Heterologous expression of adenovirus E3-gp19K in an E1a-deleted adenovirus vector inhibits MHC I expression in vitro, but does not prolong transgene expression in vivo (original) (raw)

Gene Therapy volume 4, pages 351–360 (1997)Cite this article

Abstract

An E1a-deleted adenovirus vector constitutively expressing native adenovirus E3-gp19K (Ad.RSV-gp19K) was constructed in order to determine whether or not E3-gp19K mediated interference with antigen presentation would result in prolonged transgene expression in vivo. Cultured fibroblasts infected with Ad.RSV-gp19K produced a native size gp19K protein and had decreased cell surface levels of MHC I as shown by immunoprecipitation and flow cytometry. The congenic mouse strains Balb/b (H-2b MHC I with high gp19K affinity), Balb/k (H-2k MHC I with no gp19K affinity), and Balb/c (H-2d MHC I with moderate gp19K affinity) were chosen for in vivo experiments because of their range of gp19K affinities. Following transduction of mice from each strain with Ad.RSV-gp19K and Ad/RSV-hAAT (a reporter adenovirus), or Ad/RSV-cFIX (control adenovirus) and Ad/RSV-hAAT, the level and duration of serum hAAT protein were unrelated to gp19K protein expression. Evaluation of MHC I abundance on hepatocytes following in vivo transduction demonstrated that recombinant adenovirus rapidly increased the abundance of surface MHC I molecules on hepatocytes, and surface MHC I molecules were reduced earlier and to a greater extent following wild-type adenovirus infection compared with hepatocytes transduced with control or Ad.RSV-gp19K recombinant adenovirus. This difference in surface MHC I down-regulation may be related to the different promoters (RSV-LTR versus the native E3 promoter), and will be an important consideration in the development of newer generation adenovirus vectors designed to evade host immune responses.

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Authors and Affiliations

  1. Division of Medical Genetics, Department of Internal Medicine and Markey Molecular Medicine Center, Seattle, WA, USA
    DB Schowalter, JC Tubb, M Liu & MA Kay
  2. Departments of Pediatrics and Immunology, The University of Washington, Seattle, WA, USA
    CB Wilson
  3. Departments of Biochemistry, Pathology, and Pediatrics, The University of Washington, Seattle, WA, USA
    MA Kay

Authors

  1. DB Schowalter
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  2. JC Tubb
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  3. M Liu
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  4. CB Wilson
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  5. MA Kay
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Schowalter, D., Tubb, J., Liu, M. et al. Heterologous expression of adenovirus E3-gp19K in an E1a-deleted adenovirus vector inhibits MHC I expression in vitro, but does not prolong transgene expression in vivo.Gene Ther 4, 351–360 (1997). https://doi.org/10.1038/sj.gt.3300398

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