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PMID: 14963160 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Modification to the capsid of the adenovirus vector that enhances dendritic cell infection and transgene-specific cellular immune responses.

Journal of virology ·Vol. 78 ·No. 5 ·2004-03-00 ·Pages 2572-80

Worgall S, Busch A, Rivara M, Bonnyay D, Leopold PL, Merritt R, Hackett NR, Rovelink PW, Bruder JT, Wickham TJ, Kovesdi I, Crystal RG

Abstract

Adenovirus (Ad) gene transfer vectors can be used to transfer and express antigens and function as strong adjuvants and thus are useful platforms for the development of genetic vaccines. Based on the hypothesis that Ad vectors with enhanced infectibility of dendritic cells (DC) may be able to evoke enhanced immune responses against antigens encoded by the vector in vivo, the present study analyzes the vaccine potential of an Ad vector expressing beta-galactosidase as a model antigen and genetically modified with RGD on the fiber knob [AdZ.F(RGD)] to more selectively infect DC and consequently enhance immunity against the beta-galactosidase antigen. Infection of murine DC in vitro with AdZ.F(RGD) showed an eightfold-increased transgene expression following infection compared to AdZ (also expressing beta-galactosidase, but with a wild-type capsid). Binding, cellular uptake, and trafficking in DC were also increased with AdZ.F(RGD) compared to AdZ. To determine whether AdZ.F(RGD) could evoke enhanced immune responses to beta-galactosidase in vivo, C57BL/6 mice were immunized with AdZ.F(RGD) or AdZ subcutaneously via the footpad. Humoral responses with both vectors were comparable, with similar anti-beta-galactosidase antibody levels following vector administration. However, cellular responses to beta-galactosidase were significantly enhanced, with the frequency of CD4(+) as well as the CD8(+) beta-galactosidase-specific gamma interferon response in cells isolated from the draining lymph nodes increased following immunization with AdZ.F(RGD) compared to Ad.Z (P < 0.01). Importantly, this enhanced cellular immune response of the AdZ.F(RGD) vector was sufficient to evoke enhanced inhibition of the growth of preexisting tumors expressing beta-galactosidase: BALB/c mice implanted with the CT26 syngeneic beta-galactosidase-expressing colon carcinoma cell line and subsequently immunized with AdZ.F(RGD) showed decreased tumor growth and improved survival compared to mice immunized with AdZ. These data demonstrate that addition of an RGD motif to the Ad fiber knob increases the infectibility of DC and leads to enhanced cellular immune responses to the Ad-transferred transgene, suggesting that the RGD capsid modification may be useful in developing Ad-based vaccines.

