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Journal of Virology, December 2000, p. 11329-11338, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion

Ralf Ignatius,1,dagger Mary Marovich,2 Erin Mehlhop,1 Loreley Villamide,1 Karsten Mahnke,1 William I. Cox,3 Frank Isdell,1 Sarah S. Frankel,2 John R. Mascola,2 Ralph M. Steinman,1 and Melissa Pope1,*

Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 100211; Division of Retrovirology, Walter Reed Army Institute of Research and Henry M. Jackson Foundation, Rockville, Maryland 208502; and Virogenetics Corporation, Rensselaer Technology Park, Troy, New York 121803

Received 23 August 2000/Accepted 1 September 2000

Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte-derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs. Furthermore, a subset of DCs matured in the ALVAC-exposed DC cultures. DC maturation coincided with tumor necrosis factor alpha (TNF-alpha ) secretion and was significantly blocked in the presence of anti-TNF-alpha antibodies. Interestingly, inhibition of apoptosis with a caspase 3 inhibitor also reduced some of the maturation induced by exposure to ALVAC. This indicates that both TNF-alpha and the presence of primarily apoptotic cells contributed to DC maturation. Therefore, infection of immature primate DCs with ALVAC results in apoptotic death of infected cells, which can be internalized by noninfected DCs driving DC maturation in the presence of the TNF-alpha secreted concomitantly by exposed cells. This suggests an important mechanism that may influence the immunogenicity of avipox virus vectors.

* Corresponding author. Mailing address: Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-7794. Fax: (212) 327-7764. E-mail: popem{at}rockvax.rockefeller.edu.

dagger Present address: Department of Medical Microbiology and Infectious Diseases Immunology, Institute of Infectious Diseases Medicine, Free University Berlin, 12203 Berlin, Germany.

Journal of Virology, December 2000, p. 11329-11338, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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