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Journal of Virology, August 1999, p. 6708-6714, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Resistance of Retroviral Vectors Produced from Human Cells to Serum Inactivation In Vivo and In Vitro Is Primate Species Dependent

Nicholas J. DePolo,1,* Cataline E. Harkleroad,1 Mordechai Bodner,1 Andrew T. Watt,1 Carol G. Anderson,1 Judith S. Greengard,1 Krishna K. Murthy,2 Thomas W. Dubensky Jr.,1 and Douglas J. Jolly1

Vector Technologies Group, Center for Gene Therapy, Chiron Technologies, San Diego, California 92121,1 and Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas 782272

Received 23 February 1999/Accepted 10 May 1999

The ability to deliver genes as therapeutics requires an understanding of the vector pharmacokinetics similar to that required for conventional drugs. A first question is the half-life of the vector in the bloodstream. Retroviral vectors produced in certain human cell lines differ from vectors produced in nonhuman cell lines in being substantially resistant to inactivation in vitro by human serum complement (F. L. Cosset, Y. Takeuchi, J. L. Battini, R. A. Weiss, and M. K. Collins, J. Virol. 69:7430-7436, 1995). Thus, use of human packaging cell lines (PCL) may produce vectors with longer half-lives, resulting in more-efficacious in vivo gene therapy. However, survival of human PCL-produced vectors in vivo following systemic administration has not been explored. In this investigation, the half-lives of retroviral vectors packaged by either canine D17 or human HT1080 PCL were measured in the bloodstreams of macaques and chimpanzees. Human PCL-produced vectors exhibited significantly higher concentrations of circulating biologically active vector at the earliest time points measured (>1,000-fold in chimpanzees), as well as substantially extended half-lives, compared to canine PCL-produced vectors. In addition, the circulation half-life of human PCL-produced vector was longer in chimpanzees than in macaques. This was consistent with in vitro findings which demonstrated that primate serum inactivation of vector produced from human PCL increased with increasing phylogenetic distance from humans. These results establish that in vivo retroviral vector half-life correlates with in vitro resistance to complement. Furthermore, these findings should influence the choice of animal models used to evaluate retroviral-vector-based therapies.

* Corresponding author. Mailing address: Chiron Technologies, Center for Gene Therapy, 11055 Roselle St., San Diego, CA 92121. Phone: (619) 452-1288. Fax: (619) 623-9975. E-mail: nick_depolo{at}cc.chiron.com.

Journal of Virology, August 1999, p. 6708-6714, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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