Home LiteratureArticle Details
PMID: 10477314 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

Role of alpha(v) integrins in adenovirus cell entry and gene delivery.

Microbiology and molecular biology reviews : MMBR ·Vol. 63 ·No. 3 ·1999-09-00 ·Pages 725-34

Nemerow GR, Stewart PL

Abstract

Adenoviruses (Ad) are a significant cause of acute infections in humans; however, replication-defective forms of this virus are currently under investigation for human gene therapy. Approximately 20 to 25% of all the gene therapy trials (phases I to III) conducted over the past 10 years involve the use of Ad gene delivery for treatment inherited or acquired diseases. At present, the most promising applications involve the use of Ad vectors to irradicate certain nonmetastatic tumors and to promote angiogenesis in order to alleviate cardiovascular disease. While specific problems of using Ad vectors remain to be overcome (as is true for almost all viral and nonviral delivery methods), a distinct advantage of Ad is the extensive knowledge of its macromolecular structure, genome organization, sequence, and mode of replication. Moreover, significant information has also been acquired on the interaction of Ad particles with distinct host cell receptors, events which strongly affect virus tropism. This review provides an overview of the structure and function of Ad attachment (coxsackievirus and Ad receptor [CAR]) and internalization (alpha(v) integrins) receptors and discusses their precise role in virus infection and gene delivery. Recent structure studies of integrin-Ad complexes by cryoelectron microscopy are also highlighted. Finally, unanswered questions arising from the current state of knowledge of Ad-receptor interactions are presented in the context of improving Ad vectors for future human gene therapy applications.

MeSH Terms
Adenoviruses, Human/genetics,physiology Amino Acid Sequence Antigens, CD/physiology Gene Transfer Techniques Genetic Vectors Humans Integrin alphaV Integrins/chemistry,physiology Molecular Sequence Data Receptors, Vitronectin Signal Transduction
Chemicals
Antigens, CD Integrin alphaV Integrins Receptors, Vitronectin integrin alphaVbeta5
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Nemerow G R
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. [email protected]
Stewart P L
References (103)
103 references, click to expand
  1. Targeted adenovirus-mediated gene delivery to T cells via CD3.
    J Virol. 1997 Oct;71(10):7663-9 PMID: 9311849
  2. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism.
    J Virol. 1998 Dec;72(12):9706-13 PMID: 9811704
  3. Infectious entry pathway of adenovirus type 2.
    J Virol. 1991 Nov;65(11):6061-70 PMID: 1920625
  4. Granulocyte-macrophage and macrophage colony-stimulating factors differentially regulate alpha v integrin expression on cultured human macrophages.
    Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2517-21 PMID: 7681600
  5. The actin cytoskeleton is required for receptor-mediated endocytosis in mammalian cells.
    J Biol Chem. 1997 Aug 15;272(33):20332-5 PMID: 9252336
  6. Structure of adenovirus complexed with its internalization receptor, alphavbeta5 integrin.
    J Virol. 1999 Aug;73(8):6759-68 PMID: 10400774
  7. Pervasive conformational fluctuations on microsecond time scales in a fibronectin type III domain.
    Nat Struct Biol. 1998 Jan;5(1):55-9 PMID: 9437430
  8. Spliced segments at the 5' terminus of adenovirus 2 late mRNA.
    Proc Natl Acad Sci U S A. 1977 Aug;74(8):3171-5 PMID: 269380
  9. Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization.
    J Cell Biol. 1994 Oct;127(1):257-64 PMID: 7523420
  10. Adenovirus infection in pediatric liver transplant recipients.
    J Infect Dis. 1992 Jan;165(1):170-4 PMID: 1727887
  11. Adenovirus infection in adult orthotopic liver transplant recipients: incidence and clinical significance.
    J Infect Dis. 1998 Feb;177(2):459-62 PMID: 9466537
  12. The alpha v beta 5 integrin receptor regulates receptor-mediated endocytosis of vitronectin.
    J Biol Chem. 1993 Jun 5;268(16):11492-5 PMID: 7685013
  13. Focal adhesion kinase: structure and signalling.
    J Cell Sci Suppl. 1994;18:109-13 PMID: 7883785
  14. beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7074-9 PMID: 9618541
  15. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions.
    J Virol. 1998 Feb;72(2):1438-45 PMID: 9445046
  16. The vitronectin receptor associates with clathrin-coated membrane domains via the cytoplasmic domain of its beta5 subunit.
