Molecular basis of the inflammatory response to adenovirus vectors

Adenovirus vectors are extensively studied in experimental and clinical models as agents for gene therapy. Recent generations of helper-dependent adenovirus vectors have the majority of viral genes removed and result in vectors with a large carrying capacity, reduced host adaptive immune responses and improved gene transfer efficiency. Adenovirus vectors, however, activate innate immune responses shortly after administration in vivo. Unlike the adaptive response, the innate response to adenovirus vectors is transcription independent and is caused by the viral particle or capsid. This response results in inflammation of transduced tissues and substantial loss of vector genomes in the first 24 h. The adenovirus capsid activates a number of signaling pathways following cell entry including p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) that ultimately lead to expression of proinflammatory genes. Various cytokines, chemokines and leukocyte adhesion molecules are induced by the adenovirus particle in a wide range of cell types providing a molecular basis for the inflammatory properties of these vectors. An understanding of the innate response to adenovirus vectors is essential to overcome the last remaining hurdle to improve the safety and effectiveness of these agents.

[1]  M. Rudnicki,et al.  A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  B. Trapnell,et al.  Internalization of Adenovirus by Alveolar Macrophages Initiates Early Proinflammatory Signaling during Acute Respiratory Tract Infection , 2000, Journal of Virology.

[3]  R. Wilmott,et al.  Replication-deficient adenovirus induces expression of interleukin-8 by airway epithelial cells in vitro. , 1995, Human gene therapy.

[4]  P. Crespo,et al.  The Small GTP-binding Protein Rho Activates c-Jun N-terminal Kinases/Stress-activated Protein Kinases in Human Kidney 293T Cells , 1996, The Journal of Biological Chemistry.

[5]  T. Libermann,et al.  Adenovirus vector-induced inflammation: capsid-dependent induction of the C-C chemokine RANTES requires NF-kappa B. , 2002, Human gene therapy.

[6]  G. Nemerow,et al.  Adenovirus Endocytosis Requires Actin Cytoskeleton Reorganization Mediated by Rho Family GTPases , 1998, Journal of Virology.

[7]  U. Greber,et al.  Adenovirus‐activated PKA and p38/MAPK pathways boost microtubule‐mediated nuclear targeting of virus , 2001, The EMBO journal.

[8]  G. Nemerow,et al.  Integrin alpha(v)beta1 is an adenovirus coreceptor. , 2001, Journal of virology.

[9]  J. Stark,et al.  Infection of A549 cells with a recombinant adenovirus vector induces ICAM-1 expression and increased CD-18-dependent adhesion of activated neutrophils. , 1996, Human gene therapy.

[10]  Douglas T. Golenbock,et al.  Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus , 2000, Nature Immunology.

[11]  M. Kay,et al.  Recombinant adenoviruses with large deletions generated by Cre-mediated excision exhibit different biological properties compared with first-generation vectors in vitro and in vivo , 1996, Journal of virology.

[12]  G. Nemerow,et al.  Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells , 1996, Journal of virology.

[13]  P. Lowenstein,et al.  Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[14]  B. Trapnell,et al.  Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses. , 1998, Human gene therapy.

[15]  P. Kubes,et al.  The role of selectins and integrins in adenovirus vector‐induced neutrophil recruitment to the liver , 2002, European journal of immunology.

[16]  I. Kovesdi,et al.  Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae. , 1999, Science.

[17]  G. Nemerow,et al.  Association of p130CAS with Phosphatidylinositol-3-OH Kinase Mediates Adenovirus Cell Entry* , 2000, The Journal of Biological Chemistry.

[18]  P. Stewart,et al.  Role of alpha(v) integrins in adenovirus cell entry and gene delivery. , 1999, Microbiology and molecular biology reviews : MMBR.

[19]  G. Nemerow,et al.  Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization , 1994, The Journal of cell biology.

[20]  R. Crystal,et al.  Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. , 1997, Human gene therapy.

[21]  J. Wilson,et al.  Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  G. Nemerow,et al.  Regulation of Adenovirus Membrane Penetration by the Cytoplasmic Tail of Integrin β5 , 2000, Journal of Virology.

