Immunoevasin
Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted.[1][2] Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.[1]
Mechanism edit
Each step in the peptide loading and presentation on MHC I (or MHC II) is a potential target for viral immunoevasins. These can range from targeting MHC I for lysosomal or cytoplasmic degradation, blocking TCR recognition of MHC I, inhibition of peptide transport into the ER or retention of MHC I in the ER or pre-Golgi. For MHC II, the possible evasion routes include MHC II-peptide assembly disruption, evading TCR recognition, MHC II degradation, and, conversely, CD4 co-receptor downregulation.[1] Prevention of NK cell activation may also be triggered by inhibition of presentation of induced-self molecules (ligands of NKG2D) or self molecules (MHC I) presentation (while also preventing the interaction with cytotoxic T lymphocytes).[3]
Examples edit
Herpes simplex virus (HSV-1 and HSV-2) edit
HSV produces a protein, ICP47, that binds to cytosolic surface of TAP, preventing peptides from ever entering the ER, which prevents the cascade reaction that leads to presenting the MHC complex on the cell surface.[4][5]
Human cytomegalovirus (HCMV) edit
Conversely to the HSV-1, the ATP-binding of TAP is inhibited by HCMV US6 protein, indirectly resulting in decreased peptide transport to ER.[1][5][6] Retention of MHC I in the ER and possibly also inhibition of tapasin function may be attributed to US3 protein.[1][5][6][7][8] US2 and US11 proteins forward newly-synthesized MHC I to degradation in cytoplasm by dislocating the MHC I from the ER membrane into the cytosol.[1][5][6][8] UL16 is able to bind induced-self molecules MICB, ULBP1 and ULBP2, ligands for NKG2D on NK cells.[9] Other immunoevasins, such as UL40, UL18, UL141, UL142 and pp65 also play a role in evading NK cell recognition.[6]
Murine cytomegalovirus (MCMV) edit
In MCMV infection, m152 protein is capable of withholding MHC I in ER-Golgi intermediate compartment (ERGIC).[1][3][8][10] Together with the rest of m145 family, the proteins can also downregulate ligands of NKG2D, a group of induced-self receptors on NK cells.[2][9] m06/gp48 protein binds to MHC I with the help of adaptor protein complex and directs it for lysosomal degradation from the secretory pathway. Another protein of MCMV, m04/gp34, can attach to MHC I in ER and, upon transport to the cell membrane, hinders the interaction of MHC I with TCR on cytotoxic T cells while inhibiting NK cell activation and cytotoxicity by exhibiting MHC I molecules on cell surface.[1][3][10] However, additional viral proteins may be required for successful transport of m04-bound MHC I to the cell membrane.[3]
Varicella zoster virus (VZV) edit
VZV protein ORF66 is, similarly to m152 protein in MCMV, responsible for MHC I retention in ERGIC.[5]
Kaposi's sarcoma-associated herpesvirus (KSHV) edit
KSHV proteins K3 and K5 increase the rate of endocytosis and subsequent degradation of MHC I from cell membrane.[1][5][7]
Human immunodeficiency virus (HIV) edit
Nef protein is capable of directly binding to cytosolic regions of MHC I and targeting them for degradation in lysosomes from trans-Golgi.[7] Nef and Vpu proteins can also direct CD4 co-receptor for lysosomal (Nef) or cytosolic proteasomal (Vpu) degradation, affecting the recognition of MHC II-bound peptides.[1]
Human herpesvirus 7 (HHV-7) edit
Protein U21 is responsible for targeting MHC I from the secretory pathway for lysosomal degradation.[1]
Epstein-Barr virus (EBV) edit
MHC II molecule (HLA-DR) acts as a co-receptor for the EBV entry into the cell upon binding the gp42 viral protein. Upon proteolytic cleavage and secretion of gp42, the protein can bind to MHC II, hindering the interaction with CD4+ T helper lymphocytes.[1] BNLF2a protein, which is present only in the replicative phase of the viral life cycle, functions as an inhibitor of TAP, blocking both peptide and ATP binding.[5]
Adenovirus 5 edit
The inhibition of interaction between TAP and tapasin (needed for peptide loading on the MHC I), as well as retention of MHC I in the ER, is accomplished by adenoviral E19 protein.[1][5]
Murine herpesvirus 68 (MHV-68) edit
The protein mK3 acts in a multitude of ways, including TAP complex destabilization and dislocation of MHC I to cytoplasm.[1][5][6]
Other edit
TAP function can also be inhibited by UL49.5 protein produced by bovine herpesvirus 1, pseudorabies virus, and equine herpesvirus 1.[1][5]
Research and therapeutic significance edit
Thanks to the research on immunoevasins, several molecular mechanisms were clarified, such as MHC I processing mechanism, TAP-independent peptide presentation, MHC I peptide-loading complex (PLC)-independent antigen presentation pathways, cross-presentation and ER-associated degradation (ERAD).[5] In the future, the use or knockouts of immunoevasins (where mutated or deleted immunoevasin genes would not interfere with antigen presentation on MHC I complexes upon viral infection, resulting in recognition and targeting of infected cells by T cells) may be used for vaccine development for HCMV, gene therapy, transplantation and tumor-specific immunotherapy.[5][8]
References edit
- ^ a b c d e f g h i j k l m n o Lilley, Brendan N.; Ploegh, Hidde L. (2005). "Viral modulation of antigen presentation: manipulation of cellular targets in the ER and beyond". Immunological Reviews. 207 (1): 126–144. doi:10.1111/j.0105-2896.2005.00318.x. ISSN 1600-065X. PMID 16181332. S2CID 14977488.