    J Cell Sci. 1998 Sep;111 ( Pt 18):2729-40 PMID: 9718366
  17. Determination of the nucleotide sequence for the penton-base gene of human adenovirus type 5.
    Gene. 1988 Sep 15;69(1):153-7 PMID: 3224820
  18. AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection.
    Nat Med. 1999 Jan;5(1):78-82 PMID: 9883843
  19. PI3K: downstream AKTion blocks apoptosis.
    Cell. 1997 Feb 21;88(4):435-7 PMID: 9038334
  20. Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression.
    J Virol. 1997 Jan;71(1):398-404 PMID: 8985363
  21. Solution structure and dynamics of linked cell attachment modules of mouse fibronectin containing the RGD and synergy regions: comparison with the human fibronectin crystal structure.
    J Mol Biol. 1998 Apr 3;277(3):663-82 PMID: 9533887
  22. Growth arrest of Epstein-Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes.
    Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8156-61 PMID: 9223331
  23. Intracellular pathogens and the actin cytoskeleton.
    Annu Rev Cell Dev Biol. 1998;14:137-66 PMID: 9891781
  24. The emergence of clathrin-independent pinocytic pathways.
    Curr Opin Cell Biol. 1995 Aug;7(4):573-80 PMID: 7495578
  25. Lack of high affinity fiber receptor activity explains the resistance of ciliated airway epithelia to adenovirus infection.
    J Clin Invest. 1997 Sep 1;100(5):1144-9 PMID: 9276731
  26. Arginine-glycine-aspartic acid-specific binding by foot-and-mouth disease viruses to the purified integrin alpha(v)beta3 in vitro.
    J Virol. 1997 Nov;71(11):8357-61 PMID: 9343190
  27. Adenovirus endocytosis requires actin cytoskeleton reorganization mediated by Rho family GTPases.
    J Virol. 1998 Nov;72(11):8806-12 PMID: 9765425
  28. 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):2257-63 PMID: 7533853
  29. The three-dimensional structure of foot-and-mouth disease virus at 2.9 A resolution.
    Nature. 1989 Feb 23;337(6209):709-16 PMID: 2537470
  30. Adenovirus 3 penton dodecahedron exhibits structural changes of the base on fibre binding.
    EMBO J. 1996 Dec 16;15(24):6841-6 PMID: 9003759
  31. Early events in the interaction of adenoviruses with HeLa cells. I. Penetration of type 5 and intracellular release of the DNA genome.
    Virology. 1970 Mar;40(3):462-77 PMID: 5437781
  32. HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3352-6 PMID: 9096397
  33. 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):5951-8 PMID: 7545239
  34. Adenoviruses in the immunocompromised host.
    Clin Microbiol Rev. 1992 Jul;5(3):262-74 PMID: 1323383
  35. Vitronectin receptor antibodies inhibit infection of HeLa and A549 cells by adenovirus type 12 but not by adenovirus type 2.
    J Virol. 1994 Sep;68(9):5925-32 PMID: 7520097
  36. Integrin-mediated short-term memory in Drosophila.
    Nature. 1998 Jan 29;391(6666):455-60 PMID: 9461212
  37. Is dynamin really a 'pinchase'?
    Trends Cell Biol. 1997 Jul;7(7):257-9 PMID: 17708956
  38. Limited entry of adenovirus vectors into well-differentiated airway epithelium is responsible for inefficient gene transfer.
    J Virol. 1998 Jul;72(7):6014-23 PMID: 9621064
  39. Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5389-94 PMID: 9144247
  40. Matrix valency regulates integrin-mediated lymphoid adhesion via Syk kinase.
    J Cell Biol. 1999 Feb 22;144(4):777-88 PMID: 10037798
  41. 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):5198-205 PMID: 8350395
  42. Integrins and signal transduction pathways: the road taken.
    Science. 1995 Apr 14;268(5208):233-9 PMID: 7716514
  43. Adenovirus uncoating and nuclear establishment are not affected by weak base amines.
    J Virol. 1996 Jun;70(6):3470-7 PMID: 8648679
  44. Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling.
    Curr Biol. 1994 May 1;4(5):385-93 PMID: 7922352
  45. Induction of mutant dynamin specifically blocks endocytic coated vesicle formation.
    J Cell Biol. 1994 Nov;127(4):915-34 PMID: 7962076
  46. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins.
    Curr Opin Cell Biol. 1996 Apr;8(2):146-52 PMID: 8791417
  47. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis.
    Cell. 1993 Oct 22;75(2):207-16 PMID: 7691415
  48. Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer.
    Cancer Res. 1998 Dec 15;58(24):5738-48 PMID: 9865732
  49. RGD-dependent entry of coxsackievirus A9 into host cells and its bypass after cleavage of VP1 protein by intestinal proteases.
