627.  https://doi.org/10.3390/v6114609 PubMedPubMedCentralGoogle Scholar
  77. Longatti A, Boyd B, Chisari FV (2015) Virion-independent transfer of replication-competent hepatitis C virus RNA between permissive cells. J Virol 89:2956–2961.  https://doi.org/10.1128/JVI.02721-14 PubMedGoogle Scholar
  78. Luo X, Fan Y, Park IW, He JJ (2015) Exosomes are unlikely involved in intercellular Nef transfer. PLoS One 10:e0124436.  https://doi.org/10.1371/journal.pone.0124436 PubMedPubMedCentralGoogle Scholar
  79. Madison MN, Okeoma CM (2015) Exosomes: implications in HIV-1 pathogenesis. Viruses 7:4093–4118.  https://doi.org/10.3390/v7072810 PubMedPubMedCentralGoogle Scholar
  80. Malassine A, Frendo JL, Blaise S, Handschuh K, Gerbaud P, Tsatsaris V, Heidmann T, Evain-Brion D (2008) Human endogenous retrovirus-FRD envelope protein (syncytin 2) expression in normal and trisomy 21-affected placenta. Retrovirology 5:6.  https://doi.org/10.1186/1742-4690-5-6 PubMedPubMedCentralGoogle Scholar
  81. Mameli G, Astone V, Arru G, Marconi S, Lovato L, Serra C, Sotgiu S, Bonetti B, Dolei A (2007) Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not human herpesvirus 6. Journal Gen Virol 88:264–274.  https://doi.org/10.1099/vir.0.81890-0 Google Scholar
  82. Mansky LM (2000) In vivo analysis of human T-cell leukemia virus type 1 reverse transcription accuracy. J Virol 74:9525–9531PubMedPubMedCentralGoogle Scholar
  83. Matsuo H, Chevallier J, Mayran N, le Blanc I, Ferguson C, Fauré J, Blanc NS, Matile S, Dubochet J, Sadoul R, Parton RG, Vilbois F, Gruenberg J (2004) Role of LBPA and Alix in multivesicular liposome formation and endosome. Organization. Science 303:531–534.  https://doi.org/10.1126/science.1092425 PubMedGoogle Scholar
  84. Meckes DG Jr, Raab-Traub N (2011) Microvesicles and viral infection. J Virol 85:12844–12854.  https://doi.org/10.1128/JVI.05853-11 PubMedPubMedCentralGoogle Scholar
  85. Mi S, Lee X, Li XP, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC, McCoy JM (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789.  https://doi.org/10.1038/35001608 PubMedGoogle Scholar
  86. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ, Bernad A, Sánchez-Madrid F (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282.  https://doi.org/10.1038/ncomms1285 PubMedPubMedCentralGoogle Scholar
  87. Mittelbrunn M, Sanchez-Madrid F (2012) Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol 13:328–335.  https://doi.org/10.1038/nrm3335 PubMedPubMedCentralGoogle Scholar
  88. Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B (2017) The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis. PLoS One 12:e0172415.  https://doi.org/10.1371/journal.pone.0172415 PubMedPubMedCentralGoogle Scholar
  89. Morandi E, Tarlinton RE, Gran B (2015) Multiple sclerosis between genetics and infections: human endogenous retroviruses in monocytes and macrophages. Front Immunol 6:647.  https://doi.org/10.3389/fimmu.2015.00647 PubMedPubMedCentralGoogle Scholar
  90. Narayanan A, Iordanskiy S, Das R, van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Dalby E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F, Kashanchi F (2013) Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem 288:20014–20033.  https://doi.org/10.1074/jbc.M112.438895 PubMedPubMedCentralGoogle Scholar
  91. Nexo BA, Jensen SB, Hansen B, Laska MJ (2016) Endogenous retroviruses are associated with autoimmune diseases Ugeskr Laeger 178Google Scholar
