1887

Journal of General Virology header logo

Volume 99, Issue 5

Increasing antigen presentation on HSV-1-infected cells increases lesion size but does not alter neural infection or latency Open Access

Abstract

CD8 T cells have a role in the control of acute herpes simplex virus (HSV) infection and may also be important in the maintenance of latency. In this study we have explored the consequences of boosting the efficacy of CD8 T cells against HSV by increasing the amount of an MHC I-presented epitope on the surface of infected cells. To do this we used HSVs engineered to express an extra copy of the immunodominant CD8 T cell epitope in C57Bl/6 mice, namely gB (SSIEFARL). Despite greater presentation of gB on infected cells, CD8 T cell responses to these viruses in mice were similar to those elicited by a control virus. Further, the expression of extra gB did not significantly alter the extent or stability of latency in our mouse model, and virus loads in skin and sensory ganglia of infected mice were not affected. Surprisingly, mice infected with these viruses developed significantly larger skin lesions than those infected with control viruses and notably, this phenotype was dependent on MHC haplotype. Therefore increasing the visibility of HSV-infected cells to CD8 T cell attack did not impact neural infection or latency, but rather enhanced pathology in the skin.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antigen presentation , CD8+ T cells , herpes simplex virus , HSV , immunopathology and latency
© 2018 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001059
2018-05-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/99/5/682.html?itemId=/content/journal/jgv/10.1099/jgv.0.001059&mimeType=html&fmt=ahah