- ^ a b Berry, Richard; Watson, Gabrielle M.; Jonjic, Stipan; Degli-Esposti, Mariapia A.; Rossjohn, Jamie (February 2020). "Modulation of innate and adaptive immunity by cytomegaloviruses". Nature Reviews Immunology. 20 (2): 113–127. doi:10.1038/s41577-019-0225-5. ISSN 1474-1733. PMID 31666730. S2CID 204942568.
- ^ a b c d Zeleznjak, Jelena; Popovic, Branka; Krmpotic, Astrid; Jonjic, Stipan; Lisnic, Vanda Juranic (2017-09-01). "Mouse cytomegalovirus encoded immunoevasins and evolution of Ly49 receptors – Sidekicks or enemies?". Immunology Letters. 3rd meeting of Middle-European Societies for Immunology and Allergology. 189: 40–47. doi:10.1016/j.imlet.2017.04.007. ISSN 0165-2478. PMID 28414184.
- ^ Janeway. Immuno Biology. Garland Science, Taylor & Francis Group, LLC, 2008. p. 189–190.
- ^ a b c d e f g h i j k l van de Weijer, Michael L.; Luteijn, Rutger D.; Wiertz, Emmanuel J. H. J. (2015-03-01). "Viral immune evasion: Lessons in MHC class I antigen presentation". Seminars in Immunology. What do pathogens teach us about the immune system?. 27 (2): 125–137. doi:10.1016/j.smim.2015.03.010. ISSN 1044-5323. PMID 25887630.
- ^ a b c d e Loureiro, Joana; Ploegh, Hidde L. (2006). Antigen Presentation and the Ubiquitin‐Proteasome System in Host–Pathogen Interactions. Advances in Immunology. Vol. 92. pp. 225–305. doi:10.1016/S0065-2776(06)92006-9. ISBN 9780123736369. ISSN 0065-2776. PMC 7112114. PMID 17145306.
- ^ a b c Gewurz, Benjamin E; Gaudet, Rachelle; Tortorella, Domenico; Wang, Evelyn W; Ploegh, Hidde L (2001-08-01). "Virus subversion of immunity: a structural perspective". Current Opinion in Immunology. 13 (4): 442–450. doi:10.1016/S0952-7915(00)00239-9. ISSN 0952-7915. PMID 11498300.
- ^ a b c d Reddehase, Matthias J. (November 2002). "Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance". Nature Reviews Immunology. 2 (11): 831–844. doi:10.1038/nri932. ISSN 1474-1741. PMID 12415307. S2CID 8698447.
- ^ a b Li, Yili; Mariuzza, Roy A. (2014-03-26). "Structural Basis for Recognition of Cellular and Viral Ligands by NK Cell Receptors". Frontiers in Immunology. 5: 123. doi:10.3389/fimmu.2014.00123. ISSN 1664-3224. PMC 3972465. PMID 24723923.
- ^ a b Reddehase, Matthias J; Simon, Christian O; Podlech, Jürgen; Holtappels, Rafaela (2004-05-01). "Stalemating a clever opportunist: lessons from murine cytomegalovirus". Human Immunology. 65 (5): 446–455. doi:10.1016/j.humimm.2004.02.024. ISSN 0198-8859. PMID 15172444.