  92. Nexo BA et al (2016) Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci. Immunol Res 64:55–63.  https://doi.org/10.1007/s12026-015-8671-z PubMedGoogle Scholar
  93. Noorali S, Rotar IC, Lewis C, Pestaner JP, Pace DG, Sison A, Bagasra O (2009) Role of HERV-W syncytin-1 in placentation and maintenance of human pregnancy. Appl Immunohistochem Mol Morphol 17:319–328.  https://doi.org/10.1097/PAI.0b013e31819640f9 PubMedGoogle Scholar
  94. Nour AM, Modis Y (2014) Endosomal vesicles as vehicles for viral genomes. Trends Cell Biol 24:449–454.  https://doi.org/10.1016/j.tcb.2014.03.006 PubMedPubMedCentralGoogle Scholar
  95. Novak K (1999) Ancient HTLV-1. Nat Med 5:1357.  https://doi.org/10.1038/70923 PubMedGoogle Scholar
  96. Nowak J, Januszkiewicz D, Pernak M, Liweń I, Zawada M, Rembowska J, Nowicka K, Lewandowski K, Hertmanowska H, Wender M (2003) Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients. J Neurovirol 9:112–117.  https://doi.org/10.1080/13550280390173355 PubMedGoogle Scholar
  97. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, Seabra MC, Wilson MS (2014) MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity 41:89–103.  https://doi.org/10.1016/j.immuni.2014.05.019 PubMedPubMedCentralGoogle Scholar
  98. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30; sup pp 11–13 doi: https://doi.org/10.1038/ncb2000
  99. Pelchen-Matthews A, Kramer B, Marsh M (2003) Infectious HIV-1 assembles in late endosomes in primary macrophages. J Cell Biol 162:443–455.  https://doi.org/10.1083/jcb.200304008 PubMedPubMedCentralGoogle Scholar
  100. Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M (2013) The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem 288:11649–11661.  https://doi.org/10.1074/jbc.M112.445304 PubMedPubMedCentralGoogle Scholar
  101. Perez-Hernandez J, Cortes R (2015) Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus. Dis Markers 2015:613536.  https://doi.org/10.1155/2015/613536 PubMedPubMedCentralGoogle Scholar
  102. Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, Faucard R, Veas F, Stefas I, Fabriek BO, van-Horssen J, van-der-Valk P, Gerdil C, Mancuso R, Saresella M, Clerici M, Marcel S, Creange A, Cavaretta R, Caputo D, Arru G, Morand P, Lang AB, Sotgiu S, Ruprecht K, Rieckmann P, Villoslada P, Chofflon M, Boucraut J, Pelletier J, Hartung HP (2012) Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler 18:1721–1736.  https://doi.org/10.1177/1352458512441381 PubMedPubMedCentralGoogle Scholar
  103. Piguet V, Steinman RM (2007) The interaction of HIV with dendritic cells: outcomes and pathways. Trends Immunol 28:503–510.  https://doi.org/10.1016/j.it.2007.07.010 PubMedGoogle Scholar
  104. Potgens AJ, Drewlo S, Kokozidou M, Kaufmann P (2004) Syncytin: the major regulator of trophoblast fusion? Recent developments and hypotheses on its action. Hum Reprod Update 10:487–496.  https://doi.org/10.1093/humupd/dmh039 PubMedGoogle Scholar
  105. Properzi F, Logozzi M, Fais S (2013) Exosomes: the future of biomarkers in medicine. Biomark Med 7:769–778.  https://doi.org/10.2217/bmm.13.63 PubMedGoogle Scholar
  106. Ramakrishnaiah V, Thumann C, Fofana I, Habersetzer F, Pan Q, de Ruiter PE, Willemsen R, Demmers JAA, Stalin Raj V, Jenster G, Kwekkeboom J, Tilanus HW, Haagmans BL, Baumert TF, van der Laan LJW (2013) Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells. Proc Natl Acad Sci U S A 110:13109–13113.  https://doi.org/10.1073/pnas.1221899110 PubMedPubMedCentralGoogle Scholar
