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Journal of Virology, June 2002, p. 5711-5719, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5711-5719.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Preexisting Immunity to Adenovirus in Rhesus Monkeys Fails To Prevent Vector-Induced Toxicity

Andrei N. Varnavski,1,,3 Yi Zhang,1 Michael Schnell,1,{dagger} John Tazelaar,1,{ddagger} Jean-Pierre Louboutin,1,,3 Qian-Chun Yu,1,,3 Adam Bagg,2 Guang-ping Gao,1 and James M. Wilson1,3*

Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering,1 Department of Pathology and Laboratory Medicine, University of Pennsylvania,2 The Wistar Institute, Philadelphia, Pennsylvania 191043

Received 28 November 2001/ Accepted 17 February 2002

In an earlier study we evaluated innate immune responses to a first-generation adenoviral vector infused into the portal vein of rhesus monkeys who had never been exposed to adenovirus previously. In these animals, the systemic administration of E1/E3-deleted adenoviral vectors resulted in immediate activation of innate immunity and serious toxicity caused by targeting of vector to antigen-presenting cells and systemic inflammation. We analyze here how these responses are affected by vector-specific preexisting immunity that was induced by intramuscular immunization 6 months prior to evaluation. Our results show that preexposure to the vector substantially diminishes the transgene expression in most tissues but has little effect on gene transfer. Significantly, preimmunization does not eliminate systemic vector-induced toxicity. These conclusions are based on the presence of clinical features of coagulopathy and elevated levels of proinflammatory cytokine interleukin-6 in the serum of animals treated with vector after intramuscular immunization. Furthermore, preexisting immunity appears to induce a vector-specific inhibitory effect on erythroid progenitor development in the bone marrow that is not found when naive animals are challenged with vector.

* Corresponding author. Mailing address: 204 Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268. Phone: (215) 898-3000. Fax: (215) 898-6588. E-mail: wilsonjm{at}mail.med.upenn.edu.

{dagger} Present address: Genassess, Inc., Doylestown, PA 18901.

{ddagger} Present address: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15217.

Journal of Virology, June 2002, p. 5711-5719, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5711-5719.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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