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Journal of Virology, June 2004, p. 5966-5972, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5966-5972.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo

Daniel A. Muruve,1* Matthew J. Cotter,1 Anne K. Zaiss,1 Lindsay R. White,1 Qiang Liu,1,{dagger} Trevor Chan,1 Sharon A. Clark,1 P. Joel Ross,2 Robert A. Meulenbroek,2 Gunhild M. Maelandsmo,3 and Robin J. Parks2

Department of Medicine and Libin Gene Therapy Unit, University of Calgary, Calgary, Alberta,1 Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada,2 Department of Tumor Biology, Norwegian Radium Hospital, Oslo, Norway3

Received 23 October 2003/ Accepted 3 February 2004

Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.

* Corresponding author. Mailing address: Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N.W., Calgary, AB, T2N 4N1 Canada. Phone: (403) 220-3908. Fax: (403) 270-0979. E-mail: dmuruve{at}ucalgary.ca.

{dagger} Present address: University of Saskatchewan, VIDO, Saskatoon, Saskatchewan, Canada.

Journal of Virology, June 2004, p. 5966-5972, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5966-5972.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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