The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver

Anton P. McCaffrey; Paul Fawcett; Hiroyuki Nakai; Ramona L. McCaffrey; Anja Ehrhardt; Thu Thao T. Pham; Kusum Pandey; Hui Xu; Sally Feuss; Theresa A. Storm; Mark A. Kay

doi:10.1038/mt.2008.37

The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver

Anton P. McCaffrey, Paul Fawcett, Hiroyuki Nakai, Ramona L. McCaffrey, Anja Ehrhardt, Thu Thao T. Pham, Kusum Pandey, Hui Xu, Sally Feuss, Theresa A. Storm, Mark A. Kay

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a "first-generation" adenoviral (Ad) vector, a helper-dependent "gutless" adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction.

Original language	English (US)
Pages (from-to)	931-941
Number of pages	11
Journal	Molecular Therapy
Volume	16
Issue number	5
DOIs	https://doi.org/10.1038/mt.2008.37
State	Published - May 2008
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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@article{1e10805017e54402928e930388c426c8,

title = "The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver",

abstract = "Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a {"}first-generation{"} adenoviral (Ad) vector, a helper-dependent {"}gutless{"} adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction.",

author = "McCaffrey, {Anton P.} and Paul Fawcett and Hiroyuki Nakai and McCaffrey, {Ramona L.} and Anja Ehrhardt and Pham, {Thu Thao T.} and Kusum Pandey and Hui Xu and Sally Feuss and Storm, {Theresa A.} and Kay, {Mark A.}",

note = "Funding Information: We kindly thank Patrick O. Brown for his support and guidance. This work was funded by National Institutes of Health Grant HL 64274 (M.A.K.) and Defence Advanced Research Planning Agency Grant N65236-99-1-5428 (Patrick O. Brown).",

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AU - McCaffrey, Anton P.

AU - Fawcett, Paul

AU - Nakai, Hiroyuki

AU - McCaffrey, Ramona L.

AU - Ehrhardt, Anja

AU - Pham, Thu Thao T.

AU - Pandey, Kusum

AU - Xu, Hui

AU - Feuss, Sally

AU - Storm, Theresa A.

AU - Kay, Mark A.

N1 - Funding Information: We kindly thank Patrick O. Brown for his support and guidance. This work was funded by National Institutes of Health Grant HL 64274 (M.A.K.) and Defence Advanced Research Planning Agency Grant N65236-99-1-5428 (Patrick O. Brown).

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N2 - Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a "first-generation" adenoviral (Ad) vector, a helper-dependent "gutless" adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction.

AB - Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a "first-generation" adenoviral (Ad) vector, a helper-dependent "gutless" adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction.

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The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver

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