Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Keeping it in check: chronic viral infection and antiviral immunity in the brain

Nature Reviews Neuroscience volume 17, pages 766–776 (2016)Cite this article

Subjects

Key Points

  • Three routes of viral entry into the brain have been identified: direct infection of the cells that comprise the blood–brain barrier and blood–cerebrospinal fluid barrier, infection of cells that are licensed to cross these barriers, and transneuronal migration across synapses from the periphery to the CNS.

  • Some viruses that are cytopathic in renewable cell types can switch to a non-productive, non-syncytia-forming mode of spread when infecting neurons, promoting neuron survival.

  • Long-lasting viral infections within the brain may be classified based on the state of the viral genome, its ability to produce infectious progeny and whether such progeny can infect other hosts.

  • Neurotropic viral infections pose unique challenges for the host, including the need to detect antigens within the CNS, the requirement for T lymphocytes to engage with neurons that express negligible levels of the proteins that are typically present on target cells, and the need to mitigate the risk of neuroinflammation and widespread loss of generally non-renewable neurons.

  • The identification of lymphatic drainage portals from the CNS into deep cervical lymph nodes and the presence of a fluid gradient that flushes the brain of extracellular proteins have helped to define how antigens leave the brain to educate the host response in local lymph nodes.

  • The host response to a viral infection may be tailored to promote survival of infected neurons but to destroy similarly infected epithelial or endothelial cells.

  • Non-lytic clearance of neuronal infections may allow for persistence of RNA viruses that induce pathogenesis long after primary exposure.

Abstract

It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response — when combined with the unique anatomy and physiology of the CNS — provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Viral entry into the CNS.
Figure 2: The receptor-occupancy hypothesis.
Figure 3: Tropism of neurotropic RNA viruses for distinct brain regions and neuronal subpopulations.

Similar content being viewed by others

References

  1. Paludan, S. R., Bowie, A. G., Horan, K. A. & Fitzgerald, K. A. Recognition of herpesviruses by the innate immune system. Nat. Rev. Immunol. 11, 143–154 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jones, C. A. et al. Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J. Virol. 77, 11139–11149 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Braaten, D. C., Sparks-Thissen, R. L., Kreher, S., Speck, S. H. & Virgin, H. W. An optimized CD8+ T-cell response controls productive and latent gammaherpesvirus infection. J. Virol. 79, 2573–2583 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Koyuncu, O. O., Hogue, I. B. & Enquist, L. W. Virus infections in the nervous system. Cell Host Microbe 13, 379–393 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dittmar, S. et al. Measles virus-induced block of transendothelial migration of T lymphocytes and infection-mediated virus spread across endothelial cell barriers. J. Virol. 82, 11273–11282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang, T. et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10, 1366–1373 (2004). This paper shows that WNV-induced, TLR3-dependent cytokine production mediates loss of BBB permeability, facilitating viral entry into the CNS.

    Article  CAS  PubMed  Google Scholar 

  7. Libbey, J. & Fujinami, R. S. Adaptive immune response to viral infections in the central nervous system. Hanb. Clin. Neurol. 123, 225–247 (2014).

    Article  Google Scholar 

  8. Daniels, B. P. et al. Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals. mBio 5, e01476-14 (2014). The authors demonstrate a unique duality between type I IFN signalling and activation in the brain, and suggest a role for cytokines that are produced peripherally by T cells in the regulation of BBB integrity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Daniels, B. P. & Klein, R. S. Knocking on closed doors: host interferons dynamically regulate blood-brain barrier function during viral infections of the central nervous system. PLoS Pathog. 11, e1005096 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McGavern, D. B. & Kang, S. S. Illuminating viral infections in the nervous system. Nature 11, 318–329 (2011).

