VOOZH about

URL: https://www.nature.com/articles/nri2802?error=cookies_not_supported&code=c41b88cc-37af-40ce-9b3d-0f57072d5c21

⇱ Immunity and immunopathology to viruses: what decides the outcome? | Nature Reviews Immunology


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.

Key Points

  • Humans are constantly exposed to numerous viruses but the consequences of infection are different in different individuals.

  • The outcome of host–viral interactions depend on the dose and route of infection, viral virulence properties, as well as several host factors that mainly involve innate and adaptive immunity.

  • Host factors that influence the outcome of viral infection include genetic factors, such as polymorphism in MHC alleles, mutations in genes encoding innate receptors, cytokines, chemokine receptors, age, the nature of endogenous and persistent infections and pre-exposure to other infections.

  • The host has numerous anti-inflammatory activities that limit the extent of tissue damage caused by infections.

  • Successful pathogens such as HIV, hepatitis B virus (HBV), HCV and herpesviruses persist either as chronic or latent infections in the host with or without causing immediate ill effects; however, they may have lethal consequences when the host is immunocompromised.

  • Viruses that cause chronic infection influence immune cells to produce predominantly anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-Ξ² (TGFΞ²), and they upregulate inhibitory receptors on effector T cells giving them an exhaustion phenotype.

Abstract

Many viruses infect humans and most are controlled satisfactorily by the immune system with limited damage to host tissues. Some viruses, however, do cause overt damage to the host, either in isolated cases or as a reaction that commonly occurs after infection. The outcome is influenced by properties of the infecting virus, the circumstances of infection and several factors controlled by the host. In this Review, we focus on host factors that influence the outcome of viral infection, including genetic susceptibility, the age of the host when infected, the dose and route of infection, the induction of anti-inflammatory cells and proteins, as well as the presence of concurrent infections and past exposure to cross-reactive agents.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Figure 1: Immunity or immunopathology following viral infection.
The alternative text for this image may have been generated using AI.
Figure 2: Inhibitory mechanisms to limit tissue damage caused by T cells.
The alternative text for this image may have been generated using AI.
Figure 3: Balance between pro-inflammatory and anti-inflammatory mechanisms may decide the outcome of viral infection.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

References

  1. Munz, C., Lunemann, J. D., Getts, M. T. & Miller, S. D. Antiviral immune responses: triggers of or triggered by autoimmunity? Nature Rev. Immunol. 9, 246–258 (2009).

    Google Scholar 

  2. de Martel, C. & Franceschi, S. Infections and cancer: established associations and new hypotheses. Crit. Rev. Oncol. Hematol. 70, 183–194 (2009).

    PubMed  Google Scholar 

  3. Tal, M. C. et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106, 2770–2775 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Pichlmair, A. & Reis e Sousa, C. Innate recognition of viruses. Immunity 27, 370–383 (2007).

    CAS  PubMed  Google Scholar 

  5. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).

    CAS  Google Scholar 

  6. Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nature Med. 12, 1301–1309 (2006). This paper implicated the role of IL-10 in the persistence of LCMV infection of mice and showed the therapeutic value of its neutralization in achieving viral control.

    CAS  PubMed  Google Scholar 

  7. Brady, M. T., MacDonald, A. J., Rowan, A. G. & Mills, K. H. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur. J. Immunol. 33, 3448–3457 (2003).

    CAS  PubMed  Google Scholar 

  8. Hyodo, N., Nakamura, I. & Imawari, M. Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. Clin. Exp. Immunol. 135, 462–466 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Brockman, M. A. et al. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 114, 346–356 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Smit, J. J., Rudd, B. D. & Lukacs, N. W. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. J. Exp. Med. 203, 1153–1159 (2006).

    CAS  Google Scholar 

  11. Guidotti, L. G. et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829 (1999).

    CAS  PubMed  Google Scholar 

  12. Rehermann, B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J. Clin. Invest. 119, 1745–1754 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Favre, D. et al. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog. 5, e1000295 (2009). This paper showed that T H 17 cells are induced after SIV infection and that the balance of T H 17 and T Reg cells is a crucial determinant in the progression of disease in pigtailed macaques but not in African green monkeys, in which T H 17 cells were progressively depleted by the virus.

    PubMed  PubMed Central  Google Scholar 

  14. Rowan, A. G. et al. Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-Ξ². J. Immunol. 181, 4485–4494 (2008). This is the first study to show that viral antigen-specific T H 17 cells are induced in HCV-infected individuals and that viral protein (NS4)-induced TGFΞ² can inhibit the activity of T H 17 cells.

    CAS  PubMed  Google Scholar 

  15. Bermejo-Martin, J. F. et al. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Crit. Care 13, R201 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. Culley, F. J., Pennycook, A. M., Tregoning, J. S., Hussell, T. & Openshaw, P. J. Differential chemokine expression following respiratory virus infection reflects Th1- or Th2-biased immunopathology. J. Virol. 80, 4521–4527 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ravetch, J. In vivo veritas: the surprising roles of Fc receptors in immunity. Nature Immunol. 11, 183–185 (2010).

    CAS  Google Scholar 

  18. Buchmeier, M. J. & Oldstone, M. B. Virus-induced immune complex disease: identification of specific viral antigens and antibodies deposited in complexes during chronic lymphocytic choriomeningitis virus infection. J. Immunol. 120, 1297–1304 (1978). This is the first report in which immune complex deposits were measured using sensitive immunofluorescence and radioimmunoprecipitation in the tissue sites after a viral infection.

    CAS  PubMed  Google Scholar 

  19. Nowoslawski, A., Krawczynski, K., Nazarewicz, T. & Slusarczyk, J. Immunopathological aspects of hepatitis type B. Am. J. Med. Sci. 270, 229–239 (1975).

    CAS  PubMed  Google Scholar 

  20. Johnson, R. J. et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N. Engl. J. Med. 328, 465–470 (1993).

    CAS  PubMed  Google Scholar 

  21. Kimmel, P. L. et al. Brief report: idiotypic IgA nephropathy in patients with human immunodeficiency virus infection. N. Engl. J. Med. 327, 702–706 (1992).

    CAS  PubMed  Google Scholar 

  22. Dakhama, A. et al. Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice. J. Allergy Clin. Immunol. 123, 138–145 (2009).

    CAS  PubMed  Google Scholar 

  23. Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

    CAS  PubMed  Google Scholar 

  24. Vieira, P. et al. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc. Natl Acad. Sci. USA 88, 1172–1176 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V. & Pestka, S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc. Natl Acad. Sci. USA 97, 1695–1700 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  Google Scholar 

  27. Sarangi, P. P., Sehrawat, S., Suvas, S. & Rouse, B. T. IL-10 and natural regulatory T cells: two independent anti-inflammatory mechanisms in herpes simplex virus-induced ocular immunopathology. J. Immunol. 180, 6297–6306 (2008).

    CAS  PubMed  Google Scholar 

  28. Mangia, A. et al. IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection. Cytokine 25, 103–109 (2004).

    CAS  PubMed  Google Scholar 

  29. Naicker, D. D. et al. Interleukin-10 promoter polymorphisms influence HIV-1 susceptibility and primary HIV-1 pathogenesis. J. Infect. Dis. 200, 448–452 (2009).

    CAS  PubMed  Google Scholar 

  30. Sun, J., Madan, R., Karp, C. L. & Braciale, T. J. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nature Med. 15, 277–284 (2009). This study showed that by making IL-10, effector CD8+ T cells limit the extent of pulmonary tissue damage.

    CAS  PubMed  Google Scholar 

  31. Elrefaei, M. et al. HIV-specific IL-10-positive CD8+ T cells suppress cytolysis and IL-2 production by CD8+ T cells. J. Immunol. 178, 3265–3271 (2007).

    CAS  PubMed  Google Scholar 

  32. Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007).

    CAS  PubMed  Google Scholar 

  33. Li, M. O. & Flavell, R. A. Contextual regulation of inflammation: a duet by transforming growth factor-Ξ² and interleukin-10. Immunity 28, 468–476 (2008).

    PubMed  Google Scholar 

  34. Li, M. O. & Flavell, R. A. TGF-Ξ²: a master of all T cell trades. Cell 134, 392–404 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Aung, H., Wu, M., Johnson, J. L., Hirsch, C. S. & Toossi, Z. Bioactivation of latent transforming growth factor Ξ²1 by Mycobacterium tuberculosis in human mononuclear phagocytes. Scand. J. Immunol. 61, 558–565 (2005).

    CAS  PubMed  Google Scholar 

  36. Omer, F. M., de Souza, J. B., Corran, P. H., Sultan, A. A. & Riley, E. M. Activation of transforming growth factor Ξ² by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule. J. Exp. Med. 198, 1817–1827 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schultz-Cherry, S. & Hinshaw, V. S. Influenza virus neuraminidase activates latent transforming growth factor Ξ². J. Virol. 70, 8624–8629 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Beckham, J. D., Tuttle, K. & Tyler, K. L. Reovirus activates transforming growth factor Ξ² and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection. J. Virol. 83, 5035–5045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Alatrakchi, N. et al. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor Ξ² that can suppress HCV-specific T-cell responses. J. Virol. 81, 5882–5892 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. & Zuniga, E. I. Cell-intrinsic transforming growth factor-Ξ² signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145–157 (2009). This report showed that TGFΞ² functions intrinsically to limit CD8+T cell responses to viral infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. O'Connor, W. Jr et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nature Immunol. 10, 603–609 (2009).

    CAS  Google Scholar 

  42. Hou, W., Kang, H. S. & Kim, B. S. Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J. Exp. Med. 206, 313–328 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Rabinovich, G. A. & Toscano, M. A. Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nature Rev. Immunol. 9, 338–352 (2009).

    CAS  Google Scholar 

  44. Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunol. 6, 1245–1252 (2005).

    CAS  Google Scholar 

  45. Sehrawat, S., Suryawanshi, A., Hirashima, M. & Rouse, B. T. Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. J. Immunol. 182, 3191–3201 (2009). This paper showed that galectin 9 could promote FOXP3+ T Reg cell responses and that ligation of TIM3 with galectin 9 induces apoptosis of effector T cells but not T Reg cells.

    CAS  PubMed  Google Scholar 

  46. Sehrawat, S., Reddy, P. B. J., Rajasagi, N., Suryawanshi, A., Hirashima, M. & Rouse, B. T. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8+ T cell response. PLoS Pathog. 6, e1000882 (2010).

    PubMed  PubMed Central  Google Scholar 

  47. Chagan-Yasutan, H. et al. Persistent elevation of plasma osteopontin levels in HIV patients despite highly active antiretroviral therapy. Tohoku J. Exp. Med. 218, 285–92 (2009).

    CAS  PubMed  Google Scholar 

  48. Mengshol, J. A. et al. A crucial role for kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS ONE 5, e9504 (2010).

    PubMed  PubMed Central  Google Scholar 

  49. Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000).

    CAS  PubMed  Google Scholar 

  50. Belkaid, Y. & Tarbell, K. Regulatory T cells in the control of host-microorganism interactions. Annu. Rev. Immunol. 27, 551–589 (2009).

    CAS  PubMed  Google Scholar 

  51. Suvas, S., Azkur, A. K., Kim, B. S., Kumaraguru, U. & Rouse, B. T. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J. Immunol. 172, 4123–4132 (2004).

    CAS  PubMed  Google Scholar 

  52. Ruckwardt, T. J., Bonaparte, K. L., Nason, M. C. & Graham, B. S. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. J. Virol. 83, 3019–3028 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lanteri, M. C. et al. Tregs control the development of symptomatic West Nile virus infection in humans and mice. J. Clin. Invest. 119, 3266–3277 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sehrawat, S., Suvas, S., Sarangi, P. P., Suryawanshi, A. & Rouse, B. T. In vitro-generated antigen-specific CD4+ CD25+ Foxp3+ regulatory T cells control the severity of herpes simplex virus-induced ocular immunoinflammatory lesions. J. Virol. 82, 6838–6851 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sehrawat, S. & Rouse, B. T. Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. J. Immunol. 180, 7636–7647 (2008).

    CAS  PubMed  Google Scholar 

  56. Rouse, B. T., Sarangi, P. P. & Suvas, S. Regulatory T cells in virus infections. Immunol. Rev. 212, 272–286 (2006).

    CAS  PubMed  Google Scholar 

  57. MacDonald, A. J. et al. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185, 720–727 (2002). This report showed that induction of T regulatory 1 cells in patients infected with HCV negatively correlated with the extent of liver damage.

    CAS  PubMed  Google Scholar 

  58. Liew, F. Y., Xu, D., Brint, E. K. & O'Neill, L. A. Negative regulation of Toll-like receptor-mediated immune responses. Nature Rev. Immunol. 5, 446–458 (2005).

    CAS  Google Scholar 

  59. Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).

    CAS  PubMed  Google Scholar 

  60. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006). This seminal paper showed that the functional T cell exhaustion caused by a chronic viral infection could be reversed using antibody specific for the inhibitory molecule PD1.

    CAS  PubMed  Google Scholar 

  61. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006). This report showed that antigen-specific CD8+ T cells isolated from patients with HIV expressed higher levels of the inhibitory molecule PD1 and that the exhaustion could be reversed, at least ex vivo , by using blocking antibody.

    CAS  PubMed  Google Scholar 

  62. Radziewicz, H. et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J. Virol. 81, 2545–2553 (2007).

    CAS  PubMed  Google Scholar 

  63. Maier, H., Isogawa, M., Freeman, G. J. & Chisari, F. V. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J. Immunol. 178, 2714–2720 (2007).

    CAS  PubMed  Google Scholar 

  64. Said, E. A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nature Med. 16, 452–459 (2010).

    CAS  PubMed  Google Scholar 

  65. Yao, Z. Q., King, E., Prayther, D., Yin, D. & Moorman, J. T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. Viral Immunol. 20, 276–287 (2007).

    CAS  PubMed  Google Scholar 

  66. Boasso, A. et al. PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes. Clin. Immunol. 129, 132–144 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Brooks, D. G. et al. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc. Natl Acad. Sci. USA 105, 20428–20433 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nature Immunol. 10, 29–37 (2009).

    CAS  Google Scholar 

  69. Brooks, D. G., Lee, A. M., Elsaesser, H., McGavern, D. B. & Oldstone, M. B. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J. Exp. Med. 205, 533–541 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ha, S. J. et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 205, 543–555 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Racaniello, V. R. One hundred years of poliovirus pathogenesis. Virology 344, 9–16 (2006).

    CAS  PubMed  Google Scholar 

  72. Whitley, R. J. Herpes Simplex Viruses (eds Knipe, D. M & Howley, P. M.) (Lippincott Williams & Wilkins, New York, 2001).

    Google Scholar 

  73. Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunol. 7, 156–164 (2006).

    CAS  Google Scholar 

  74. Zhang, S. Y. et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007).

    CAS  PubMed  Google Scholar 

  75. McIntosh, E. D. Paediatric infections: prevention of transmission and disease β€” implications for adults. Vaccine 23, 2087–2089 (2005).

    PubMed  Google Scholar 

  76. Rothberg, M. B., Haessler, S. D. & Brown, R. B. Complications of viral influenza. Am. J. Med. 121, 258–264 (2008).

    PubMed  PubMed Central  Google Scholar 

  77. Tregoning, J. S. & Schwarze, J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin. Microbiol Rev. 23, 74–98 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Collins, P. L. & Graham, B. S. Viral and host factors in human respiratory syncytial virus pathogenesis. J. Virol. 82, 2040–2055 (2008).

    CAS  PubMed  Google Scholar 

  79. Spann, K. M., Tran, K. C., Chi, B., Rabin, R. L. & Collins, P. L. Suppression of the induction of Ξ±, Ξ², and Ξ» interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages. J. Virol. 78, 4363–4369 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Smit, J. J. et al. The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections. PLoS ONE 3, e1720 (2008).

    PubMed  PubMed Central  Google Scholar 

  81. Culley, F. J., Pollott, J. & Openshaw, P. J. Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J. Exp. Med. 196, 1381–1386 (2002). The influence of age at first exposure to a viral infection on the susceptibility of the same infection later in the life was shown in a mouse model of RSV infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Whitley, R. J. A 70-year-old woman with shingles: review of herpes zoster. JAMA 302, 73–80 (2009).

    CAS  PubMed  Google Scholar 

  83. Rouse, B. T. & Kaistha, S. D. A tale of 2 alpha-herpesviruses: lessons for vaccinologists. Clin. Infect. Dis. 42, 810–817 (2006).

    PubMed  Google Scholar 

  84. Nikolich-Zugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nature Rev. Immunol. 8, 512–522 (2008).

    CAS  Google Scholar 

  85. Maue, A. C. et al. T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol. 30, 301–305 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Snyder, C. M. et al. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29, 650–659 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Schakel, K. Dendritic cells β€” why can they help and hurt us. Exp. Dermatol. 18, 264–273 (2009).

    PubMed  Google Scholar 

  88. Haaland, R. E. et al. Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. PLoS Pathog. 5, e1000274 (2009).

    PubMed  PubMed Central  Google Scholar 

  89. McDermott, A. B. et al. Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates. J. Virol. 78, 3140–3144 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Oh, S., McCaffery, J. M. & Eichelberger, M. C. Dose-dependent changes in influenza virus-infected dendritic cells result in increased allogeneic T-cell proliferation at low, but not high, doses of virus. J. Virol. 74, 5460–5469 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Legge, K. L. & Braciale, T. J. Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression. Immunity 23, 649–659 (2005).

    CAS  PubMed  Google Scholar 

  92. Asabe, S. et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83, 9652–9662 (2009). This study investigated the influence of dose of infecting HBV on the pathogenesis of liver disease and clearly showed that very high or very low doses of infection led to severe liver damage.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. King, N. J. et al. Immunopathology of flavivirus infections. Immunol. Cell Biol. 85, 33–42 (2007).

    CAS  PubMed  Google Scholar 

  94. Wang, T. et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nature Med. 10, 1366–1373 (2004).

    CAS  PubMed  Google Scholar 

  95. Koelle, D. M. & Corey, L. Herpes simplex: insights on pathogenesis and possible vaccines. Annu. Rev. Med. 59, 381–395 (2008).

    CAS  PubMed  Google Scholar 

  96. Weiner, L. P. Pathogenesis of demyelination induced by a mouse hepatitis. Arch. Neurol. 28, 298–303 (1973).

    CAS  PubMed  Google Scholar 

  97. Fazakerley, J. K. & Walker, R. Virus demyelination. J. Neurovirol. 9, 148–164 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Cole, G. A., Nathanson, N. & Prendergast, R. A. Requirement for ΞΈ-bearing cells in lymphocytic choriomeningitis virus-induced central nervous system disease. Nature 238, 335–337 (1972).

    CAS  PubMed  Google Scholar 

  99. Halstead, S. B. Dengue. Lancet 370, 1644–1652 (2007).

    PubMed  Google Scholar 

  100. Mathew, A. & Rothman, A. L. Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol. Rev. 225, 300–313 (2008).

    CAS  PubMed  Google Scholar 

  101. Hadinoto, V. et al. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111, 1420–1427 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Clute, S. C. et al. Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J. Clin. Invest. 115, 3602–3612 (2005). This study showed that major contributors to infectious mononucleosis are cross-reactive T cells specific for a previously encountered virus.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kim, S. K. et al. Private specificities of CD8 T cell responses control patterns of heterologous immunity. J. Exp. Med. 201, 523–533 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Welsh, R. M. & Fujinami, R. S. Pathogenic epitopes, heterologous immunity and vaccine design. Nature Rev. Microbiol. 5, 555–563 (2007).

    CAS  Google Scholar 

  105. Segal, S. & Hill, A. V. Genetic susceptibility to infectious disease. Trends Microbiol. 11, 445–448 (2003).

    CAS  PubMed  Google Scholar 

  106. Goulder, P. J. & Watkins, D. I. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nature Rev. Immunol. 8, 619–630 (2008).

    CAS  Google Scholar 

  107. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).

    CAS  PubMed  Google Scholar 

  108. Good, R. A. & Hansen, M. A. Primary immunodeficiency diseases. Adv. Exp. Med. Biol. 73, 155–178 (1976).

    PubMed  Google Scholar 

  109. Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    CAS  PubMed  Google Scholar 

  110. Hill, A. V. Aspects of genetic susceptibility to human infectious diseases. Annu. Rev. Genet. 40, 469–486 (2006).

    CAS  PubMed  Google Scholar 

  111. Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).

    CAS  PubMed  Google Scholar 

  112. Zhang, S. Y. et al. Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-Ξ±/Ξ², IFN-Ξ³, and IFN-Ξ» in host defense. Immunol. Rev. 226, 29–40 (2008).

    CAS  PubMed  Google Scholar 

  113. Kaur, G. & Mehra, N. Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection. Tissue Antigens 73, 289–301 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Hubert, J. B. et al. Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group. AIDS 14, 123–131 (2000). This study showed that some patients with HIV can control the virus for a long time without the need for antiretroviral therapy.

    CAS  PubMed  Google Scholar 

  115. Seifarth, W. et al. Comprehensive analysis of human endogenous retrovirus transcriptional activity in human tissues with a retrovirus-specific microarray. J. Virol. 79, 341–352 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lower, R., Lower, J. & Kurth, R. The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. Proc. Natl Acad. Sci. USA 93, 5177–5184 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Wilkins, C. & Gale, M. Jr. Recognition of viruses by cytoplasmic sensors. Curr. Opin. Immunol. 22, 41–47 (2001).

    Google Scholar 

  118. York, I. A. et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77, 525–535 (1994).

    CAS  PubMed  Google Scholar 

  119. Ahn, K. et al. Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc. Natl Acad. Sci. USA 93, 10990–10995 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Gilbert, M. J., Riddell, S. R., Plachter, B. & Greenberg, P. D. Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature 383, 720–722 (1996).

    CAS  PubMed  Google Scholar 

  121. Levitskaya, J., Sharipo, A., Leonchiks, A., Ciechanover, A. & Masucci, M. G. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc. Natl Acad. Sci. USA 94, 12616–12621 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Koppelman, B., Neefjes, J. J., de Vries, J. E. & de Waal Malefyt, R. Interleukin-10 down-regulates MHC class II Ξ±Ξ² peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7, 861–871 (1997).

    CAS  PubMed  Google Scholar 

  123. Greenberg, M. E. et al. Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. EMBO J. 16, 6964–6976 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Holmes, E. C. Evolutionary history and phylogeography of human viruses. Annu. Rev. Microbiol. 62, 307–328 (2008).

    CAS  PubMed  Google Scholar 

  125. Devergne, O., Birkenbach, M. & Kieff, E. Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc. Natl Acad. Sci. USA 94, 12041–12046 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

    CAS  PubMed  Google Scholar 

  127. Periwal, S. B. & Cebra, J. J. Respiratory mucosal immunization with reovirus serotype 1/L stimulates virus-specific humoral and cellular immune responses, including double-positive (CD4+/CD8+) T cells. J. Virol. 73, 7633–7640 (1999).

    CAS  PubMed  Google Scholar 

  128. Fulton, J. R., Smith, J., Cunningham, C. & Cuff, C. F. Influence of the route of infection on development of T-cell receptor Ξ²-chain repertoires of reovirus-specific cytotoxic T lymphocytes. J. Virol. 78, 1582–1590 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Le Goffic, R. et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2, e53 (2006).

    PubMed  Google Scholar 

  130. Bochud, P. Y., Magaret, A. S., Koelle, D. M., Aderem, A. & Wald, A. Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus type 2 infection. J. Infect. Dis. 196, 505–509 (2007).

    CAS  PubMed  Google Scholar 

  131. Almarri, A. & Batchelor, J. R. HLA and hepatitis B infection. Lancet 344, 1194–1195 (1994).

    CAS  PubMed  Google Scholar 

  132. Gao, X. et al. AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. Nature Med. 11, 1290–1292 (2005).

    CAS  PubMed  Google Scholar 

  133. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Fanning, L. J. et al. HLA class II genes determine the natural variance of hepatitis C viral load. Hepatology 33, 224–230 (2001).

    CAS  PubMed  Google Scholar 

  135. Thomas, D. L. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    CAS  PubMed  Google Scholar 

  137. Knapp, S. et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun. 4, 411–419 (2003).

    CAS  PubMed  Google Scholar 

  138. Monto, A. S. Epidemiology of influenza. Vaccine 26, D45–D48 (2008).

    PubMed  Google Scholar 

  139. Peebles, R. S. Jr & Graham, B. S. Pathogenesis of respiratory syncytial virus infection in the murine model. Proc. Am. Thorac Soc. 2, 110–115 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nature Rev. Immunol. 8, 327–336 (2008).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Masopust and M. Sangster for valuable comments. The work was supported by US National Institutes of Health grants RO1 AI 106336501 and RO1 EY 05093.

Author information

Authors and Affiliations

  1. Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, 37996-0845, Tennessee, USA

    Barry T. Rouse

  2. Whitehead Institute of Biomedical Research, 9 Cambridge center, Cambridge, 02142, Massachusetts, USA

    Sharvan Sehrawat

Authors
  1. Barry T. Rouse
  2. Sharvan Sehrawat

Corresponding author

Correspondence to Barry T. Rouse.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Barry T. Rouse's homepage

Glossary

Plasmacytoid DC

A dendritic cell (DC) subset with a morphology that resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Resolvins

Resolution-phase interaction products that are made by the host from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and that have anti-inflammatory properties.

Galectins

A family of lectin proteins that bind a wide variety of glycoproteins and glycolipids containing Ξ²-galactosides through their carbohydrate-recognition domain. They have extracellular and intracellular functions, including the regulation of apoptosis, RAS signalling, cell adhesion and angiogenesis.

Regulatory T (TReg) cells

A subset of T cells that control the activity of effector T cells under inflammatory or steady state conditions.

Protectins

A family of compounds that are derived from DHA and that are characterized by a conjugated triene-containing structure. They have been shown to regulate the influx of neutrophils at inflammatory sites.

Exhaustion

Impaired ability of effector T cells to carry out their functions such as cytotoxicity and cytokine secretion owing to chronic stimulation by antigen.

Latent infection

A dormant infection with a microorganism that persists in the body for a long period of time, but it can be reactivated under certain conditions, such as immunosuppression.

Shingles

A viral disease characterized by painful, blistering skin rashes due to infection or recurrence of infection with varicella zoster virus.

Innate receptors

The receptors that are present either on the surface or in the cytoplasm of innate immune cells that recognize microbial surface patterns or their replicative products and induce cytokine production.

Dengue haemorrhagic fever

A viral disease transmitted by the bites of Aedes egypti mosquitos that carry dengue virus and is characterized by headache, fever, rash and evidence of haemorrhage in the body.

Infectious mononucleosis

A viral disease caused by infection with Epstein–Barr virus most commonly during adolescence and young adulthood. The classical symptoms include fever, sore throat and swollen lymph glands, especially in the neck.

Virome

The total virus-derived genetic material present in the host owing to integrated or persistent exogenous viruses.

About this article

Cite this article

Rouse, B., Sehrawat, S. Immunity and immunopathology to viruses: what decides the outcome?. Nat Rev Immunol 10, 514–526 (2010). https://doi.org/10.1038/nri2802

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nri2802

This article is cited by

Search

Advanced search

Quick links

πŸ‘ Nature Briefing

Sign up for the Nature Briefing newsletter β€” 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