    J Virol. 1991 Sep;65(9):4735-40 PMID: 1870199
  50. High-efficiency gene transfer employing adenovirus-polylysine-DNA complexes.
    Nat Immun. 1994 Mar-Jun;13(2-3):141-64 PMID: 8173235
  51. Regulation of cell motility by mitogen-activated protein kinase.
    J Cell Biol. 1997 Apr 21;137(2):481-92 PMID: 9128257
  52. Integrin-mediated cell adhesion activates mitogen-activated protein kinases.
    J Biol Chem. 1994 Oct 28;269(43):26602-5 PMID: 7929388
  53. A protein factor responsible for the early cytopathic effect of adenoviruses.
    Virology. 1958 Dec;6(3):601-11 PMID: 13616174
  54. Evidence that the penton base of adenovirus is involved in potentiation of toxicity of Pseudomonas exotoxin conjugated to epidermal growth factor.
    Mol Cell Biol. 1984 Aug;4(8):1528-33 PMID: 6333584
  55. The role of the adenovirus protease on virus entry into cells.
    EMBO J. 1996 Apr 15;15(8):1766-77 PMID: 8617221
  56. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5.
    Science. 1997 Feb 28;275(5304):1320-3 PMID: 9036860
  57. Hemorrhagic cystitis due to adenovirus infection following bone marrow transplantation.
    J Urol. 1994 Apr;151(4):1013-4 PMID: 8126773
  58. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis.
    N Engl J Med. 1995 Sep 28;333(13):823-31 PMID: 7544439
  59. 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):1401-5 PMID: 7877990
  60. Adenovirus 2 Ip+ locus codes for a 19 kd tumor antigen that plays an essential role in cell transformation.
    Cell. 1983 Jul;33(3):759-66 PMID: 6871992
  61. The DNA sequence of adenovirus type 40.
    J Mol Biol. 1993 Dec 20;234(4):1308-16 PMID: 8263936
  62. Adenovirus dodecahedron, a new vector for human gene transfer.
    Nat Biotechnol. 1997 Jan;15(1):52-6 PMID: 9035106
  63. Identification of the integrin VLA-2 as a receptor for echovirus 1.
    Science. 1992 Mar 27;255(5052):1718-20 PMID: 1553561
  64. Adenovirus-mediated in vivo gene transfer.
    Ann N Y Acad Sci. 1994 May 31;716:90-101; discussion 101-3 PMID: 7517653
  65. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells.
    Science. 1996 Oct 18;274(5286):373-6 PMID: 8832876
  66. Adenovirus-dependent increase in cell membrane permeability.
    J Biol Chem. 1985 Aug 15;260(17):9598-602 PMID: 4019489
  67. The coxsackievirus-adenovirus receptor protein can function as a cellular attachment protein for adenovirus serotypes from subgroups A, C, D, E, and F.
    J Virol. 1998 Oct;72(10):7909-15 PMID: 9733828
  68. Multiple adenovirus serotypes use alpha v integrins for infection.
    J Virol. 1994 Oct;68(10):6811-4 PMID: 8084019
  69. Binding of adenovirus and its external proteins to Triton X-114. Dependence on pH.
    J Biol Chem. 1985 Nov 25;260(27):14431-4 PMID: 4055783
  70. A helper-independent adenovirus vector with E1, E3, and fiber deleted: structure and infectivity of fiberless particles.
    J Virol. 1999 Feb;73(2):1601-8 PMID: 9882366
  71. Adenovirus internalization and infection require dynamin.
    J Virol. 1998 Apr;72(4):3455-8 PMID: 9525681
  72. Interactions of soluble recombinant integrin alphav beta5 with human adenoviruses.
    J Virol. 1998 Nov;72(11):8669-75 PMID: 9765407
  73. Coxsackievirus and adenovirus receptor cytoplasmic and transmembrane domains are not essential for coxsackievirus and adenovirus infection.
    J Virol. 1999 Mar;73(3):2559-62 PMID: 9971843
  74. Nucleotide sequence of human adenovirus type 12 DNA: comparative functional analysis.
    J Virol. 1994 Jan;68(1):379-89 PMID: 8254750
  75. Adenovirus-dependent release of 51Cr from KB cells at an acidic pH.
    J Biol Chem. 1984 Dec 10;259(23):14350-3 PMID: 6334083
  76. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2.