  107. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383.  https://doi.org/10.1083/jcb.201211138 PubMedPubMedCentralGoogle Scholar
  108. Rende F, Cavallari I, Corradin A, Silic-Benussi M, Toulza F, Toffolo GM, Tanaka Y, Jacobson S, Taylor GP, D'Agostino DM, Bangham CRM, Ciminale V (2011) Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs. Blood 117:4855–4859.  https://doi.org/10.1182/blood-2010-11-316463 PubMedPubMedCentralGoogle Scholar
  109. Retrovidae (2012). In: King A, Lefkowitz E, Adams MJ, Carstens EB (ed) Virus Taxonomy. Ninth Report of the International Committee on Taxonomy of Viruses edn. Elsevier, pp 477–495Google Scholar
  110. Rider MA, Hurwitz SN, Meckes DG Jr (2016) ExtraPEG: a polyethylene glycol-based method for enrichment of extracellular vesicles. Sci Rep 6:23978.  https://doi.org/10.1038/srep23978 PubMedPubMedCentralGoogle Scholar
  111. Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195–208.  https://doi.org/10.1038/nri3622 PubMedPubMedCentralGoogle Scholar
  112. Romanelli MG, Diani E, Bergamo E, Casoli C, Ciminale V, Bex F, Bertazzoni U (2013) Highlights on distinctive structural and functional properties of HTLV tax proteins. Front Microbiol 4:271.  https://doi.org/10.3389/fmicb.2013.00271 PubMedPubMedCentralGoogle Scholar
  113. Roucourt B, Meeussen S, Bao J, Zimmermann P, David G (2015) Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res 25:412–428.  https://doi.org/10.1038/cr.2015.29 PubMedPubMedCentralGoogle Scholar
  114. Ryan FP (2004) Human endogenous retroviruses in health and disease: a symbiotic perspective. J R Soc Med 97:560–565.  https://doi.org/10.1258/jrsm.97.12.560 PubMedPubMedCentralGoogle Scholar
  115. Ryan FP (2011) Human endogenous retroviruses in multiple sclerosis: potential for novel neuro-pharmacological research. Curr Neuropharmacol 9:360–369.  https://doi.org/10.2174/157015911795596568 PubMedPubMedCentralGoogle Scholar
  116. Sampey GC, Meyering SS, Asad Zadeh M, Saifuddin M, Hakami RM, Kashanchi F (2014) Exosomes and their role in CNS viral infections. J Neurovirol 20:199–208.  https://doi.org/10.1007/s13365-014-0238-6 PubMedPubMedCentralGoogle Scholar
  117. Sampey GC, Saifuddin M, Schwab A, Barclay R, Punya S, Chung MC, Hakami RM, Asad Zadeh M, Lepene B, Klase ZA, el-Hage N, Young M, Iordanskiy S, Kashanchi F (2016) Exosomes from HIV-1-infected cells stimulate production of pro-inflammatory cytokines through trans-activating response (TAR) RNA. J Biol Chem 291:1251–1266.  https://doi.org/10.1074/jbc.M115.662171 PubMedGoogle Scholar
  118. Savina A, Fader CM, Damiani MT, Colombo MI (2005) Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6:131–143.  https://doi.org/10.1111/j.1600-0854.2004.00257.x PubMedGoogle Scholar
  119. Schmidt O, Teis D (2012) The ESCRT machinery. Curr Biol 22:R116–R120.  https://doi.org/10.1016/j.cub.2012.01.028 PubMedPubMedCentralGoogle Scholar
  120. Schorey JS, Cheng Y, Singh PP, Smith VL (2015) Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep 16:24–43.  https://doi.org/10.15252/embr.201439363 PubMedGoogle Scholar
  121. Schulz WA, Steinhoff C, Florl AR (2006) Methylation of endogenous human retroelements in health and disease. Curr Top Microbiol Immunol 310:211–250PubMedGoogle Scholar
