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Journal of Virology, June 2002, p. 5692-5700, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5692-5700.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

Huang-Ge Zhang,1,2 Jinfu Xie,1 Liang Xu,1 Pingar Yang,1 Xin Xu,1 Sheher Sun,1 Yongming Wang,1 David T. Curiel,3 Hui-Chen Hsu,1 and John D. Mountz1,2*

Division of Clinical Immunology and Rheumatology,1 Division of Human Gene Therapy, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294,3 Veterans Administration Medical Center, Birmingham, Alabama 352332

Received 26 July 2001/ Accepted 21 February 2002

A major limitation of adenovirus (Ad) gene therapy product expression in the liver is subsequent elimination of the hepatocytes expressing the gene therapy product. This elimination is caused by both necrosis and apoptosis related to the innate and cell-mediated immune response to the Ad. Apoptosis of hepatocytes can be induced by the innate immune response by signaling through death domain receptors on hepatocytes including the tumor necrosis factor alpha (TNF-{alpha}) receptor (TNFR), Fas, and death domain receptors DR4 and DR5. We have previously shown that blocking signaling through TNFR enhances and prolongs gene therapy product expression in the liver. In the present study, we constructed an Ad that produces a soluble DR5-Fc (AdsDR5), which is capable of neutralizing TNF-related apoptosis-inducing ligand (TRAIL). AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ administration and enhances the level and duration of lacZ transgene expression in the liver. In addition to blocking TRAIL and directly inhibiting apoptosis, AdsDR5 decreases production of gamma interferon (IFN-{gamma}) and TNF-{alpha} and decreases NK cell activation, all of which limit Ad-mediated transgene expression in the liver. These results indicate that (i) AdsDR5 produces a DR5-Fc capable of neutralizing TRAIL, (ii) AdsDR5 can reduce activation of NK cells and reduce induction of IFN-{gamma} and TNF-{alpha} after Ad administration, and (iii) administration of AdsDR5 can enhance Ad gene therapy in the liver.

* Corresponding author. Mailing address: The University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, 701 South 19th St., LHRB 473, Birmingham, AL 35294. Phone: (205) 934-8909. Fax: (205) 975-6648. E-mail: john.mountz{at}ccc.uab.edu.

Journal of Virology, June 2002, p. 5692-5700, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5692-5700.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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