References

  1. Simmons A, Tscharke D, Speck P. The role of immune mechanisms in control of herpes simplex virus infection of the peripheral nervous system. Curr Top Microbiol Immunol 1992; 179:31–56[PubMed]
     [Google Scholar]
  2. Bedoui S, Greyer M. The role of dendritic cells in immunity against primary herpes simplex virus infections. Front Microbiol 2014; 5:533 [View Article][PubMed]
     [Google Scholar]
  3. Egan KP, Wu S, Wigdahl B, Jennings SR. Immunological control of herpes simplex virus infections. J Neurovirol 2013; 19:328–345 [View Article][PubMed]
     [Google Scholar]
  4. Ouwendijk WJ, Laing KJ, Verjans GM, Koelle DM. T-cell immunity to human alphaherpesviruses. Curr Opin Virol 2013; 3:452–460 [View Article][PubMed]
     [Google Scholar]
  5. Sandgren KJ, Bertram K, Cunningham AL. Understanding natural herpes simplex virus immunity to inform next-generation vaccine design. Clin Transl Immunology 2016; 5:e94 [View Article][PubMed]
     [Google Scholar]
  6. York IA, Roop C, Andrews DW, Riddell SR, Graham FL et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 1994; 77:525–535 [View Article][PubMed]
     [Google Scholar]
  7. Hill A, Jugovic P, York I, Russ G, Bennink J et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 1995; 375:411–415 [View Article][PubMed]
     [Google Scholar]
  8. Früh K, Ahn K, Djaballah H, Sempé P, van Endert PM et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 1995; 375:415–418 [View Article][PubMed]
     [Google Scholar]
  9. Tomazin R, van Schoot NE, Goldsmith K, Jugovic P, Sempé P et al. Herpes simplex virus type 2 ICP47 inhibits human TAP but not mouse TAP. J Virol 1998; 72:2560–2563[PubMed]
     [Google Scholar]
  10. Goldsmith K, Chen W, Johnson DC, Hendricks RL. Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response. J Exp Med 1998; 187:341–348 [View Article][PubMed]
     [Google Scholar]
  11. Ahn K, Meyer TH, Uebel S, Sempé P, Djaballah H et al. Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47. Embo J 1996; 15:3247–3255[PubMed]
     [Google Scholar]
  12. Divito S, Cherpes TL, Hendricks RL. A triple entente: virus, neurons, and CD8+ T cells maintain HSV-1 latency. Immunol Res 2006; 36:119–126 [View Article][PubMed]
     [Google Scholar]
  13. Orr MT, Mathis MA, Lagunoff M, Sacks JA, Wilson CB. CD8 T cell control of HSV reactivation from latency is abrogated by viral inhibition of MHC class I. Cell Host Microbe 2007; 2:172–180 [View Article][PubMed]
     [Google Scholar]
  14. van Velzen M, Jing L, Osterhaus AD, Sette A, Koelle DM et al. Local CD4 and CD8 T-cell reactivity to HSV-1 antigens documents broad viral protein expression and immune competence in latently infected human trigeminal ganglia. PLoS Pathog 2013; 9:e1003547 [View Article][PubMed]
     [Google Scholar]
  15. Porgador A, Yewdell JW, Deng Y, Bennink JR, Germain RN. Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. Immunity 1997; 6:715–726 [View Article][PubMed]
     [Google Scholar]
  16. Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity 2003; 18:343–354 [View Article][PubMed]
     [Google Scholar]
  17. Anton LC, Yewdell JW, Bennink JR. MHC class I-associated peptides produced from endogenous gene products with vastly different efficiencies. J Immunol 1997; 158:2535–2542[PubMed]
     [Google Scholar]
  18. Bacik I, Cox JH, Anderson R, Yewdell JW, Bennink JR. TAP (transporter associated with antigen processing)-independent presentation of endogenously synthesized peptides is enhanced by endoplasmic reticulum insertion sequences located at the amino- but not carboxyl-terminus of the peptide. J Immunol 1994; 152:381–387[PubMed]
     [Google Scholar]
  19. Mueller SN, Jones CM, Smith CM, Heath WR, Carbone FR. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J Exp Med 2002; 195:651–656 [View Article][PubMed]
     [Google Scholar]
  20. Yuen TJ, Flesch IE, Hollett NA, Dobson BM, Russell TA et al. Analysis of A47, an immunoprevalent protein of vaccinia virus, leads to a reevaluation of the total antiviral CD8+ T cell response. J Virol 2010; 84:10220–10229 [View Article][PubMed]
     [Google Scholar]
  21. Simmons A, Tscharke DC. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J Exp Med 1992; 175:1337–1344 [View Article][PubMed]
     [Google Scholar]
  22. Decman V, Kinchington PR, Harvey SA, Hendricks RL. Gamma interferon can block herpes simplex virus type 1 reactivation from latency, even in the presence of late gene expression. J Virol 2005; 79:10339–10347 [View Article][PubMed]
     [Google Scholar]
  23. Sheridan BS, Khanna KM, Frank GM, Hendricks RL. Latent virus influences the generation and maintenance of CD8+ T cell memory. J Immunol 2006; 177:8356–8364 [View Article][PubMed]
     [Google Scholar]
  24. Knickelbein JE, Khanna KM, Yee MB, Baty CJ, Kinchington PR et al. Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 2008; 322:268–271 [View Article][PubMed]
     [Google Scholar]
  25. Mackay LK, Wakim L, van Vliet CJ, Jones CM, Mueller SN et al. Maintenance of T cell function in the face of chronic antigen stimulation and repeated reactivation for a latent virus infection. J Immunol 2012; 188:2173–2178 [View Article][PubMed]
     [Google Scholar]
  26. Ma JZ, Russell TA, Spelman T, Carbone FR, Tscharke DC. Lytic gene expression is frequent in HSV-1 latent infection and correlates with the engagement of a cell-intrinsic transcriptional response. PLoS Pathog 2014; 10:e1004237 [View Article][PubMed]
     [Google Scholar]
  27. Russell TA, Tscharke DC. Lytic promoters express protein during herpes simplex virus latency. PLoS Pathog 2016; 12:e1005729 [View Article][PubMed]
     [Google Scholar]
  28. Proença JT, Coleman HM, Connor V, Winton DJ, Efstathiou S. A historical analysis of herpes simplex virus promoter activation in vivo reveals distinct populations of latently infected neurones. J Gen Virol 2008; 89:2965–2974 [View Article][PubMed]