    CAS  Google Scholar 

  11. Kramer-Hämmerle, S., Rothenaigner, I., Wolff, H., Bell, J. E. & Brack-Werner, R. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res. 111, 194–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Kramer, T. & Enquist, L. Directional spread of alphaherpesviruses in the nervous system. Viruses 5, 678–707 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Howard, P. W., Howard, T. L. & Johnson, D. C. Herpes simplex virus membrane proteins gE/gI and US9 act cooperatively to promote transport of capsids and glycoproteins from neuron cell bodies into initial axon segments. J. Virol. 87, 403–414 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Kramer, T. et al. Kinesin-3 mediates axonal sorting and directional transport of alphaherpesvirus particles in neurons. Cell Host Microbe 12, 806–814 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zaichick, S. V. et al. The herpesvirus VP1/2 Protein is an effector of dynein-mediated capsid transport and neuroinvasion. Cell Host Microbe 13, 193–203 (2013). This paper shows that tegument proteins of the herpesvirus PRV tether viral capsids to dynein and dynactin to enhance microtubule transport, neuroinvasion and pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  16. Granstedt, A. E., Brunton, B. W. & Enquist, L. W. Imaging the transport dynamics of single alphaherpesvirus particles in intact peripheral nervous system explants from infected mice. mBio 4, e00358-13 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hagendorf, N. & Conzelmann, K.-K. Recombinant fluorescent rabies virus vectors for tracing neurons and synaptic connections. Cold Spring Harb. Protoc. http://dx.doi.org/10.1101/pdb.top089391 (2015).

  18. Flint, J., Racaniello, V., Rall, G. F., Skalka, A. M. & Enquist, L. W. Principles of Virology 4th edn (American Society for Microbiology, 2015).

    Google Scholar 

  19. Lawrence, D. M. P. et al. Measles virus spread between neurons requires cell contact but not CD46 expression, syncytium formation, or extracellular virus production. J. Virol. 74, 1908–1918 (2000). This article demonstrates that the spread of MV in neurons occurs via a receptor-independent mechanism and in the absence of the syncytia formation that is typically observed upon MV infection of non-neuronal cell types.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Makhortova, N. R. et al. Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology 362, 235–244 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Iwasaki, Y., Ohtani, S. & Clark, H. F. Maturation of rabies virus by budding from neuronal cell membrane in suckling mouse brain. J. Virol. 15, 1020–1023 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Wherry, E. J. & Ahmed, R. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535–5545 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Oldstone, M. B. A. Anatomy of viral persistence. PLoS Pathog. 5, e1000523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kinchington, P. R., Leger, A. J. S., Guedon, J.-M. G. & Hendricks, R. L. Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae 3, 5 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jiang, X. et al. The herpes simplex virus type 1 latency-associated transcript can protect neuron-derived C1300 and Neuro2A cells from granzyme B-induced apoptosis and CD8 T-cell killing. J. Virol. 85, 2325–2332 (2011). The authors demonstrate that the expression of latency-associated transcripts alone (which is observed during HSV latency) can potently reduce the lytic effects of granzyme B in neuronal cell lines.

    Article  CAS  PubMed  Google Scholar 

  26. Mohammadi, P., Ciuffi, A. & Beerenwinkel, N. Dynamic models of viral replication and latency. Curr. Opin. HIV AIDS 10, 90–95 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Oldstone, M. B. A. Viral persistence: parameters, mechanisms and future predictions. Virology 344, 111–118 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Traub, E. Persistence of lymphocytic choriomeningitis virus in immune animals and its relation to immunity. J. Exp. Med. 63, 847–861 (1936).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brot, M. D., Rall, G. F., Oldstone, M. B. A., Koob, G. F. & Gold, L. H. Deficits in discriminated learning remain despite clearance of long-term persistent viral infection in mice. J. Neurovirol. 3, 265–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Norrby, E. & Kristensson, K. Measles virus in the brain. Brain Res. Bull. 44, 213–220 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Gutierrez, J., Issacson, R. S. & Koppel, B. S. Subacute sclerosing panencephalitis: an update. Dev. Med. Child Neurol. 52, 901–907 (2010).

    Article  PubMed  Google Scholar 

  32. Griffin, D. E. Measles virus and the nervous system. Handb. Clin. Neurol. 123, 577–590 (2014).

    Article  PubMed  Google Scholar 

  33. Griffin, D. E., Lin, W.-H. & Pan, C.-H. Measles virus, immune control, and persistence. FEMS Microbiol. Rev. 36, 649–662 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Hayashi, M. et al. Neurodegenerative mechanisms in subacute sclerosing panencephalitis. J. Child Neurol. 17, 725–730 (2002).

