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. 1996 Jul;70(7):4502–4508. doi: 10.1128/jvi.70.7.4502-4508.1996

Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells.

S Huang 1, T Kamata 1, Y Takada 1, Z M Ruggeri 1, G R Nemerow 1
PMCID: PMC190385  PMID: 8676475

Abstract

A major impediment to the effective use of adenovirus vectors for gene therapy is a lack of knowledge of how these vectors interact with diverse cell types in vivo. Adenovirus attachment to most human cell types is mediated by the fiber protein, which binds to an as yet unidentified cell receptor. In contrast to this, we report that adenovirus type 2 (Ad2) attachment to hematopoietic cells is facilitated by interaction of the penton base protein with members of the beta2 integrin family. Adenovirus particles were capable of binding to human monocytic cells, which lack fiber receptors, and virus binding could be blocked by a soluble penton base or by a function-blocking monoclonal antibody to integrin alphaMbeta2. To confirm the role of alphaMbeta2 integrins in Ad2 binding to hematopoietic cells, we analyzed virus attachment and gene delivery to CHO cells expressing recombinant beta2 integrins. alphaMbeta2-expressing CHO cells supported 3- to 5-fold-higher levels of Ad2 binding and 5- to 10-fold-larger amounts of gene delivery than did nontransfected CHO cells, indicating that alphaMbeta2 facilitates adenovirus attachment to and infection of hematopoietic cells. While beta2 integrins promote Ad2 attachment to hematopoietic cells, further studies demonstrated that alphav integrins were required for the next step in infection, virus internalization into cell endosomes. These studies reveal a novel pathway of Ad2 infection of hematopoietic cells mediated by distinct integrins which facilitate separate events in virus entry. They also suggest a possible strategy for selective adenovirus-mediated gene delivery to hematopoietic cells.