     [Google Scholar]
  29. Stock AT, Jones CM, Heath WR, Carbone FR. CTL response compensation for the loss of an immunodominant class I-restricted HSV-1 determinant. Immunol Cell Biol 2006; 84:543–550 [View Article][PubMed]
     [Google Scholar]
  30. Tigges MA, Leng S, Johnson DC, Burke RL. Human herpes simplex virus (HSV)-specific CD8+ CTL clones recognize HSV-2-infected fibroblasts after treatment with IFN-gamma or when virion host shutoff functions are disabled. J Immunol 1996; 156:3901–3910[PubMed]
     [Google Scholar]
  31. Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 2006; 25:153–162 [View Article][PubMed]
     [Google Scholar]
  32. Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 2009; 10:488–495 [View Article][PubMed]
     [Google Scholar]
  33. Macleod BL, Bedoui S, Hor JL, Mueller SN, Russell TA et al. Distinct APC subtypes drive spatially segregated CD4+ and CD8+ T-cell effector activity during skin infection with HSV-1. PLoS Pathog 2014; 10:e1004303 [View Article][PubMed]
     [Google Scholar]
  34. Wolkers MC, Brouwenstijn N, Bakker AH, Toebes M, Schumacher TN. Antigen bias in T cell cross-priming. Science 2004; 304:1314–1317 [View Article][PubMed]
     [Google Scholar]
  35. Norbury CC, Basta S, Donohue KB, Tscharke DC, Princiotta MF et al. CD8+ T cell cross-priming via transfer of proteasome substrates. Science 2004; 304:1318–1321 [View Article][PubMed]
     [Google Scholar]
  36. Lev A, Takeda K, Zanker D, Maynard JC, Dimberu P et al. The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. Immunity 2008; 28:787–798 [View Article][PubMed]
     [Google Scholar]
  37. Lin LC, Flesch IE, Tscharke DC. Immunodomination during peripheral vaccinia virus infection. PLoS Pathog 2013; 9:e1003329 [View Article][PubMed]
     [Google Scholar]
  38. Liu T, Khanna KM, Chen X, Fink DJ, Hendricks RL. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J Exp Med 2000; 191:1459–1466 [View Article][PubMed]
     [Google Scholar]
  39. Khanna KM, Lepisto AJ, Decman V, Hendricks RL. Immune control of herpes simplex virus during latency. Curr Opin Immunol 2004; 16:463–469 [View Article][PubMed]
     [Google Scholar]
  40. Khanna KM, Bonneau RH, Kinchington PR, Hendricks RL. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity 2003; 18:593–603 [View Article][PubMed]
     [Google Scholar]
  41. van Lint AL, Kleinert L, Clarke SR, Stock A, Heath WR et al. Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia. J Virol 2005; 79:14843–14851 [View Article][PubMed]
     [Google Scholar]
  42. Abendroth A, Simmons A, Efstathiou S, Pereira RA. Infection with an H2 recombinant herpes simplex virus vector results in expression of MHC class I antigens on the surfaces of human neuroblastoma cells in vitro and mouse sensory neurons in vivo. J Gen Virol 2000; 81:2375–2383 [View Article][PubMed]
     [Google Scholar]
  43. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 2008; 319:198–202 [View Article][PubMed]
     [Google Scholar]
  44. Liu T, Khanna KM, Chen X, Fink DJ, Hendricks RL. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J Exp Med 2000; 191:1459–1466 [View Article][PubMed]
     [Google Scholar]
  45. Hull CM, Harmenberg J, Arlander E, Aoki F, Bring J et al. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol 2011; 64:696.e1–696.e11 [View Article][PubMed]
     [Google Scholar]
  46. Tscharke DC, Karupiah G, Zhou J, Palmore T, Irvine KR et al. Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines. J Exp Med 2005; 201:95–104 [View Article][PubMed]
     [Google Scholar]
  47. Russell TA, Stefanovic T, Tscharke DC. Engineering herpes simplex viruses by infection-transfection methods including recombination site targeting by CRISPR/Cas9 nucleases. J Virol Methods 2015; 213:18–25 [View Article][PubMed]
     [Google Scholar]
  48. Lee EC, Yu D, Martinez de Velasco J, Tessarollo L, Swing DA et al. A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 2001; 73:56–65 [View Article][PubMed]
     [Google Scholar]
  49. Blaney JE, Nobusawa E, Brehm MA, Bonneau RH, Mylin LM et al. Immunization with a single major histocompatibility complex class I-restricted cytotoxic T-lymphocyte recognition epitope of herpes simplex virus type 2 confers protective immunity. J Virol 1998; 72:9567–9574[PubMed]
     [Google Scholar]
  50. Cong L, Ran FA, Cox D, Lin S, Barretto R et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339:819–823 [View Article][PubMed]
     [Google Scholar]
  51. Croft NP, Smith SA, Wong YC, Tan CT, Dudek NL et al. Kinetics of antigen expression and epitope presentation during virus infection. PLoS Pathog 2013; 9:e1003129 [View Article][PubMed]
     [Google Scholar]
  52. Sanderson S, Shastri N. LacZ inducible, antigen/MHC-specific T cell hybrids. Int Immunol 1994; 6:369–376 [View Article][PubMed]
     [Google Scholar]
  53. Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 1999; 21:70–71 [View Article][PubMed]
     [Google Scholar]
  54. Flesch IE, Randall KL, Hollett NA, Di Law H, Miosge LA et al. Delayed control of herpes simplex virus infection and impaired CD4+ T-cell migration to the skin in mouse models of DOCK8 deficiency. Immunol Cell Biol 2015; 93:517–521 [View Article][PubMed]
     [Google Scholar]
  55. Rasband WS. Image J U.S. National Institutes of Health: Bethesda, Maryland, USA; 1997–2012 http://imagej.nih.gov/ij/
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001059
Loading
Increasing antigen presentation on HSV-1-infected cells increases lesion size but does not alter neural infection or latency
J. Gen. Virol. 99, 682 (2018); https://doi.org/10.1099/jgv.0.001059
/content/journal/jgv/10.1099/jgv.0.001059
/content/journal/jgv/10.1099/jgv.0.001059
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error