#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Soluble Rhesus Lymphocryptovirus gp350 Protects against Infection and Reduces Viral Loads in Animals that Become Infected with Virus after Challenge


Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans.


Vyšlo v časopise: Soluble Rhesus Lymphocryptovirus gp350 Protects against Infection and Reduces Viral Loads in Animals that Become Infected with Virus after Challenge. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002308
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002308

Souhrn

Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans.


Zdroje

1. NorthJRMorganAJThompsonJLEpsteinMA 1982 Purified Epstein-Barr virus Mr 340,000 glycoprotein induces potent virus-neutralizing antibodies when incorporated in liposomes. Proc Natl Acad Sci U S A 79 7504 7508

2. EpsteinMAMorganAJFinertySRandleBJKirkwoodJK 1985 Protection of cottontop tamarins against Epstein-Barr virus-induced malignant lymphoma by a prototype subunit vaccine. Nature 318 287 289

3. MorganAJFinertySLovgrenKScullionFTMoreinB 1988 Prevention of Epstein-Barr (EB) virus-induced lymphoma in cottontop tamarins by vaccination with the EB virus envelope glycoprotein gp340 incorporated into immune-stimulating complexes. J Gen Virol 69 2093 2096

4. MorganAJAllisonACFinertySScullionFTByarsNE 1989 Validation of a first-generation Epstein-Barr virus vaccine preparation suitable for human use. J Med Virol 29 74 78

5. FinertySMackettMArrandJRWatkinsPETarltonJ 1994 Immunization of cottontop tamarins and rabbits with a candidate vaccine against the Epstein-Barr virus based on the major viral envelope glycoprotein gp340 and alum. Vaccine 12 1180 1184

6. FinertySTarltonJMackettMConwayMArrandJR 1992 Protective immunization against Epstein-Barr virus-induced disease in cottontop tamarins using the virus envelope glycoprotein gp340 produced from a bovine papillomavirus expression vector. J Gen Virol 73 449 453

7. RagotTFinertySWatkinsPEPerricaudetMMorganAJ 1993 Replication-defective recombinant adenovirus expressing the Epstein-Barr virus (EBV) envelope glycoprotein gp340/220 induces protective immunity against EBV-induced lymphomas in the cottontop tamarin. J Gen Virol 74 501 507

8. MorganAJMackettMFinertySArrandJRScullionFT 1988 Recombinant vaccinia virus expressing Epstein-Barr virus glycoprotein gp340 protects cottontop tamarins against EB virus-induced malignant lymphomas. J Med Virol 25 189 195

9. GuSYHuangTMRuanLMiaoYHLuH 1995 First EBV vaccine trial in humans using recombinant vaccinia virus expressing the major membrane antigen. Dev Biol Stand 84 171 177

10. MoutschenMLéonardPSokalEMSmetsFHaumontM 2007 Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. Vaccine 25 4697 4705

11. SokalEMHoppenbrouwersKVandermeulenCMoutschenMLéonardP 2007 Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis 196 1749 1753

12. HislopADTaylorGSSauceDRickinsonAB 2007 Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25 587 617

13. GottschalkSHeslopHERooneyCM 2002 Treatment of Epstein-Barr virus-associated malignancies with specific T cells. Adv Cancer Res 84 175 201

14. HaqueTWilkieGMJonesMMHigginsCDUrquhartG 2007 Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 110 1123 1131

15. GottschalkSNgCYPerezMSmithCASampleC 2001 An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 97 835 843

16. ElliottSLSuhrbierAMilesJJLawrenceGPyeSJ 2008 Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J Virol 82 1448 1457

17. CadavidLFMejíaBEWatkinsDI 1999 MHC class I genes in a New World primate, the cotton-top tamarin (Saguinus oedipus), have evolved by an active process of loci turnover. Immunogenetics 49 196 205

18. WangF 2001 A new animal model for Epstein-Barr virus pathogenesis. Curr Top Microbiol Immunol 258 201 219

19. MoghaddamARosenzweigMLee-ParritzDAnnisBJohnsonRP 1997 An animal model for acute and persistent Epstein-Barr virus infection. Science 276 2030 2033

20. HabisABaskinGSimpsonLFortgangIMurphey-CorbM 2000 Rhesus lymphocryptovirus infection during the progression of SAIDS and SAIDS-associated lymphoma in the rhesus macaque. AIDS Res Hum Retroviruses 16 163 171

21. RivaillerPJiangHChoYGQuinkCWangF 2002 Complete nucleotide sequence of the rhesus lymphocryptovirus: genetic validation for an Epstein-Barr virus animal model. J Virol 76 421 426

22. RanganSRMartinLNBozelkaBEWangNGormusBJ 1986 Epstein-Barr virus-related herpesvirus from a rhesus monkey (Macaca mulatta) with malignant lymphoma. Int J Cancer 38 425 432

23. CohenJIWangFKieffE 1991 Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. J Virol 65 2545 2554

24. CohenJIWangFMannickJKieffE 1989 Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A 86 9558 9562

25. SashiharaJBurbeloPDSavoldoBPiersonTCCohenJI 2009 Human antibody titers to Epstein-Barr Virus (EBV) gp350 correlate with neutralization of infectivity better than antibody titers to EBV gp42 using a rapid flow cytometry-based EBV neutralization assay. Virology 391 249 256

