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PMID: 19759141 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Interaction of ICP34.5 with Beclin 1 modulates herpes simplex virus type 1 pathogenesis through control of CD4+ T-cell responses.

Journal of virology ·Vol. 83 ·No. 23 ·2009-12-00 ·Pages 12164-71

Leib DA, Alexander DE, Cox D, Yin J, Ferguson TA

Abstract

Autophagy is an important component of host innate and adaptive immunity to viruses. It is critical for the degradation of intracellular pathogens and for promoting antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces an autophagy response, but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5. This is due, in part, to its interaction with the essential autophagy protein Beclin 1 (Atg6) via the Beclin-binding domain (BBD) of ICP34.5. Using a recombinant virus lacking the BBD, we examined pathogenesis and immune responses using mouse models of infection. The BBD-deficient virus (Delta68H) replicated equivalently to its marker-rescued counterpart (Delta68HR) at early times but was cleared more rapidly than Delta68HR from all tissues at late times following corneal infection. In addition, the infection of the cornea with Delta68H induced less ocular disease than Delta68HR. These results suggested that Delta68H was attenuated due to its failure to control adaptive rather than innate immunity. In support of this idea, Delta68H stimulated a significantly stronger CD4(+) T-cell-mediated delayed-type hypersensitivity response and resulted in significantly more production of gamma interferon and interleukin-2 from HSV-specific CD4(+) T cells than Delta68HR. Taken together, these data suggest a role for the BBD of ICP34.5 in precluding autophagy-mediated class II antigen presentation, thereby enhancing the virulence and pathogenesis of HSV-1.

