CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection
Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.
Vyšlo v časopise:
CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection. PLoS Pathog 7(11): e32767. doi:10.1371/journal.ppat.1002367
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002367
Souhrn
Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.
Zdroje
1. ArvinAM 2000 Varicella-Zoster virus: pathogenesis, immunity, and clinical management in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 6 219 230
2. NagelMACohrsRJMahalingamRWellishMCForghaniB 2008 The varicella zoster virus vasculopathies: Clinical, CSF, imaging, and virologic features. Neurology 70 853 860
3. MuellerNHGildenDHCohrsRJMahalingamRNagelMA 2008 Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin 26 675 697, viii
4. RagozzinoMWMelton3rdLJKurlandLTChuCPPerryHO 1982 Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 61 310 316
5. InsingaRPItzlerRFPellissierJMSaddierPNikasAA 2005 The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 20 748 753
6. WeaverBA 2009 Herpes Zoster Overview: Natural History and Incidence. J Am Osteopath Assoc 109 S2 6
7. GoulleretNMauvisseauEEssevaz-RouletMQuinlivanMBreuerJ 2010 Safety profile of live varicella virus vaccine (Oka/Merck): five-year results of the European Varicella Zoster Virus Identification Program (EU VZVIP). Vaccine 28 5878 5882
8. MarinMZhangJXSewardJF 2011 Near Elimination of Varicella Deaths in the US After Implementation of the Vaccination Program. Pediatrics 128 214 220
9. OxmanMNLevinMJJohnsonGRSchmaderKEStrausSE 2005 A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352 2271 2284
10. OxmanMNLevinMJ 2008 Vaccination against Herpes Zoster and Postherpetic Neuralgia. J Infect Dis 197 Suppl 2 S228 236
11. LevinMJOxmanMNZhangJHJohnsonGRStanleyH 2008 Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 197 825 835
12. ArvinAM 1996 Immune responses to varicella-zoster virus. Infect Dis Clin North Am 10 529 570
13. SchmaderK 2001 Herpes zoster in older adults. Clin Infect Dis 32 1481 1486
14. BurkeBLSteeleRWBeardOWWoodJSCainTD 1982 Immune responses to varicella-zoster in the aged. Arch Intern Med 142 291 293
15. BergerRFlorentGJustM 1981 Decrease of the lymphoproliferative response to varicella-zoster virus antigen in the aged. Infect Immun 32 24 27
16. ArvinAMKoropchakCMWilliamsBRGrumetFCFoungSK 1986 Early immune response in healthy and immunocompromised subjects with primary varicella-zoster virus infection. J Infect Dis 154 422 429
17. NaderSBergenRSharpMArvinAM 1995 Age-related differences in cell-mediated immunity to varicella-zoster virus among children and adults immunized with live attenuated varicella vaccine. J Infect Dis 171 13 17
18. RedmanRLNaderSZerboniLLiuCWongRM 1997 Early reconstitution of immunity and decreased severity of herpes zoster in bone marrow transplant recipients immunized with inactivated varicella vaccine. J Infect Dis 176 578 585
19. WilsonASharpMKoropchakCMTingSFArvinAM 1992 Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 165 119 126
20. ZerboniLNaderSAokiKArvinAM 1998 Analysis of the persistence of humoral and cellular immunity in children and adults immunized with varicella vaccine. J Infect Dis 177 1701 1704
21. ArvinAMPollardRBRasmussenLEMeriganTC 1978 Selective impairment of lymphocyte reactivity to varicella-zoster virus antigen among untreated patients with lymphoma. J Infect Dis 137 531 540
22. CamittaBChusidMJStarshakRJGottschallJL 1994 Use of irradiated lymphocytes from immune donors for treatment of disseminated varicella. J Pediatr 124 593 596