26. ReedLJMuenchH 1983 A simple method of estimating fifty percent endpoints. Amer. J of Hygiene 27 493 497

27. GedeyRJinXLHinthongOShislerJL 2006 Poxviral regulation of the host NF-kappaB response: the vaccinia virus M2L protein inhibits induction of NF-kappaB activation via an ERK2 pathway in virus-infected human embryonic kidney cells. J Virol 80 8676 8685

28. YuenLMossB 1987 Oligonucleotide sequence signaling transcriptional termination of vaccinia virus early genes. Proc Natl Acad Sci U S A 84 6417 6421

29. GiriJGAhdiehMEisenmanJShanebeckKGrabsteinK 1994 Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13 2822 2830

30. JiangHChoYGWangF 2000 Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus. J Virol 74 5921 5932

31. RivaillerPCarvilleAKaurARaoPQuinkC 2004 Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host. Blood 104 1482 1489

32. KamrudKICusterMDudekJMOwensGAltersonKD 2007 Alphavirus replicon approach to promoterless analysis of IRES elements. Virology 360 376 387

33. KamrudKIAltersonKCusterMDudekJGoodmanC 2010 Development and characterization of promoterless helper RNAs for the production of alphavirus replicon particle. J Gen Virol 91 1723 1727

34. PushkoPParkerMLudwigGVDavisNLJohnstonRE 1997 Replicon-helper systems from attenuated Venezuelan equine encephalitis virus: expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology 239 389 401

35. RaoPJiangHWangF 2000 Cloning of the rhesus lymphocryptovirus viral capsid antigen and Epstein-Barr virus-encoded small RNA homologues and use in diagnosis of acute and persistent infections. J Clin Microbiol 38 3219 3225

36. MaruoSJohannsenEIllanesDCooperAZhaoB 2005 Epstein-Barr virus nuclear protein 3A domains essential for growth of lymphoblasts: transcriptional regulation through RBP-Jkappa/CBF1 is critical. J Virol 79 10171 10179

37. MossDJBurrowsSRSilinsSLMiskoIKhannaR 2001 The immunology of Epstein-Barr virus infection. Philos Trans R Soc Lond B Biol Sci 29: 356 475 488

38. KhannaRBurrowsSRKurillaMGJacobCAMiskoIS 1992 Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med 176 169 176

39. RickinsonABMossDJ 1997 Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol 15 405 431

40. PearsonGDeweyFKleinGHenléGHenléW 1970 Relation between neutralization of Epstein-Barr virus and antibodies to cell-membrane antigens induced by the virus. J. Natl. Cancer Inst 45 989 995

41. NorthJRMorganAJEpsteinMA 1980 Observations on the EB virus envelope and virus-determined membrane antigen (MA) polypeptides. Int J Cancer 26 231 240

42. Thorley-LawsonDAPoodryCA 1982 Identification and isolation of the main component (gp350-gp220) of Epstein-Barr virus responsible for generating neutralizing antibodies in vivo. J Virol 43 730 736

43. KhyattiMPatelPCStefanescuIMenezesJ 1991 Epstein-Barr virus (EBV) glycoprotein gp350 expressed on transfected cells resistant to natural killer cell activity serves as a target antigen for EBV-specific antibody-dependent cellular cytotoxicity. J Virol 65 996 1001

44. EpsteinMARandleBJFinertySKirkwoodJK 1986 Not all potently neutralizing, vaccine-induced antibodies to Epstein-Barr virus ensure protection of susceptible experimental animals. Clin Exp Immunol 63 485 490

45. EminiEASchleifWASilberklangMLehmanDEllisRW 1989 Vero cell-expressed Epstein-Barr virus (EBV) gp350/220 protects marmosets from EBV challenge). J Med Virol 27 120 123

46. RaynerJODrygaSAKamrudKI 2002 Alphavirus vectors and vaccination. Rev Med Virol 12 279 296

47. KhannaRSherrittMBurrowsSR 1999 EBV structural antigens, gp350 and gp85, as targets for ex vivo virus-specific CTL during acute infectious mononucleosis: potential use of gp350/gp85 CTL epitopes for vaccine design. J Immunol 162 3063 3069

48. AdhikaryDBehrendsUMoosmannAWitterKBornkammGW 2006 Control of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins. J Exp Med 203 995 1006

49. WallaceLEWrightJUlaetoDOMorganAJRickinsonAB 1991 Identification of two T-cell epitopes on the candidate Epstein-Barr virus vaccine glycoprotein gp340 recognized by CD4+ T-cell clones. J Virol 65 3821 3828

50. GulleyMLTangW 2010 Using Epstein-Barr viral load assays to diagnose, monitor, and prevent posttransplant lymphoproliferative disorder. Clin Microbiol Rev 23 350 366

51. AaltoSMJuvonenETarkkanenJVolinLHaarioH 2007 Epstein-Barr viral load and disease prediction in a large cohort of allogeneic stem cell transplant recipients. Clin Infect Dis 45 1305 1309

52. van EsserJWNiestersHGvan der HoltBMeijerEOsterhausAD 2002 Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 99 4364 4369

53. WalkerRCMarshallWFStricklerJGWiesnerRHVelosaJA 1995 Habermann TM, McGregor CG, Paya CV. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis 20 1346 1353

54. KerstenMJKleinMRHolwerdaAMMiedemaFvanOersMH 1997 Epstein-Barr virus-specific cytotoxic T cell responses in HIV-1 infection: different kinetics in patients progressing to opportunistic infection or non-Hodgkin's lymphoma. J Clin Invest 99 1525 1533

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2011 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#