    Article  PubMed  Google Scholar 

  35. Clarke, P., Beckham, J. D., Leser, J. S., Hoyt, C. C. & Tyler, K. L. Fas-mediated apoptotic signaling in the mouse brain following reovirus infection. J. Virol. 83, 6161–6170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Berens, H. M. & Tyler, K. L. The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis. J. Virol. 85, 3858–3871 (2011). This paper shows that the pro-apoptotic protein BAX is important for reovirus growth and pathogenesis in neurons and that it mediates its effects via release of mitochondrial cytochrome c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Goodbourn, S., Didcock, L. & Randall, R. E. Interferons: cell signalling, immune modulation, antiviral responses and virus countermeasures. J. Gen. Virol. 81, 2341–2364 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Delhaye, S. et al. Neurons produce type I interferon during viral encephalitis. Proc. Natl Acad. Sci. USA 103, 7835–7840 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Faul, E. J. et al. Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. PLoS Pathog. 6, e1001016 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rose, R. W., Vorobyeva, A. G., Skipworth, J. D., Nicolas, E. & Rall, G. F. Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J. Neuroimmunol. 192, 145–156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cavanaugh, S. E., Holmgren, A. M. & Rall, G. F. Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J. Neuroimmunol. 279, 11–19 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Podolsky, M. A. et al. Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma. J. Neuroimmunol. 251, 33–38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zurney, J., Howard, K. E. & Sherry, B. Basal expression levels of IFNAR and Jak-STAT components are determinants of cell-type-specific differences in cardiac antiviral responses. J. Virol. 81, 13668–13680 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rosato, P. C. & Leib, D. A. Neuronal interferon signaling is required for protection against herpes simplex virus replication and pathogenesis. PLoS Pathog. 11, e1005028 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Song, R. et al. Two modes of the axonal interferon response limit alphaherpesvirus neuroinvasion. mBio 7, e02145-15 (2016). This paper shows that axons respond differentially to type I and type II IFNs: the response to type I IFNs is rapid and restricted to the axon, whereas the response to type II IFNs involves long-distance signalling to the PNS cell body.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kapil, P., Butchi, N. B., Stohlman, S. A. & Bergmann, C. C. Oligodendroglia are limited in type I interferon induction and responsiveness in vivo. Glia 60, 1555–1566 (2012). The authors show that oligodendrocytes are poor sensors of viral infection and require exogenous IFNα and IFNβ to establish an antiviral state.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Paul, S., Ricour, C., Sommereyns, C., Sorgeloos, F. & Michiels, T. Type I interferon response in the central nervous system. Biochimie 89, 770–778 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Holmgren, A. M., Miller, K. D., Cavanaugh, S. E. & Rall, G. F. Bst2/tetherin is induced in neurons by type I interferon and viral infection but is dispensable for protection against neurotropic viral challenge. J. Virol. 89, 11011–11018 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ireland, D. D. C., Stohlman, S. A., Hinton, D. R., Atkinson, R. & Bergmann, C. C. Type I interferons are essential in controlling neurotropic coronavirus infection irrespective of functional CD8 T cells. J. Virol. 82, 300–310 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Weber, E. et al. Type I Interferon protects mice from fatal neurotropic infection with langat virus by systemic and local antiviral responses. J. Virol. 88, 12202–12212 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fensterl, V. et al. Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis. PLoS Pathog. 8, e1002712 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Samuel, M. A. & Diamond, M. S. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J. Virol. 79, 13350–13361 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lobigs, M., Mullbacher, A., Wang, Y., Pavy, M. & Lee, E. Role of type I and type II interferon responses in recovery from infection with an encephalitic flavivirus. J. Gen. Virol. 84, 567–572 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Nayak, D. et al. Type I interferon programs innate myeloid dynamics and gene expression in the virally infected nervous system. PLoS Pathog. 9, e1003395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Detje, C. N. et al. Local type I IFN receptor signaling protects against virus spread within the central nervous system. J. Immunol. 182, 2297–2304 (2009). The authors illustrate the crucial role of neuron specific IFN signalling in controlling vesicular stomatitis virus infection within the brain.

    Article  CAS  PubMed  Google Scholar 

  56. van den Pol, A. N., Ding, S. & Robek, M. D. Long-distance interferon signaling within the brain blocks virus spread. J. Virol. 88, 3695–3704 (2014). This paper shows that IFNβ, which is released by infected neurons in the olfactory bulb, can induce ISGs in the posterior regions of the brain, activating an antiviral state and preventing further virus invasion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jessen, N. A., Munk, A. S. F., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner's guide. Neurochem. Res. 40, 2583–2599 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl Med. 4, 147ra111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Neumann, H., Cavalie, A., Jenne, D. E. & Wekerle, H. Induction of MHC class I genes in neurons. Science 269, 549–552 (2016). This article demonstrates that transcription of MHC class I genes is rare in healthy neurons but detected in electrically silent neurons, suggesting that immunosurveillance by cytotoxic T cells may be focused on functionally impaired neurons.

