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Journal of Virology, June 2004, p. 6151-6161, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6151-6161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus

Marie Larsson,1* Ethan Babcock,1 Arash Grakoui,2 Naglaa Shoukry,3 Georg Lauer,4 Charles Rice,2 Christopher Walker,3 and Nina Bhardwaj1

Departments of Medicine and Pathology, School of Medicine, New York University, New York, New York 10016,1 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10021,2 The Center for Vaccines and Immunity, Columbus Children's Research Institute, and Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205,3 Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 021144

Received 16 November 2003/ Accepted 10 February 2004

Dendritic cells (DCs), which are potent antigen-presenting cells (APCs), are used as adjuvants for the treatment of cancer and infectious diseases in human and nonhuman primates, with documented clinical efficacy. The hepatitis C virus (HCV)-chimpanzee model is the best available model for testing the immunotherapeutic effects of DCs in the setting of a chronic infection, as chimpanzees develop a persistent infection resembling that seen in humans. However, several reports have suggested that DCs derived from chronically infected individuals or nonhuman primates are functionally compromised. As a prelude to clinical studies, we evaluated whether functionally mature DCs could be generated in chimpanzee plasma by good manufacturing practice using CD14+ mononuclear precursors from chronically infected chimpanzees. DCs generated in a medium with HCV-negative plasma and treated with a defined cocktail of cytokines or a CD40 ligand trimer matured fully, as measured by the induction of CD83 expression and the upregulation of costimulatory molecules. Furthermore, the expression of CCR7 was induced, suggesting an acquisition of migration capacity. Mature DCs were capable of stimulating allogeneic T cells, antigen-specific memory CD4+ T cells, and HCV-specific CD8+-T-cell clones. In all cases, there was no evidence of HCV infection in DCs. Furthermore, these DCs maintained their phenotype and APC function after cryopreservation. Finally, no discernible differences were noted between DCs derived from HCV-infected and uninfected chimpanzees. In summary, precursor cells from HCV-infected chimpanzees are fully capable of differentiating into functional, mature DCs, which can now be reproducibly prepared for investigations of their immunotherapeutic potential in the setting of chronic HCV infection.

* Corresponding author. Mailing address: New York University School of Medicine, New York, NY 10016. Phone: (212) 263-6727. Fax: (212) 263-6729. E-mail: larssm01{at}med.nyu.edu.

Journal of Virology, June 2004, p. 6151-6161, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6151-6161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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