  122. Serrao E, Engelman AN (2016) Sites of retroviral DNA integration: from basic research to clinical applications. Crit Rev Biochem Mol Biol 51:26–42.  https://doi.org/10.3109/10409238.2015.1102859 PubMedGoogle Scholar
  123. Sharp PM, Hahn BH (2011) Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med 1:a006841.  https://doi.org/10.1101/cshperspect.a006841 PubMedPubMedCentralGoogle Scholar
  124. Shembade N, Harhaj EW (2010) Role of post-translational modifications of HTLV-1 tax in NF-kappaB activation. World J Biol Chem 1:13–20.  https://doi.org/10.4331/wjbc.v1.i1.13 PubMedPubMedCentralGoogle Scholar
  125. Shen B, Wu N, Yang JM, Gould SJ (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem 286:14383–14395.  https://doi.org/10.1074/jbc.M110.208660 PubMedPubMedCentralGoogle Scholar
  126. Stengel S, Fiebig U, Kurth R, Denner J (2010) Regulation of human endogenous retrovirus-K expression in melanomas by CpG methylation. Genes Chromosomes Cancer 49:401–411.  https://doi.org/10.1002/gcc.20751 PubMedGoogle Scholar
  127. Stoorvogel W (2015) Resolving sorting mechanisms into exosomes. Cell Res 25:531–532.  https://doi.org/10.1038/cr.2015.39 PubMedPubMedCentralGoogle Scholar
  128. Stuffers S, Sem Wegner C, Stenmark H, Brech A (2009) Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10:925–937.  https://doi.org/10.1111/j.1600-0854.2009.00920.x PubMedGoogle Scholar
  129. Subramanian RP, Wildschutte JH, Russo C, Coffin JM (2011) Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90.  https://doi.org/10.1186/1742-4690-8-90 PubMedPubMedCentralGoogle Scholar
  130. Sundquist WI, Krausslich HG (2012) HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med 2:a006924.  https://doi.org/10.1101/cshperspect.a006924 PubMedPubMedCentralGoogle Scholar
  131. Swaminathan G, Navas-Martin S, Martin-Garcia J (2014) MicroRNAs and HIV-1 infection: antiviral activities and beyond. J Mol Biol 426:1178–1197.  https://doi.org/10.1016/j.jmb.2013.12.017 PubMedGoogle Scholar
  132. Tamai K, Tanaka N, Nakano T, Kakazu E, Kondo Y, Inoue J, Shiina M, Fukushima K, Hoshino T, Sano K, Ueno Y, Shimosegawa T, Sugamura K (2010) Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem Biophys Res Commun 399:384–390.  https://doi.org/10.1016/j.bbrc.2010.07.083 PubMedGoogle Scholar
  133. Thali M (2009) The roles of tetraspanins in HIV-1 replication. Curr Top Microbiol Immunol 339:85–102.  https://doi.org/10.1007/978-3-642-02175-6_5 PubMedPubMedCentralGoogle Scholar
  134. Thali M (2011) Tetraspanin functions during HIV-1 and influenza virus replication. Biochem Soc Trans 39:529–531.  https://doi.org/10.1042/BST0390529 PubMedPubMedCentralGoogle Scholar
  135. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247.  https://doi.org/10.1126/science.1153124 PubMedGoogle Scholar
  136. Tremblay MJ, Fortin JF, Cantin R (1998) The acquisition of host-encoded proteins by nascent HIV-1. Immunol Today 19:346–351PubMedGoogle Scholar
  137. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ, Infectious Diseases Society of America (2008) The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis : An Official Publication of the Infectious Diseases Society of America 47:303–327.  https://doi.org/10.1086/589747 Google Scholar
  138. Urbanelli L, Magini A, Buratta S, Brozzi A, Sagini K, Polchi A, Tancini B, Emiliani C (2013) Signaling pathways in exosomes biogenesis, secretion and fate. Genes (Basel) 4:152–170.  https://doi.org/10.3390/genes4020152 Google Scholar