[23]  J. Gutkind,et al.  Signaling from the Small GTP-binding Proteins Rac1 and Cdc42 to the c-Jun N-terminal Kinase/Stress-activated Protein Kinase Pathway , 1996, The Journal of Biological Chemistry.

[24]  Luigi Naldini,et al.  Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics , 2001, Nature Medicine.

[25]  F. Giancotti,et al.  Complexity and specificity of integrin signalling , 2000, Nature Cell Biology.

[26]  T. Libermann,et al.  Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. , 1999, Human gene therapy.

[27]  H. Ertl,et al.  MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. , 1994, Immunity.

[28]  J. Wilson,et al.  Adenoviruses as gene-delivery vehicles. , 1996, The New England journal of medicine.

[29]  R. Crystal,et al.  CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts. , 1999, The Journal of clinical investigation.

[30]  M. Chilosi,et al.  Heparan Sulfate Glycosaminoglycans Are Receptors Sufficient To Mediate the Initial Binding of Adenovirus Types 2 and 5 , 2001, Journal of Virology.

[31]  T. Libermann,et al.  Adenovirus Vector-Induced Expression of the C-X-C Chemokine IP-10 Is Mediated through Capsid-Dependent Activation of NF-κB , 2000, Journal of Virology.

[32]  P. Seth,et al.  The release of inflammatory cytokines from human peripheral blood mononuclear cells in vitro following exposure to adenovirus variants and capsid. , 2002, Human gene therapy.

[33]  Ari Helenius,et al.  Stepwise dismantling of adenovirus 2 during entry into cells , 1993, Cell.

[34]  G. Nemerow,et al.  Adenovirus endocytosis via alpha(v) integrins requires phosphoinositide-3-OH kinase. , 1998, Journal of virology.

[35]  M. Hollenberg,et al.  Activation of p38 and ERK Signaling during Adenovirus Vector Cell Entry Lead to Expression of the C-X-C Chemokine IP-10 , 2002, Journal of Virology.

[36]  Urs F. Greber,et al.  Microtubule-dependent Plus- and Minus End–directed Motilities Are Competing Processes for Nuclear Targeting of Adenovirus , 1999, The Journal of cell biology.

[37]  A. Helenius,et al.  The role of the nuclear pore complex in adenovirus DNA entry , 1997, The EMBO journal.

[38]  P. Stewart,et al.  Role of αv Integrins in Adenovirus Cell Entry and Gene Delivery , 1999, Microbiology and Molecular Biology Reviews.

[39]  E. Marshall.  Gene Therapy's Web of Corporate Connections , 2000, Science.

[40]  I. Kovesdi,et al.  Reducing the Native Tropism of Adenovirus Vectors Requires Removal of both CAR and Integrin Interactions , 2001, Journal of Virology.

[41]  R. D. McCoy,et al.  Pulmonary inflammation induced by incomplete or inactivated adenoviral particles. , 1995, Human gene therapy.

[42]  J. Bergelson,et al.  Isolation of a Common Receptor for Coxsackie B Viruses and Adenoviruses 2 and 5 , 1997, Science.

[43]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[44]  G. Nemerow,et al.  Integrin αvβ1 Is an Adenovirus Coreceptor , 2001, Journal of Virology.

[45]  D. Brough,et al.  The Coxsackievirus-Adenovirus Receptor Protein Can Function as a Cellular Attachment Protein for Adenovirus Serotypes from Subgroups A, C, D, E, and F , 1998, Journal of Virology.

[46]  E. Furth,et al.  Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[47]  I. Kovesdi,et al.  Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression , 1997, Journal of virology.

[48]  S. Rafii,et al.  Infection of Endothelium With E1−E4+, but Not E1−E4−, Adenovirus Gene Transfer Vectors Enhances Leukocyte Adhesion and Migration by Modulation of ICAM-1, VCAM-1, CD34, and Chemokine Expression , 2001, Circulation research.

[49]  G. Nemerow,et al.  Integrins α v β 3 and α v β 5 promote adenovirus internalization but not virus attachment , 1993, Cell.

[50]  J. Wilson,et al.  Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[51]  F. Chisari,et al.  Noncytolytic control of viral infections by the innate and adaptive immune response. , 2001, Annual review of immunology.