    Article  Google Scholar 

  62. Neumann, H., Schmidt, H., Cavalie, A., Jenne, D. & Wekerle, H. Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN). J. Exp. Med. 185, 305–316 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Joly, E., Mucke, L. & Oldstone, M. B. A. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253, 1283–1285 (2016).

    Article  Google Scholar 

  64. Calzascia, T. et al. Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J. Immunol. 171, 2187–2191 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Jeon, S., St Leger, A. J., Cherpes, T. L., Sheridan, B. S. & Hendricks, R. L. PD-L1/B7-H1 regulates the survival but not the function of CD8+ T cells in herpes simplex virus type 1 latently infected trigeminal ganglia. J. Immunol. 190, 6277–6286 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Huh, G. S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Goddard, C. A., Butts, D. A. & Shatz, C. J. Regulation of CNS synapses by neuronal MHC class I. Proc. Natl Acad. Sci. USA 104, 6828–6833 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  68. O'Donnell, L. A. et al. STAT1-independent control of a neurotropic measles virus challenge in primary neurons and infected mice. J. Immunol. 188, 1915–1923 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Burdeinick-Kerr, R., Govindarajan, D. & Griffin, D. E. Noncytolytic clearance of sindbis virus infection from neurons by gamma interferon is dependent on Jak/Stat Signaling. J. Virol. 83, 3429–3435 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Patterson, C. E., Lawrence, D. M. P., Echols, L. A. & Rall, G. F. Immune-mediated protection from measles virus-induced central nervous system disease is noncytolytic and gamma interferon dependent. J. Virol. 76, 4497–4506 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Parra, B. et al. IFN-γ is required for viral clearance from central nervous system oligodendroglia. J. Immunol. 162, 1641–1647 (1999).

    CAS  PubMed  Google Scholar 

  72. González, J. M. et al. Inhibition of interferon-γ signaling in oligodendroglia delays coronavirus clearance without altering demyelination. Am. J. Pathol. 168, 796–804 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. O'Donnell, L. A. et al. Interferon gamma induces protective non-canonical signaling pathways in primary neurons. J. Neurochem. 135, 309–322 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. St Leger, A. J. & Hendricks, R. L. CD8+ T cells patrol HSV-1-infected trigeminal ganglia and prevent viral reactivation. J. Neurovirol. 17, 528–534 (2011).

    Article  PubMed  Google Scholar 

  75. Liu, T., Khanna, K. M., Chen, X., Fink, D. J. & Hendricks, R. L. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J. Exp. Med. 191, 1459–1466 (2000). The authors demonstrate that CD8+ T cells residing alongside trigeminal ganglionic neurons infected with HSV are essential in preventing viral reactivation in the absence of neuronal death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Theil, D. et al. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am. J. Pathol. 163, 2179–2184 (2014).

    Article  Google Scholar 

  77. Liu, T., Khanna, K. M., Carriere, B. N. & Hendricks, R. L. Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons. J. Virol. 75, 11178–11184 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu, T., Tang, Q. & Hendricks, R. L. Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J. Virol. 70, 264–271 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wakim, L. M., Woodward-Davis, A. & Bevan, M. J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl Acad. Sci. USA 107, 17872–17879 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wakim, L. M. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 189, 3462–3471 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Knickelbein, J. E. et al. Noncytototoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268–271 (2008). This paper shows that non-cytotoxic CD8+ T cells mediate prevention of HSV reactivation from latency that is triggered by granzyme B-mediated cleavage of an essential early HSV protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Marcet-Palacios, M. et al. Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3. PLoS Pathog. 7, e1002447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Himmelein, S. et al. Latent herpes simplex virus 1 infection does not induce apoptosis in human trigeminal ganglia. J. Virol. 89, 5747–5750 (2011).

    Article  CAS  Google Scholar 

  85. Howe, C. L. et al. Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection. Sci. Rep. 2, 545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Phares, T., Stohlman, S. & Bergmann, C. Intrathecal humoral immunity to encephalitic RNA viruses. Viruses 5, 732–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Skoldenberg, B., Kalimo, K., Carlstrom, A., Forgren, M. & Halonen, P. Herpes simplex encephalitis: a serological follow-up study. Acta Neuropathol. 63, 273–285 (1981).