23. ParyaniSGArvinAMKoropchakCMDobkinMBWittekAE 1984 Comparison of varicella zoster antibody titers in patients given intravenous immune serum globulin or varicella zoster immune globulin. J Pediatr 105 200 205
24. BrunellPARossAMillerLHKuoB 1969 Prevention of varicella by zoster immune globulin. N Engl J Med 280 1191 1194
25. OrensteinWAHeymannDLEllisRJRosenbergRLNakanoJ 1981 Prophylaxis of varicella in high-risk children: dose-response effect of zoster immune globulin. J Pediatr 98 368 373
26. WeigleKAGroseC 1984 Molecular dissection of the humoral immune response to individual varicella-zoster viral proteins during chickenpox, quiescence, reinfection, and reactivation. J Infect Dis 149 741 749
27. JuraEChadwickEGJosephsSHSteinbergSPYogevR 1989 Varicella-zoster virus infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 8 586 590
28. AbendrothASlobedmanBLeeEMellinsEWallaceM 2000 Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J Virol 74 1900 1907
29. JonesLBlackAPMalavigeGNOggGS 2006 Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4+ T Cells after Primary Infection. J Virol 80 9772 9778
30. MalavigeGNJonesLBlackAPOggGS 2007 Rapid Effector Function of Varicella-Zoster Virus Glycoprotein I-Specific CD4 + T Cells Many Decades after Primary Infection. J Infect Dis 195 660 664
31. ArvinAMSharpMSmithSKoropchakCMDiazPS 1991 Equivalent recognition of a varicella-zoster virus immediate early protein (IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype. J Immunol 146 257 264
32. FreyCRSharpMAMinASSchmidDSLoparevV 2003 Identification of CD8+ T cell epitopes in the immediate early 62 protein (IE62) of varicella-zoster virus, and evaluation of frequency of CD8+ T cell response to IE62, by use of IE62 peptides after varicella vaccination. J Infect Dis 188 40 52
33. AsanumaHSharpMMaeckerHTMainoVCArvinAM 2000 Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression. J Infect Dis 181 859 866
34. AbendrothAArvinAM 2001 Immune evasion as a pathogenic mechanism of varicella zoster virus. Semin Immunol 13 27 39
35. KinchingtonPR 1999 Latency of varicella zoster virus; a persistently perplexing state. Front Biosci 4 D200 211
36. MyersMGDuerHLHauslerCK 1980 Experimental infection of guinea pigs with varicella-zoster virus. J Infect Dis 142 414 420
37. WroblewskaZValyi-NagyTOtteJDillnerAJacksonA 1993 A mouse model for varicella-zoster virus latency. Microb Pathog 15 141 151
38. MyersMGConnellyBLStanberryLR 1991 Varicella in hairless guinea pigs. J Infect Dis 163 746 751
39. MyersMGConnellyBL 1992 Animal models of varicella. J Infect Dis 166 Suppl 1 S48 50
40. KuC-CBesserJAbendrothAGroseCArvinAM 2005 Varicella-Zoster Virus Pathogenesis and Immunobiology: New Concepts Emerging from Investigations with the SCIDhu Mouse Model. J Virol 79 2651 2658
41. GrayWLOakesJE 1984 Simian varicella virus DNA shares homology with human varicella-zoster virus DNA. Virology 136 241 246
42. GrayWLPumphreyCYRuyechanWTFletcherTM 1992 The simian varicella virus and varicella zoster virus genomes are similar in size and structure. Virology 186 562 572
43. GrayWLStarnesBWhiteMWMahalingamR 2001 The DNA sequence of the simian varicella virus genome. Virology 284 123 130
44. MahalingamRTraina-DorgeVWellishMSmithJGildenDH 2002 Naturally acquired simian varicella virus infection in African green monkeys. J Virol 76 8548 8550
45. GrayWL 2003 Pathogenesis of simian varicella virus. J Med Virol 70 Suppl 1 S4 8
46. MessaoudiIBarronAWellishMEngelmannFLegasseA 2009 Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans. PLoS Pathog 5 e1000657