MeSH Terms
Adenoviridae/genetics,physiology Animals Antibody Formation CD4-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/immunology Cancer Vaccines/genetics,immunology Capsid Proteins/genetics,metabolism Dendritic Cells/immunology,virology Genes, Reporter/genetics Genetic Therapy/methods Genetic Vectors/genetics Immunity, Cellular Immunization Mice Mice, Inbred C57BL Neoplasms/genetics,immunology,pathology,therapy Survival Rate Transgenes/genetics beta-Galactosidase/genetics,immunology
Chemicals
Cancer Vaccines Capsid Proteins beta-Galactosidase
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Worgall Stefan
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. [email protected]
Busch Annette
Rivara Michael
Bonnyay David
Leopold Philip L
Merritt Robert
Hackett Neil R
Rovelink Peter W
Bruder Joseph T
Wickham Thomas J
Kovesdi Imi
Crystal Ronald G
References (49)
49 references, click to expand
  1. Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae.
    Science. 1999 Nov 19;286(5444):1568-71 PMID: 10567265
  2. Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy.
    J Virol. 1996 Nov;70(11):7498-509 PMID: 8892868
  3. Modifications of the fiber in adenovirus vectors increase tropism for malignant glioma models.
    Cancer Gene Ther. 2000 Jan;7(1):13-9 PMID: 10678351
  4. Identification of contact residues and definition of the CAR-binding site of adenovirus type 5 fiber protein.
    J Virol. 2000 Mar;74(6):2804-13 PMID: 10684297
  5. Adenovirus vector-mediated gene transfer to regional lymph nodes.
    Hum Gene Ther. 2000 Mar 20;11(5):759-69 PMID: 10757355
  6. Immunobiology of dendritic cells.
    Annu Rev Immunol. 2000;18:767-811 PMID: 10837075
  7. DNA vaccines: immunology, application, and optimization*.
    Annu Rev Immunol. 2000;18:927-74 PMID: 10837079
  8. Development of a preventive vaccine for Ebola virus infection in primates.
    Nature. 2000 Nov 30;408(6812):605-9 PMID: 11117750
  9. Th1 and Th2 cells.
    Curr Opin Hematol. 2001 Jan;8(1):47-51 PMID: 11138626
  10. Plasmid DNA adsorbed onto cationic microparticles mediates target gene expression and antigen presentation by dendritic cells.
    Gene Ther. 2000 Dec;7(24):2105-12 PMID: 11223992
  11. Antivector and antitransgene host responses in gene therapy.
    Curr Opin Mol Ther. 2000 Aug;2(4):376-82 PMID: 11249767
  12. Targeting antigen in mature dendritic cells for simultaneous stimulation of CD4+ and CD8+ T cells.
    J Immunol. 2001 Apr 15;166(8):5250-7 PMID: 11290810
  13. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5.
    Science. 1997 Feb 28;275(5304):1320-3 PMID: 9036860
  14. Delayed-type hypersensitivity response to high doses of adenoviral vectors.
    Hum Gene Ther. 1997 Feb 10;8(3):323-30 PMID: 9048199
  15. Cytotoxic T lymphocyte responses to proteins encoded by heterologous transgenes transferred in vivo by adenoviral vectors.
    Hum Gene Ther. 1997 Jul 1;8(10):1207-17 PMID: 9215738
  16. Multi-epitope DNA vaccines.
    Immunol Cell Biol. 1997 Aug;75(4):402-8 PMID: 9315485
  17. Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.
    J Exp Med. 1997 Oct 20;186(8):1247-56 PMID: 9334364
  18. Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins.
    J Virol. 1997 Nov;71(11):8221-9 PMID: 9343173
  19. High efficiency adenovirus-mediated gene transfer to human dendritic cells.
    Blood. 1998 Jan 15;91(2):392-8 PMID: 9427691
  20. Increased immune response elicited by DNA vaccination with a synthetic gp120 sequence with optimized codon usage.
    J Virol. 1998 Feb;72(2):1497-503 PMID: 9445053
  21. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.
    Nature. 1998 Mar 5;392(6671):86-9 PMID: 9510252
  22. Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers.
    J Virol. 1998 May;72(5):4212-23 PMID: 9557710
  23. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells.
    J Exp Med. 1998 Dec 7;188(11):2163-73 PMID: 9841929
  24. CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts.
    J Clin Invest. 1999 Feb;103(4):579-87 PMID: 10021467
  25. Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector.
    J Immunol. 1999 Jun 1;162(11):6378-83 PMID: 10352250
  26. Fiber swap between adenovirus subgroups B and C alters intracellular trafficking of adenovirus gene transfer vectors.
    J Virol. 1999 Jul;73(7):6056-65 PMID: 10364358
  27. Challenges and opportunities for development of an AIDS vaccine.
    Nature. 2001 Apr 19;410(6831):1002-7 PMID: 11309631
  28. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages.
    Mol Ther. 2001 May;3(5 Pt 1):697-707 PMID: 11356075
  29. Efficient antigen gene transduction using Arg-Gly-Asp fiber-mutant adenovirus vectors can potentiate antitumor vaccine efficacy and maturation of murine dendritic cells.
    Cancer Res. 2001 Nov 1;61(21):7913-9 PMID: 11691812
  30. Adenovirus hexon protein is a potent adjuvant for activation of a cellular immune response.
    J Virol. 2002 Jan;76(1):127-35 PMID: 11739678
  31. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.
    Nature. 2002 Jan 17;415(6869):331-5 PMID: 11797011
  32. Adenovirus binding to the coxsackievirus and adenovirus receptor or integrins is not required to elicit brain inflammation but is necessary to transduce specific neural cell types.
    J Virol. 2002 Apr;76(7):3452-60 PMID: 11884569
  33. Infection of mouse bone marrow-derived dendritic cells with recombinant adenovirus vectors leads to presentation of encoded antigen by both MHC class I and class II molecules-potential benefits in vaccine design.
    Vaccine. 2002 Dec 13;21(3-4):231-42 PMID: 12450698
  34. Pattern recognition receptors: doubling up for the innate immune response.
    Cell. 2002 Dec 27;111(7):927-30 PMID: 12507420
  35. The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies.
    J Exp Med. 1990 May 1;171(5):1753-71 PMID: 2185332
  36. Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo.
    Science. 1991 Apr 19;252(5004):431-4 PMID: 2017680
  37. Comparisons of standard curve-fitting methods to quantitate Neisseria meningitidis group A polysaccharide antibody levels by enzyme-linked immunosorbent assay.
    J Clin Microbiol. 1991 Jul;29(7):1439-46 PMID: 1909345
  38. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium.
    Cell. 1992 Jan 10;68(1):143-55 PMID: 1370653
  39. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment.
    Cell. 1993 Apr 23;73(2):309-19 PMID: 8477447
  40. Multiple adenovirus serotypes use alpha v integrins for infection.
    J Virol. 1994 Oct;68(10):6811-4 PMID: 8084019
  41. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses.
    J Virol. 1995 Apr;69(4):2004-15 PMID: 7884845
  42. Modulation of gene expression after replication-deficient, recombinant adenovirus-mediated gene transfer by the product of a second adenovirus vector.
    Gene Ther. 1995 Mar;2(2):124-31 PMID: 7719929
  43. Recombinant adenoviruses as vaccines.
    Biologicals. 1995 Jun;23(2):145-57 PMID: 7546657
  44. Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11671-5 PMID: 8524826
  45. Therapeutic antitumor response after immunization with a recombinant adenovirus encoding a model tumor-associated antigen.
    J Immunol. 1996 Jan 1;156(1):224-31 PMID: 8598466
  46. Adenoviruses as gene-delivery vehicles.
    N Engl J Med. 1996 May 2;334(18):1185-7 PMID: 8602187
  47. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors.
    Nat Med. 1996 May;2(5):545-50 PMID: 8616713
  48. Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs.
    Gene Ther. 1995 Dec;2(10):750-6 PMID: 8750015
  49. Cellular immune responses of healthy individuals to intradermal administration of an E1-E3- adenovirus gene transfer vector.
    Hum Gene Ther. 1999 Nov 20;10(17):2823-37 PMID: 10584928
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.78.5.2572-2580.2004
Email
[email protected]
Published
2004-03-00
Pages
2572-80
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC369215
Subset
IM
Grants
NCRR NIH HHS · M01 RR000047 · United States
NHLBI NIH HHS · U01 HL066952 · United States
NCRR NIH HHS · M01RR00047 · United States
NHLBI NIH HHS · U01 HL66952 · United States
External Links
PubMed source DOI: 10.1128/jvi.78.5.2572-2580.2004 PMC Full Text View journal details
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