MeSH Terms
Animals Apoptosis Regulatory Proteins Beclin-1 CD4-Positive T-Lymphocytes/immunology Chlorocebus aethiops Herpesvirus 1, Human/genetics,immunology,pathogenicity Male Mice Mice, Inbred C57BL Mice, Knockout Protein Interaction Domains and Motifs Recombinant Proteins/genetics,metabolism Sequence Deletion Vero Cells Viral Proteins/genetics,metabolism
Chemicals
Apoptosis Regulatory Proteins Beclin-1 Becn1 protein, mouse Recombinant Proteins Viral Proteins gamma 34.5 protein, Human herpesvirus 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Leib David A
Department of Microbiology and Immunology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. David.A.Leib@Dartmouth.edu
Alexander Diane E
Cox Douglas
Yin Jiyi
Ferguson Thomas A
References (57)
57 references, click to expand
  1. Differences in susceptibility to herpes simplex virus infection of inbred strains of mice.
    IARC Sci Publ. 1978;(24 Pt 2):783-8 PMID: 221403
  2. Herpes simplex virus 1 gamma(1)34.5 gene function, which blocks the host response to infection, maps in the homologous domain of the genes expressed during growth arrest and DNA damage.
    Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5247-51 PMID: 8202476
  3. Autophagy as a regulated pathway of cellular degradation.
    Science. 2000 Dec 1;290(5497):1717-21 PMID: 11099404
  4. Role of the VP16-binding domain of vhs in viral growth, host shutoff activity, and pathogenesis.
    J Virol. 2004 Dec;78(24):13562-72 PMID: 15564467
  5. Control of TANK-binding kinase 1-mediated signaling by the gamma(1)34.5 protein of herpes simplex virus 1.
    J Biol Chem. 2009 Jan 9;284(2):1097-105 PMID: 19010780
  6. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole.
    J Biol Chem. 2006 Apr 21;281(16):11374-83 PMID: 16495224
  7. Cell-specific IRF-3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms.
    PLoS Pathog. 2007 Jul 27;3(7):e106 PMID: 17676997
  8. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance.
    Immunity. 1996 Jul;5(1):7-16 PMID: 8758890
  9. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
    Cell. 2005 Sep 23;122(6):927-39 PMID: 16179260
  10. Coronavirus replication complex formation utilizes components of cellular autophagy.
    J Biol Chem. 2004 Mar 12;279(11):10136-41 PMID: 14699140
  11. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice.
    Genes Dev. 1994 May 1;8(9):1030-42 PMID: 7926785
  12. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages.
    J Exp Med. 2006 Sep 4;203(9):2063-71 PMID: 16940170
  13. Autophagy defends cells against invading group A Streptococcus.
    Science. 2004 Nov 5;306(5698):1037-40 PMID: 15528445
  14. Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages.
    J Cell Biol. 2009 Jul 27;186(2):255-68 PMID: 19635843
  15. Subversion of cellular autophagosomal machinery by RNA viruses.
    PLoS Biol. 2005 May;3(5):e156 PMID: 15884975
  16. Autophagy, immunity, and microbial adaptations.
    Cell Host Microbe. 2009 Jun 18;5(6):527-49 PMID: 19527881
  17. The V(D)J recombination activating gene, RAG-1.
    Cell. 1989 Dec 22;59(6):1035-48 PMID: 2598259
  18. Construction and characterization of bacterial artificial chromosomes containing HSV-1 strains 17 and KOS.
    J Virol Methods. 2006 Aug;135(2):197-206 PMID: 16647145
  19. Cytoplasmic bacteria can be targets for autophagy.
    Cell Microbiol. 2003 Jul;5(7):455-68 PMID: 12814436
  20. Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans.
    J Virol. 2000 Dec;74(23):10930-8 PMID: 11069987
  21. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein.
    J Virol. 1998 Nov;72(11):8586-96 PMID: 9765397
  22. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes.
    J Clin Invest. 2006 Sep;116(9):2366-77 PMID: 16955139
  23. Intracellular protein catabolism and its control during nutrient deprivation and supply.
    Annu Rev Nutr. 1987;7:539-64 PMID: 3300746
  24. A critical role for the autophagy gene Atg5 in T cell survival and proliferation.
    J Exp Med. 2007 Jan 22;204(1):25-31 PMID: 17190837
  25. The herpes simplex virus type 1 strain 17+ gamma 34.5 deletion mutant 1716 is avirulent in SCID mice.
    J Gen Virol. 1994 Aug;75 ( Pt 8):2059-63 PMID: 8046409
  26. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture.
    J Virol. 2007 Nov;81(22):12128-34 PMID: 17855538
  27. In vivo characterization of site-directed mutations in the promoter of the herpes simplex virus type 1 latency-associated transcripts.
    J Gen Virol. 1993 Sep;74 ( Pt 9):1859-69 PMID: 8397283
  28. Autophagy and related mechanisms of lysosome-mediated protein degradation.
    Trends Cell Biol. 1994 Apr;4(4):139-43 PMID: 14731737
  29. CD4+ T cells are required for the priming of CD8+ T cells following infection with herpes simplex virus type 1.
    J Virol. 2009 May;83(10):5256-68 PMID: 19279095
  30. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes.
    Immunity. 2007 Jan;26(1):79-92 PMID: 17182262
  31. PKR-dependent autophagic degradation of herpes simplex virus type 1.
    Autophagy. 2006 Jan-Mar;2(1):24-9 PMID: 16874088
  32. Full resistance of herpes simplex virus type 1-infected primary human cells to alpha interferon requires both the Us11 and gamma(1)34.5 gene products.
    J Virol. 2004 Sep;78(18):10193-6 PMID: 15331752
  33. The carboxyl terminus of the murine MyD116 gene substitutes for the corresponding domain of the gamma(1)34.5 gene of herpes simplex virus to preclude the premature shutoff of total protein synthesis in infected human cells.
    J Virol. 1996 Jan;70(1):84-90 PMID: 8523596
  34. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense.
    Cell. 2005 Jan 28;120(2):159-62 PMID: 15680321
  35. Role of the virion host shutoff (vhs) of herpes simplex virus type 1 in latency and pathogenesis.
    J Virol. 1995 Nov;69(11):6779-86 PMID: 7474089
  36. Association of a M(r) 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5- mutants of herpes simplex virus 1.
    Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10516-20 PMID: 7479831
  37. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein.
    Cell Host Microbe. 2007 Mar 15;1(1):23-35 PMID: 18005679
  38. Autophagy and intracellular surveillance: Modulating MHC class II antigen presentation with stress.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):7779-80 PMID: 15911750
  39. Endogenous MHC class II processing of a viral nuclear antigen after autophagy.
    Science. 2005 Jan 28;307(5709):593-6 PMID: 15591165
  40. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network.
    EMBO Rep. 2001 Apr;2(4):330-5 PMID: 11306555
  41. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction.
    Immunity. 2000 Oct;13(4):539-48 PMID: 11070172
  42. Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway.
    Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):190-5 PMID: 11756670
  43. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase.
    Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):843-8 PMID: 9023344
  44. CD154 signaling regulates the Th1 response to herpes simplex virus-1 and inflammation in infected corneas.
    J Immunol. 2004 Jul 15;173(2):1232-9 PMID: 15240715
  45. Induction of autophagy and inhibition of tumorigenesis by beclin 1.
    Nature. 1999 Dec 9;402(6762):672-6 PMID: 10604474
  46. Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1.
    J Virol. 2002 Jul;76(14):6974-86 PMID: 12072498
  47. Autophagy is an immediate macrophage response to Legionella pneumophila.
    Cell Microbiol. 2005 Jun;7(6):765-78 PMID: 15888080
  48. Protein turnover via autophagy: implications for metabolism.
    Annu Rev Nutr. 2007;27:19-40 PMID: 17311494
  49. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function.
    Autophagy. 2005 Apr;1(1):46-52 PMID: 16874027
  50. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):7922-7 PMID: 15894616
  51. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection.
    Nat Immunol. 2009 May;10(5):480-7 PMID: 19305394
  52. The autophagy gene ATG5 plays an essential role in B lymphocyte development.
    Autophagy. 2008 Apr;4(3):309-14 PMID: 18188005
  53. On the essential involvement of neutrophils in the immunopathologic disease: herpetic stromal keratitis.
    J Immunol. 1997 Feb 1;158(3):1383-91 PMID: 9013983
  54. Herpes simplex virus virion host shutoff (vhs) activity alters periocular disease in mice.
    J Virol. 2000 Apr;74(8):3598-604 PMID: 10729135
  55. Autophagy genes in immunity.
    Nat Immunol. 2009 May;10(5):461-70 PMID: 19381141
  56. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency.
    J Virol. 1989 Feb;63(2):759-68 PMID: 2536101
  57. Autophagy: from phenomenology to molecular understanding in less than a decade.
    Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7 PMID: 17712358
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
1098-5514
DOI
10.1128/JVI.01676-09
Email
david.a.leib@dartmouth.edu
Published
2009-12-00
Epub
2009-00-16
Pages
12164-71
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC2786728
Subset
IM
Grants
NEI NIH HHS · F32 EY006765 · United States
NEI NIH HHS · T32 EY013360 · United States
NEI NIH HHS · EY09083 · United States
NEI NIH HHS · R01 EY006765 · United States
NEI NIH HHS · R01 EY009083 · United States
NEI NIH HHS · EY013360 · United States
NEI NIH HHS · EY02687 · United States
NEI NIH HHS · P30 EY002687 · United States
NEI NIH HHS · R01 EY015570 · United States
NEI NIH HHS · EY015570 · United States
NEI NIH HHS · EY06765 · United States
External Links
PubMed source DOI: 10.1128/JVI.01676-09 PMC Full Text View journal details
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