  139. van Niel G, Charrin S, Simoes S, Romao M, Rochin L, Saftig P, Marks MS, Rubinstein E, Raposo G (2011) The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell 21:708–721.  https://doi.org/10.1016/j.devcel.2011.08.019 PubMedPubMedCentralGoogle Scholar
  140. Vargas A, Zhou S, Ethier-Chiasson M, Flipo D, Lafond J, Gilbert C, Barbeau B (2014) Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia. FASEB J 28:3703–3719.  https://doi.org/10.1096/fj.13-239053 PubMedGoogle Scholar
  141. Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E (2007) Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 7:266–281.  https://doi.org/10.1016/S1473-3099(07)70081-6 PubMedGoogle Scholar
  142. Verweij FJ, van Eijndhoven MAJ, Hopmans ES, Vendrig T, Wurdinger T, Cahir-McFarland E, Kieff E, Geerts D, van der Kant R, Neefjes J, Middeldorp JM, Pegtel DM (2011) LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-kappaB activation. EMBO J 30:2115–2129.  https://doi.org/10.1038/emboj.2011.123 PubMedPubMedCentralGoogle Scholar
  143. Villarroya-Beltri C, Baixauli F, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13.  https://doi.org/10.1016/j.semcancer.2014.04.009 PubMedPubMedCentralGoogle Scholar
  144. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sánchez-Madrid F (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980.  https://doi.org/10.1038/ncomms3980 PubMedPubMedCentralGoogle Scholar
  145. Wiley RD, Gummuluru S (2006) Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc Natl Acad Sci U S A 103:738–743.  https://doi.org/10.1073/pnas.0507995103 PubMedPubMedCentralGoogle Scholar
  146. Yamano Y, Takenouchi N, Li HC, Tomaru U, Yao K, Grant CW, Maric DA, Jacobson S (2005) Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease. J Clin Invest 115:1361–1368.  https://doi.org/10.1172/JCI23913 PubMedPubMedCentralGoogle Scholar
  147. Yelamanchili SV, Lamberty BG, Rennard DA, Morsey BM, Hochfelder CG, Meays BM, Levy E, Fox HS (2015) MiR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in SIV neurological disease. PLoS Pathog 11:e1005032.  https://doi.org/10.1371/journal.ppat.1005032 PubMedPubMedCentralGoogle Scholar
  148. Zeringer E, Barta T, Li M, Vlassov AV (2015) Strategies for isolation of exosomes. Cold Spring Harb Protoc 2015:319–323.  https://doi.org/10.1101/pdb.top074476 PubMedGoogle Scholar
  149. Zhang J, Li S, Li L, Li M, Guo C, Yao J, Mi S (2015) Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics 13:17–24.  https://doi.org/10.1016/j.gpb.2015.02.001 PubMedPubMedCentralGoogle Scholar
  150. Zhou L, Miranda-Saksena M, Saksena NK (2013) Viruses and neurodegeneration. Virol J 10:172.  https://doi.org/10.1186/1743-422X-10-172 PubMedPubMedCentralGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Monique Anderson
    • 1
    • 2
  • Fatah Kashanchi
    • 3
  • Steven Jacobson
    • 1
  1. 1.National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Viral Immunology SectionNational Institutes of HealthBethesdaUSA
  2. 2.Department of Pathology, Molecular and Cellular Basis of Disease Graduate ProgramUniversity of Virginia School of MedicineCharlottesvilleUSA
  3. 3.National Center for Biodefense and Infectious Disease, Laboratory of Molecular VirologyGeorge Mason UniversityManassasUSA

Personalised recommendations