Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long- term gene expression

Y. Ilan, G. Droguett, N. R. Chowdhury, Y. Li, K. Sengupta, N. R. Thummala, A. Davidson, Jayanta Roy-Chowdhury, M. S. Horwitz

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

Recombinant adenoviruses (Ads) are highly efficient at transferring FOreign genes to the liver in vivo; however, the duration of gene expression is limited by the host antiviral immune response, which prevents expression upon readministration of the virus. To test whether overexpression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expression of foreign genes delivered by Ad vectors, we injected a recombinant Ad (Ad-E3-hBUGT), containing both E3 and the human bilirubin-uridine-diphosphoglucuronate- glucuronosyltransferase (BUGT) genes, into BUGT-deficient hyperbilirubinemic Gunn rats. Control Gunn rats received Ad-hBUGT, which expresses human BUGT alone. An initial injection of either virus resulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubin levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days. In Ad-E3-hBUGT-injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 days after infection, but a second administration of the virus on that day resulted in a hypobilirubinemic response similar to that seen with the first injection. In contrast, rats receiving Ad-hBUGT had serum bilirubin levels of 7 mg/dl on day 84 after infection, but showed no reduction of serum bilirubin by reinjection of the virus on that day. In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad-specific cytotoxic T lymphocyte responses. This is the first demonstration that insertion of E3 genes in recombinant Ads facilitates readministration of a functional vector for long-term correction of an inherited metabolic disorder.

Original languageEnglish (US)
Pages (from-to)2587-2592
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number6
DOIs
StatePublished - 1997

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Humoral Immunity
Bilirubin
Cellular Immunity
Antiviral Agents
Gene Expression
Glucuronosyltransferase
Uridine
Gunn Rats
Viruses
Serum
Adenoviridae
Injections
Insertional Mutagenesis
Liver
Cytotoxic T-Lymphocytes
Infection
Bile
Genes
Genome
Antibodies

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long- term gene expression. / Ilan, Y.; Droguett, G.; Chowdhury, N. R.; Li, Y.; Sengupta, K.; Thummala, N. R.; Davidson, A.; Roy-Chowdhury, Jayanta; Horwitz, M. S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 1997, p. 2587-2592.

Research output: Contribution to journalArticle

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abstract = "Recombinant adenoviruses (Ads) are highly efficient at transferring FOreign genes to the liver in vivo; however, the duration of gene expression is limited by the host antiviral immune response, which prevents expression upon readministration of the virus. To test whether overexpression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expression of foreign genes delivered by Ad vectors, we injected a recombinant Ad (Ad-E3-hBUGT), containing both E3 and the human bilirubin-uridine-diphosphoglucuronate- glucuronosyltransferase (BUGT) genes, into BUGT-deficient hyperbilirubinemic Gunn rats. Control Gunn rats received Ad-hBUGT, which expresses human BUGT alone. An initial injection of either virus resulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubin levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days. In Ad-E3-hBUGT-injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 days after infection, but a second administration of the virus on that day resulted in a hypobilirubinemic response similar to that seen with the first injection. In contrast, rats receiving Ad-hBUGT had serum bilirubin levels of 7 mg/dl on day 84 after infection, but showed no reduction of serum bilirubin by reinjection of the virus on that day. In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad-specific cytotoxic T lymphocyte responses. This is the first demonstration that insertion of E3 genes in recombinant Ads facilitates readministration of a functional vector for long-term correction of an inherited metabolic disorder.",
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AU - Droguett, G.

AU - Chowdhury, N. R.

AU - Li, Y.

AU - Sengupta, K.

AU - Thummala, N. R.

AU - Davidson, A.

AU - Roy-Chowdhury, Jayanta

AU - Horwitz, M. S.

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