    CAS  Google Scholar 

  88. Burke, D. S., Nisalak, A., Lorsomrudee, W., Ussery, M. A. & Laorpongse, T. Virus-specific antibody producing cells in blood and cerebrospinal fluid in acute Japanese encephalitis. J. Med. Virol. 17, 283–292 (1985).

    Article  CAS  PubMed  Google Scholar 

  89. Cho, H. et al. Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat. Med. 19, 458–464 (2013). The authors demonstrate that neurons vary in susceptibility to viral infection in a subtype- and brain region-specific manner, as a result of basal differences in ISG expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jehmlich, U., Ritzer, J., Grosche, J., Härtig, W. & Liebert, U. G. Experimental measles encephalitis in Lewis rats: dissemination of infected neuronal cell subtypes. J. Neurovirol. 19, 461–470 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Liebert, U. G., Baczko, K., Budka, H. & ter Meulen, V. Restricted expression of measles virus proteins in brains from cases of subacute sclerosing panencephalitis. J. Gen. Virol. 67, 2435–2444 (1986).

    Article  CAS  PubMed  Google Scholar 

  92. Backzo, K. et al. Restriction of measles virus gene expression in measles inclusion body encephalitis. J. Infect. Dis. 158, 144–150 (1988).

    Article  Google Scholar 

  93. Zerboni, L. & Arvin, A. Neuronal subtype and satellite cell tropism are determinants of varicella-zoster virus virulence in human dorsal root ganglia xenografts in vivo. PLoS Pathog. 11, e1004989 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lucas, T. M., Richner, J. M. & Diamond, M. S. The interferon-stimulated gene Ifi27l2a restricts West Nile virus infection and pathogenesis in a cell-type and region-specific manner. J. Virol. 90, 2600–2615 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Gomme, E. A., Wirblich, C., Addya, S., Rall, G. F. & Schnell, M. J. Immune clearance of attenuated rabies virus results in neuronal survival with altered gene expression. PLoS Pathog. 8, e1002971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Katayama, Y. et al. Detection of measles virus mRNA from autopsied human tissues. J. Clin. Microbiol. 36, 299–301 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nakayama, T. et al. Detection of measles virus genome directly from clinical samples by reverse transcriptase-polymerase chain reaction and genetic variability. Virus Res. 35, 1–16 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Kawashima, H. et al. A case of intractable epilepsy positive for the detection of measles virus genome in the cerebrospinal fluid and peripheral mononuclearcells using reverse transcriptase-polymerase chain reaction. Brain Dev. 18, 220–223 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Haase, A. T. et al. Natural history of restricted synthesis and expression of measles virus genes in subacute sclerosing panencephalitis. Proc. Natl Acad. Sci. USA 82, 3020–3024 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Katayama, Y., Hotto, H., Nishimura, A., Tatsuno, Y. & Homma, M. Detection of measles virus nucleoprotein mRNA in autopsied brain tissues. J. Gen. Virol. 76, 3201–3204 (1995). The authors show that MV mRNA is detectable in the brain of humans who died of natural causes in the absence of clinical CNS disease, presumably, decades after acute MV infection.

    Article  CAS  PubMed  Google Scholar 

  101. Hanninen, P., Arstila, P., Lang, H., Salmi, A. & Panelius, M. Involvement of the central nervous system in acute, uncomplicated measles virus infection. J. Clin. Microbiol. 11, 610–613 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Allen, I. V., McQuaid, S., McMahon, J., Kirk, J. & McConnell, R. The significance of measles virus antigen and genome distribution in the CNS in SSPE for mechanims of viral spread and demyelination. J. Neuropathol. Exp. Neurol. 55, 471–480 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Matthews, A. E. et al. Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver. J. Immunol. 167, 5254–5263 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Lavi, E., Gilden, D. H., Hihkin, M. K. & Weiss, S. Persistence of mouse hepatits virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybriization. J. Virol. 51, 563–566 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Koch, E. M., Neubert, W. J. & Hofschneider, P. H. Lifelong persistence of paramyxovirus Sendai-6/94 in C129 mice: detection of latent viral RNA by hybridization with a cloned genomic cDNA probe. Virology 136, 78–88 (1984).

    Article  CAS  PubMed  Google Scholar 

  106. Griffin, D. E. & Levine, B. Persistence of viral RNA in mouse brains after recovery from acute alphavirus encephalitis. J. Virol. 66, 6429–6435 (1992).