    Nat Med. 1999 Jan;5(1):71-7 PMID: 9883842
  77. Difference imaging of adenovirus: bridging the resolution gap between X-ray crystallography and electron microscopy.
    EMBO J. 1993 Jul;12(7):2589-99 PMID: 8334984
  78. The coxsackievirus A9 RGD motif is not essential for virus viability.
    J Virol. 1995 Dec;69(12):8035-40 PMID: 7494317
  79. A single amino acid in the adenovirus type 37 fiber confers binding to human conjunctival cells.
    J Virol. 1999 Apr;73(4):2798-802 PMID: 10074127
  80. An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA.
    Cell. 1977 Sep;12(1):1-8 PMID: 902310
  81. Adenovirus endocytosis via alpha(v) integrins requires phosphoinositide-3-OH kinase.
    J Virol. 1998 Mar;72(3):2055-61 PMID: 9499060
  82. A toxin-like material separable from type 5 adenovirus particles.
    Virology. 1958 Dec;6(3):770-1 PMID: 13616188
  83. Stepwise dismantling of adenovirus 2 during entry into cells.
    Cell. 1993 Nov 5;75(3):477-86 PMID: 8221887
  84. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A.
    Nature. 1996 Jul 25;382(6589):319-24 PMID: 8684459
  85. Cryo-EM visualization of an exposed RGD epitope on adenovirus that escapes antibody neutralization.
    EMBO J. 1997 Mar 17;16(6):1189-98 PMID: 9135136
  86. Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells.
    J Virol. 1996 Jul;70(7):4502-8 PMID: 8676475
  87. Integrins: versatility, modulation, and signaling in cell adhesion.
    Cell. 1992 Apr 3;69(1):11-25 PMID: 1555235
  88. Avian adenovirus induces ion channels in model bilayer lipid membranes.
    Biochem Biophys Res Commun. 1997 Jul 30;236(3):750-3 PMID: 9245727
  89. Ultrastructural and immunofluorescence studies of early events in adenovirus-HeLa cell interactions.
    J Gen Virol. 1983 May;64(Pt 5):1091-9 PMID: 6341509
  90. Chicken adenovirus (CELO virus) particles augment receptor-mediated DNA delivery to mammalian cells and yield exceptional levels of stable transformants.
    J Virol. 1993 Jul;67(7):3777-85 PMID: 8099627
  91. pH-dependent lysis of liposomes by adenovirus.
    Biochemistry. 1986 Apr 22;25(8):2231-7 PMID: 3754765
  92. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.
    Science. 1996 May 10;272(5263):872-7 PMID: 8629022
  93. The assembly of integrin adhesion complexes requires both extracellular matrix and intracellular rho/rac GTPases.
    J Cell Biol. 1995 Dec;131(6 Pt 2):1857-65 PMID: 8557752
  94. Actin microfilaments play a critical role in endocytosis at the apical but not the basolateral surface of polarized epithelial cells.
    J Cell Biol. 1993 Feb;120(3):695-710 PMID: 8381123
  95. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase.
    Nature. 1994 Dec 22-29;372(6508):786-91 PMID: 7997267
  96. Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor.
    Science. 1998 Jun 5;280(5369):1618-20 PMID: 9616127
  97. Adenovirus infections in patients undergoing bone-marrow transplantation.
    N Engl J Med. 1985 Feb 28;312(9):529-33 PMID: 2982098
  98. The adenovirus protease is required for virus entry into host cells.
    Virology. 1995 Nov 10;213(2):494-502 PMID: 7491774
  99. Image reconstruction reveals the complex molecular organization of adenovirus.
    Cell. 1991 Oct 4;67(1):145-54 PMID: 1913814
  100. 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
  101. Adenovirus vector-based purging of multiple myeloma cells.
    Blood. 1998 Dec 15;92(12):4591-601 PMID: 9845525
  102. Protein ligands of the human adenovirus type 2 outer capsid identified by biopanning of a phage-displayed peptide library on separate domains of wild-type and mutant penton capsomers.
    EMBO J. 1995 Oct 2;14(19):4714-27 PMID: 7588601
  103. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia.
    Cell. 1995 Apr 7;81(1):53-62 PMID: 7536630
Article Info
Journal
Microbiology and molecular biology reviews : MMBR
Abbr.
Microbiol Mol Biol Rev
ISSN
1092-2172
DOI
10.1128/MMBR.63.3.725-734.1999
Email
[email protected]
Published
1999-09-00
Pages
725-34
Language
English
Region
United States
NLM ID
9706653
PMCID
PMC103752
Subset
IM
Grants
NCRR NIH HHS · M01 RR000833 · United States
NHLBI NIH HHS · R01 HL054352 · United States
NIAID NIH HHS · R01 AI042929 · United States
NHLBI NIH HHS · HL54352 · United States
NIAID NIH HHS · R29 AI042929 · United States
NEI NIH HHS · R01 EY011431 · United States
NIAID NIH HHS · AI42929 · United States
NEI NIH HHS · EY11431 · United States
External Links
PubMed source DOI: 10.1128/MMBR.63.3.725-734.1999 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2