47. ArvinAM 1996 Varicella-zoster virus. Clin Microbiol Rev 9 361 381
48. KuCCPadillaJAGroseCButcherECArvinAM 2002 Tropism of varicella-zoster virus for human tonsillar CD4(+) T lymphocytes that express activation, memory, and skin homing markers. J Virol 76 11425 11433
49. KuC-CZerboniLItoHGrahamBSWallaceM 2004 Varicella-Zoster Virus Transfer to Skin by T Cells and Modulation of Viral Replication by Epidermal Cell Interferon-{alpha}. J Exp Med 200 917 925
50. MehtaSKCohrsRJForghaniBZerbeGGildenDH 2004 Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 72 174 179
51. MehtaSKTyringSKGildenDHCohrsRJLealMJ 2008 Varicella-Zoster Virus in the Saliva of Patients with Herpes Zoster. J Infect Dis 197 654 657
52. HaywardAGillerRLevinM 1989 Phenotype, cytotoxic, and helper functions of T cells from varicella zoster virus stimulated cultures of human lymphocytes. Viral Immunol 2 175 184
53. GershonAASteinbergSBrunellPA 1974 Zoster immune globulin. A further assessment. N Engl J Med 290 243 245
54. SoikeKF 1992 Simian varicella virus infection in African and Asian monkeys. The potential for development of antivirals for animal diseases. Ann N Y Acad Sci 653 323 333
55. SoikeKFRanganSRGeronePJ 1984 Viral disease models in primates. Adv Vet Sci Comp Med 28 151 199
56. WellerTH 1983 Varicella and Herpes Zoster. N Engl J Med 309 1362 1368
57. VossenMTBiezeveldMHde JongMDGentMRBaarsPA 2005 Absence of circulating natural killer and primed CD8+ cells in life-threatening varicella. J Infect Dis 191 198 206
58. NakanishiYLuBGerardCIwasakiA 2009 CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462 510 513
59. DiazPSSmithSHunterEArvinAM 1989 T lymphocyte cytotoxicity with natural varicella-zoster virus infection and after immunization with live attenuated varicella vaccine. J Immunol 142 636 641
60. HicklingJKBorysiewiczLKSissonsJG 1987 Varicella-zoster virus-specific cytotoxic T lymphocytes (Tc): detection and frequency analysis of HLA class I-restricted Tc in human peripheral blood. J Virol 61 3463 3469
61. HaywardARPontesilliOHerbergerMLaszloMLevinM 1986 Specific lysis of varicella zoster virus-infected B lymphoblasts by human T cells. J Virol 58 179 184
62. MilikanJCMBaarsmaGSKuijpersRWAMOsterhausADMEVerjansGMGM 2009 Human Ocular-Derived Virus-Specific CD4+ T Cells Control Varicella Zoster Virus Replication in Human Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci 50 743 751
63. MilikanJCMKuijpersRWAMBaarsmaGSOsterhausADMEVerjansGMGM 2006 Characterization of the varicella zoster virus (VZV)-specific intra-ocular T-cell response in patients with VZV-induced uveitis. Exp Eye Res 83 69 75
64. VossenMTGentMRWeelJFde JongMDvan LierRA 2004 Development of virus-specific CD4+ T cells on reexposure to Varicella-Zoster virus. J Infect Dis 190 72 82
65. SundFLidehallAKClaessonKFossATottermanTH 2010 CMV-specific T-cell immunity, viral load, and clinical outcome in seropositive renal transplant recipients: a pilot study. Clin Transplant 24 401 409
66. SoikeKFFelsenfeldADGeronePJ 1981 Acyclovir treatment of experimental simian varicella infection of monkeys. Antimicrob Agents Chemother 20 291 297
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2011 Číslo 11
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Multiple Candidate Effectors from the Oomycete Pathogen Suppress Host Plant Immunity
- The Splicing Factor Proline-Glutamine Rich (SFPQ/PSF) Is Involved in Influenza Virus Transcription
- A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis
- SH3 Domain-Mediated Recruitment of Host Cell Amphiphysins by Alphavirus nsP3 Promotes Viral RNA Replication