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Selected References

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  1. Addison C. L., Braciak T., Ralston R., Muller W. J., Gauldie J., Graham F. L. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8522–8526. doi: 10.1073/pnas.92.18.8522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andiman W. A., Miller G. Persistent infection with adenovirus types 5 and 6 in lymphoid cells from humans and woolly monkeys. J Infect Dis. 1982 Jan;145(1):83–88. doi: 10.1093/infdis/145.1.83. [DOI] [PubMed] [Google Scholar]
  3. Arnaout M. A. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990 Mar 1;75(5):1037–1050. [PubMed] [Google Scholar]
  4. Bai M., Harfe B., Freimuth P. Mutations that alter an Arg-Gly-Asp (RGD) sequence in the adenovirus type 2 penton base protein abolish its cell-rounding activity and delay virus reproduction in flat cells. J Virol. 1993 Sep;67(9):5198–5205. doi: 10.1128/jvi.67.9.5198-5205.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Challberg S. S., Ketner G. Deletion mutants of adenovirus 2: isolation and initial characterization of virus carrying mutations near the right end of the viral genome. Virology. 1981 Oct 15;114(1):196–209. doi: 10.1016/0042-6822(81)90265-8. [DOI] [PubMed] [Google Scholar]
  6. Chu Y., Sperber K., Mayer L., Hsu M. T. Persistent infection of human adenovirus type 5 in human monocyte cell lines. Virology. 1992 Jun;188(2):793–800. doi: 10.1016/0042-6822(92)90534-v. [DOI] [PubMed] [Google Scholar]
  7. Crystal R. G. Transfer of genes to humans: early lessons and obstacles to success. Science. 1995 Oct 20;270(5235):404–410. doi: 10.1126/science.270.5235.404. [DOI] [PubMed] [Google Scholar]
  8. Dai Y., Schwarz E. M., Gu D., Zhang W. W., Sarvetnick N., Verma I. M. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1401–1405. doi: 10.1073/pnas.92.5.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. De Nichilo M. O., Shafren D. R., Carter W. M., Berndt M. C., Burns G. F., Boyd A. W. A common epitope on platelet integrin alpha IIb beta 3 (glycoprotein IIbIIIa; CD41b/CD61) and alpha M beta 2 (Mac-1; CDIIb/CD18) detected by a monoclonal antibody. J Immunol. 1996 Jan 1;156(1):284–288. [PubMed] [Google Scholar]
  10. Ginsberg H. S., Moldawer L. L., Sehgal P. B., Redington M., Kilian P. L., Chanock R. M., Prince G. A. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1651–1655. doi: 10.1073/pnas.88.5.1651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goldman M. J., Wilson J. M. Expression of alpha v beta 5 integrin is necessary for efficient adenovirus-mediated gene transfer in the human airway. J Virol. 1995 Oct;69(10):5951–5958. doi: 10.1128/jvi.69.10.5951-5958.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hierholzer J. C. Adenoviruses in the immunocompromised host. Clin Microbiol Rev. 1992 Jul;5(3):262–274. doi: 10.1128/cmr.5.3.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huang S., Endo R. I., Nemerow G. R. Upregulation of integrins alpha v beta 3 and alpha v beta 5 on human monocytes and T lymphocytes facilitates adenovirus-mediated gene delivery. J Virol. 1995 Apr;69(4):2257–2263. doi: 10.1128/jvi.69.4.2257-2263.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  15. Kamata T., Wright R., Takada Y. Critical threonine and aspartic acid residues within the I domains of beta 2 integrins for interactions with intercellular adhesion molecule 1 (ICAM-1) and C3bi. J Biol Chem. 1995 May 26;270(21):12531–12535. doi: 10.1074/jbc.270.21.12531. [DOI] [PubMed] [Google Scholar]
  16. Michishita M., Videm V., Arnaout M. A. A novel divalent cation-binding site in the A domain of the beta 2 integrin CR3 (CD11b/CD18) is essential for ligand binding. Cell. 1993 Mar 26;72(6):857–867. doi: 10.1016/0092-8674(93)90575-b. [DOI] [PubMed] [Google Scholar]
  17. Neumann R., Chroboczek J., Jacrot B. Determination of the nucleotide sequence for the penton-base gene of human adenovirus type 5. Gene. 1988 Sep 15;69(1):153–157. doi: 10.1016/0378-1119(88)90389-7. [DOI] [PubMed] [Google Scholar]
  18. Niiya K., Hodson E., Bader R., Byers-Ward V., Koziol J. A., Plow E. F., Ruggeri Z. M. Increased surface expression of the membrane glycoprotein IIb/IIIa complex induced by platelet activation. Relationship to the binding of fibrinogen and platelet aggregation. Blood. 1987 Aug;70(2):475–483. [PubMed] [Google Scholar]
  19. Philipson L., Lonberg-Holm K., Pettersson U. Virus-receptor interaction in an adenovirus system. J Virol. 1968 Oct;2(10):1064–1075. doi: 10.1128/jvi.2.10.1064-1075.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Relman D., Tuomanen E., Falkow S., Golenbock D. T., Saukkonen K., Wright S. D. Recognition of a bacterial adhesion by an integrin: macrophage CR3 (alpha M beta 2, CD11b/CD18) binds filamentous hemagglutinin of Bordetella pertussis. Cell. 1990 Jun 29;61(7):1375–1382. doi: 10.1016/0092-8674(90)90701-f. [DOI] [PubMed] [Google Scholar]
  21. Ruoslahti E. Integrins. J Clin Invest. 1991 Jan;87(1):1–5. doi: 10.1172/JCI114957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Schmidt-Wolf G. D., Schmidt-Wolf I. G. Cytokines and gene therapy. Immunol Today. 1995 Apr;16(4):173–175. doi: 10.1016/0167-5699(95)80116-2. [DOI] [PubMed] [Google Scholar]
  23. Springer T., Galfré G., Secher D. S., Milstein C. Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol. 1979 Apr;9(4):301–306. doi: 10.1002/eji.1830090410. [DOI] [PubMed] [Google Scholar]
  24. Stratford-Perricaudet L. D., Makeh I., Perricaudet M., Briand P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest. 1992 Aug;90(2):626–630. doi: 10.1172/JCI115902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tomiyama Y., Brojer E., Ruggeri Z. M., Shattil S. J., Smiltneck J., Gorski J., Kumar A., Kieber-Emmons T., Kunicki T. J. A molecular model of RGD ligands. Antibody D gene segments that direct specificity for the integrin alpha IIb beta 3. J Biol Chem. 1992 Sep 5;267(25):18085–18092. [PubMed] [Google Scholar]
  26. Wickham T. J., Filardo E. J., Cheresh D. A., Nemerow G. R. Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol. 1994 Oct;127(1):257–264. doi: 10.1083/jcb.127.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wickham T. J., Mathias P., Cheresh D. A., Nemerow G. R. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell. 1993 Apr 23;73(2):309–319. doi: 10.1016/0092-8674(93)90231-e. [DOI] [PubMed] [Google Scholar]
  28. Yang Y., Nunes F. A., Berencsi K., Furth E. E., Gönczöl E., Wilson J. M. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]

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