    PubMed  PubMed Central  Google Scholar 

  107. Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl Med. 7, 307ra153 (2015). The authors identify a human endogenous retrovirus as a causative agent in neurodegenerative disease, positing an aetiology of amyotrophic lateral sclerosis.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro — preliminary report. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1602412 (2016).

  109. Rasmussen, S. A., Jamieson, D. J., Honein, M. A. & Petersen, L. R. Zika virus and birth defects — reviewing the evidence for causality. N. Engl. J. Med. 374, 1981–1987 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. Wiley, C. A., Bhardwaj, N., Ross, T. M. & Bissel, S. J. Emerging Infections of CNS: avian influenza A virus, Rift Valley fever virus and human parechovirus. Brain Pathol. 25, 634–650 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Söderberg-Nauclér, C. & Johnsen, J. I. Cytomegalovirus in human brain tumors: role in pathogenesis and potential treatment options. WJEM 5, 1–10 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Sudhakar, P., Bachman, D. M., Mark, A. S., Berger, J. R. & Kedar, S. Progressive multifocal leukoencephalopathy. J. Neuroophthamol. 35, 296–305 (2015).

    Article  Google Scholar 

  113. Maehlen, J., Wallen, P., Love, A., Norrby, E. & Kristensson, K. Paramyxovirus infections alter certain functional properties in cultured sensory neurons. Brain Res. 540, 123–130 (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Zhong, P., Agosto, L. M., Munro, J. B. & Mothes, W. Cell-to-cell transmission of viruses. Curr. Opin. Virol. 3, 44–50 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Watanabe, S. et al. Measles virus mutants possessing the fusion protein with enhanced fusion activity spread effectively in neuronal cells, but not in other cells, without causing strong cytopathology. J. Virol. 89, 2710–2717 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Taylor, M. P., Kobiler, O. & Enquist, L. W. Alphaherpesvirus axon-to-cell spread involves limited virion transmission. Proc. Natl Acad. Sci. USA 109, 17046–17051 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Lancaster, K. Z. & Pfeiffer, J. K. Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response. PLoS Pathog. 6, e1000791 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sattentau, Q. Avoiding the void: cell-to-cell spread of human viruses. Nat. Rev. Microbiol. 6, 815–826 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge L. Enquist, O. Koyuncu and C. Matullo for their input and contributions to this manuscript. They also gratefully acknowledge support from the F. M. Kirby Foundation.

Author information

Authors and Affiliations

  1. Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Katelyn D. Miller

  2. Program in Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, 19111, Pennsylvania, USA

    Katelyn D. Miller & Glenn F. Rall

  3. Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA

    Matthias J. Schnell

Authors
  1. Katelyn D. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias J. Schnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Glenn F. Rall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glenn F. Rall.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Cytokines

Small proteins released by cells that affect cell signalling and act to regulate cell growth, maturation and effector functions.

Interferons

(IFNs). Signalling proteins that are released by cells in response to infection to promote an antiviral state.

RNA viruses

Viruses with genomic material that is composed of RNA rather than DNA. Genomic viral RNA can be double stranded, single stranded, positive sense or negative sense.

DNA viruses

Viruses with genomic material that is composed of DNA.

Virions

Complete forms of an infectious viral particle.

Permissive cells

Cells that actively express viral receptor proteins, thereby facilitating viral entry and infection.

Budding

The final step of viral release during which a virion gains its outer membrane by bursting through the host cell membrane.

Viral fusion proteins

Viral glycoproteins that are essential in mediating the virus–host interaction in which the viral membrane fuses with the host membrane releasing a virion into the host cell.

Syncytia

The result of infected cells fusing with adjacent uninfected cells, producing large, multinucleated clusters.

Cytotoxic T cells

A subset of T cells that are primed to kill target cells.

Memory T cells

A subset of T cells that have previously interacted with their cognate antigen.

Perforin

A protein that is stored by cytotoxic T cells and that creates holes in target cell membranes, allowing for the delivery of cytotoxic granzymes.

Stress granules

Dense aggregates of protein and RNA that are present in the cytoplasm and are typically associated with the endoplasmic reticulum.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miller, K., Schnell, M. & Rall, G. Keeping it in check: chronic viral infection and antiviral immunity in the brain. Nat Rev Neurosci 17, 766–776 (2016). https://doi.org/10.1038/nrn.2016.140

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2016.140

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing