Immune Evasion by Viruses

Abstract

When a virus infects a host, a complex immune response develops to eliminate the invading pathogen. Viruses, in turn, have evolved a profusion of strategies to escape from the immune system. Mechanisms of viral evasion can be separated into those that occur at the cellular level and those that are important at the systemic level. Viruses can avoid detection by both innate and adaptive immune responses. Pattern recognition receptors in infected cells, interferons, dendritic cells, T cell receptors and antibodies are all targets of viral evasion proteins. Viruses can express proteins that directly interfere with host processes or mimic host proteins and compete to bind specific receptors. Pathogens are also able to directly deplete immune cells, and prevent their recruitment to the site of infection. In a state of latency, viruses remain dormant and undetectable in host cells. The diversity of these mechanisms has allowed us to dissect the immune system further and understand how viruses persist despite such a strong counterattack by the immune system.

Key Concepts:

  • Viruses have evolved a plethora of mechanisms to inhibit every step of the innate and adaptive immune responses.

  • Viruses avoid detection by pattern recognition receptors, T cell receptors and antibodies by modifying the ligands for these receptors.

  • Different viruses target every stage of antigen processing and presentation by MHC molecules, thus inhibiting recognition by T cells.

  • Interferons, cytokines and chemokines are mimicked or blocked by viral proteins to prevent the efficient development of an immune response.

  • Through repression of their replication, viruses are able to enter latency and remain dormant inside the cell, remaining undetectable.

Keywords: virus; immune evasion; escape; antigen presentation; cellular response MHC; immune response; antibodies; latency; interferons

Figure 1.

Interference with the MHC‐peptide presentation pathway. Viruses encode a plethora of proteins that disrupt this pathway at all levels. (1) Inhibition of MHC transcription. (2) Inhibition of proteasomal degradation. (3) TAP inhibition prevents peptide transport into the ER. (4) Tapasin inhibition prevents the interaction between the peptide and class I MHC protein. (5) MHC molecules are prevented from leaving the ER. (6) MHC molecules are targeted for proteasomal degradation. (7) Translocation of MHC molecules to the surface is disrupted.

Figure 2.

Physical shielding from the immune system. (1) Replication of Dengue virus occurs in ER‐derived structures called Vesicle Packets. (2) Viruses such as HIV‐1 are able to suppress viral protein transcription by inducing latency and integrating the host genome or enter an episomal form.

Figure 3.

Viral escape from T cells and NK cells. Viruses generate mutants of their sequence thereby either preventing peptide binding to MHC molecule (1) or by creating a variant unable to trigger a new cellular response (original antigenic sin, (2)). The recognition of virus by T cells is blocked by the downregulation of MHC molecules (Figure 1), whereas this would activate NK cells. To avoid this, viruses express MHC class I homologues (3) which bind to NK inhibitory receptors, and they allow the presentation of HLA‐C and E molecules (4) which are also recognised by these NK cell receptors. A further evasion strategy involves virus inhibiting the expression of NK activating receptor ligands such as MICA, MICB or UL16‐binding protein (ULBP) (5).

close

References

Adhya D and Basu A (2010) Epigenetic modulation of host: new insights into immune evasion by viruses. Journal of Biosciences 35(4): 647–663.

Alcami A and Koszinowski UH (2000) Viral mechanisms of immune evasion. Trends in Microbiology 8(9): 410–418.

Andersson M, Pääbo S, Nilsson T and Peterson PA (1985) Impaired intracellular transport of class I MHC antigens as a possible means for adenoviruses to evade immune surveillance. Cell 43(1): 215–222.

Archin NM, Liberty AL, Kashuba AD et al. (2012) Administration of vorinostat disrupts HIV‐1 latency in patients on antiretroviral therapy. Nature 487(7408): 482–485.

Avirutnan P, Hauhart RE, Somnuke P et al. (2011) Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. Journal of Immunology 187(1): 424–433.

Bellare P and Ganem D (2009) Regulation of KSHV lytic switch protein expression by a virus‐encoded microRNA: an evolutionary adaptation that fine‐tunes lytic reactivation. Cell Host & Microbe 6(6): 570–575.

Benedict CA, Norris PS and Ware CF (2002) To kill or be killed: viral evasion of apoptosis. Nature Immunology 3(11): 1013–1018.

Biron CA (1997) Activation and function of natural killer cell responses during viral infections. Current Opinion in Immunology 9(1): 24–34.

Boss IW and Renne R (2011) Viral miRNAs and immune evasion. Biochimica et Biophysica Acta 1809(11–12): 708–714.

Burke KP and Cox AL (2010) Hepatitis C virus evasion of adaptive immune responses: a model for viral persistence. Immunologic Research 47(1–3): 216–227.

Chen P, Hübner W, Spinelli MA and Chen BK (2007) Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env‐dependent neutralization‐resistant virological synapses. Journal of Virology 81(22): 12582–12595.

Cox AL, Mosbruger T, Mao Q et al. (2005) Cellular immune selection with hepatitis C virus persistence in humans. Journal of Experimental Medicine 201(11): 1741–1752.

Day CL, Kaufmann DE, Kiepiela P et al. (2006) PD‐1 expression on HIV‐specific T cells is associated with T‐cell exhaustion and disease progression. Nature 443(7109): 350–354.

Di Lorenzo C, Angus AGN and Patel AH (2011) Hepatitis C virus evasion mechanisms from neutralizing antibodies. Viruses 3(11): 2280–2300.

Farrell HE, Vally H, Lynch DM et al. (1997) Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 386(6624): 510–514.

Finlay BB and McFadden G (2006) Anti‐immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124(4): 767–782.

García‐Sastre A (2011) 2 methylate or not 2 methylate: viral evasion of the type I interferon response. Nature Immunology 12(2): 114–115.

Goulder PJ, Brander C, Tang Y et al. (2001) Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412(6844): 334–338.

Grey F, Meyers H, White EA, Spector DH and Nelson J (2007) A human cytomegalovirus‐encoded microRNA regulates expression of multiple viral genes involved in replication. PLoS Pathogens 3(11): e163.

Hansen TH and Bouvier M (2009) MHC class I antigen presentation: learning from viral evasion strategies. Nature Reviews Immunology 9(7): 503–513.

Hastie KM, Bale S, Kimberlin CR and Saphire EO (2012) Hiding the evidence: two strategies for innate immune evasion by hemorrhagic fever viruses. Current Opinion in Virology 2(2): 151–156.

Klenerman P and Zinkernagel RM (1998) Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394(6692): 482–485.

Lee H‐R, Brulois K, Wong L and Jung JU (2012) Modulation of immune system by kaposi's sarcoma‐associated herpesvirus: lessons from viral evasion strategies. Frontiers in Microbiology 3: 44.

Li XD, Sun L, Seth RB, Pineda G and Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proceedings of the National Academy of Sciences of the USA 102(49): 17717–17722.

Liu H, Fu J and Bouvier M (2007) Allele‐ and locus‐specific recognition of class I MHC molecules by the immunomodulatory E3‐19K protein from adenovirus. Journal of Immunology 178(7): 4567–4575.

Lu F, Stedman W, Yousef M, Renne R and Lieberman PM (2010) Epigenetic regulation of Kaposi's sarcoma‐associated herpesvirus latency by virus‐encoded microRNAs that target Rta and the cellular Rbl2‐DNMT pathway. Journal of Virology 84(6): 2697–2706.

Lucas M, Karrer U, Lucas A and Klenerman P (2001) Viral escape mechanisms – escapology taught by viruses. International Journal of Experimental Pathology 82(5): 269–286.

Martin N and Sattentau Q (2009) Cell‐to‐cell HIV‐1 spread and its implications for immune evasion. Current Opinion in HIV and AIDS 4(2): 143–149.

Morrison J, Aguirre S and Fernandez‐Sesma A (2012) Innate immunity evasion by Dengue virus. Viruses 4(3): 397–413.

Murphy E, Vanícek J, Robins H, Shenk T and Levine AJ (2008) Suppression of immediate‐early viral gene expression by herpesvirus‐coded microRNAs: implications for latency. Proceedings of the National Academy of Sciences of the USA 105(14): 5453–5458.

Orange JS, Fassett MS, Koopman LA, Boyson JE and Strominger JL (2002) Viral evasion of natural killer cells. Nature Immunology 3(11): 1006–1012.

Orvedahl A and Levine B (2008) Viral evasion of autophagy. Autophagy 4(3): 280–285.

Petrovas C, Mueller YM and Katsikis PD (2005) Apoptosis of HIV‐specific CD8+ T cells: an HIV evasion strategy. Cell Death and Differentiation 12(suppl. 1): 859–870.

Pfeffer S, Zavolan M, Grässer FA et al. (2004) Identification of virus‐encoded microRNAs. Science 304(5671): 734–736.

Player MR, Barnard DL and Torrence PF (1998) Potent inhibition of respiratory syncytial virus replication using a 2‐5A‐antisense chimera targeted to signals within the virus genomic RNA. Proceedings of the National Academy of Sciences of the USA 95(15): 8874–8879.

Posavad CM, Newton JJ and Rosenthal KL (1994) Infection and inhibition of human cytotoxic T lymphocytes by herpes simplex virus. Journal of Virology 68(6): 4072–4074.

Radkov SA, Touitou R, Brehm A et al. (1999) Epstein‐Barr virus nuclear antigen 3C interacts with histone deacetylase to repress transcription. Journal of Virology 73(7): 5688–5697.

Reyburn HT, Mandelboim O, Valés‐Gómez M et al. (1997) The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386(6624): 514–517.

Romani B, Engelbrecht S and Glashoff RH (2010) Functions of Tat: the versatile protein of human immunodeficiency virus type 1. Journal of General Virology 91(Pt 1): 1–12.

Sadler AJ and Williams BRG (2008) Interferon‐inducible antiviral effectors. Nature Reviews Immunology 8(7): 559–568.

Samols MA, Skalsky RL, Maldonado AM et al. (2007) Identification of cellular genes targeted by KSHV‐encoded microRNAs. PLoS Pathogens 3(5): e65.

Schmidt K, Wies E and Neipel F (2011) Kaposi's sarcoma‐associated herpesvirus viral interferon regulatory factor 3 inhibits gamma interferon and major histocompatibility complex class II expression. Journal of Virology 85(9): 4530–4537.

Tailor P, Tamura T and Ozato K (2006) IRF family proteins and type I interferon induction in dendritic cells. Cell Research 16(2): 134–140.

Thomas M, Boname JM, Field S et al. (2008) Down‐regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma‐associated herpesvirus K5 protects against NK cell cytotoxicity. Proceedings of the National Academy of Sciences of the USA 105(5): 1656–1661.

Timpe JM, Stamataki Z, Jennings A et al. (2008) Hepatitis C virus cell‐cell transmission in hepatoma cells in the presence of neutralizing antibodies. Hepatology 47(1): 17–24.

Tomasec P, Braud VM, Rickards C et al. (2000) Surface expression of HLA‐E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287(5455): 1031.

Wherry EJ and Ahmed R (2004) Memory CD8 T‐cell differentiation during viral infection. Journal of Virology 78(11): 5535–5545.

Yewdell JW and Hill AB (2002) Viral interference with antigen presentation. Nature Immunology 3(11): 1019–1025.

Zinkernagel RM and Doherty PC (1974) Restriction of in vitro T cell‐mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248(450): 701–702.

Further Reading

Coscoy L (2007) Immune evasion by Kaposi's sarcoma‐associated herpesvirus. Nature Reviews Immunology 7: 391–401.

Urbani S, Amadei B, Tola D et al. (2006) PD‐1 expression in acute hepatitis C virus (HCV) infection is associated with HCV‐specific CD8 exhaustion. Journal of Virology 80(22): 11398–11403.

Wölfl M, Rutebemberwa A, Mosbruger T et al. (2008) Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. Journal of Immunology 181(9): 6435–6446.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Simmons, Ruth A, Willberg, Christian B, and Paul, Klenerman(Jun 2013) Immune Evasion by Viruses. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024790]