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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1963-1969. Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-04-1513. This Article Full Text (PDF) All Versions of this Article: 2005-04-1513v1 107/5/1963    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kavanagh, D. G Articles by Bhardwaj, N. Search for Related Content PubMed PubMed Citation Articles by Kavanagh, D. G Articles by Bhardwaj, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 14, 2005 Accepted October 4, 2005 Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef Daniel G Kavanagh*, Daniel E Kaufmann, Sherzana Sunderji, Nicole Frahm, Sylvie Le Gall, David Boczkowski, Eric S Rosenberg, David R Stone, Mary N Johnston, Bradford S Wagner, Mohammad T Zaman, Christian Brander, Eli Gilboa, Bruce D Walker, and Nina Bhardwaj Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Department of Surgery, Duke University Medical Center, Durham, NC, USA Lemuel Shattuck Hospital, Boston, MA, USA Cancer Institute, Tumor Vaccine Program, New York University School of Medicine, New York, NY, USA; Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA * Corresponding author; email: dkavanagh{at}partners.org. Transfection with synthetic mRNA is a safe and efficient method of delivering antigens to dendritic cells for immunotherapy. Targeting antigens to the lysosome can sometimes enhance the CD4+ T cell response. We transfected antigen presenting cells with mRNA encoding Gag-p24 and cytoplasmic, lysosomal, and secreted forms of Nef. Antigen-specific cytotoxic T cells were able to lyse the majority of transfected targets, indicating that transfection was efficient. Transfection of APCs with a Nef construct bearing lysosomal targeting signals produced rapid and prolonged antigen presentation to CD4+ and CD8+ T cells. Polyclonal CD4+ and CD8+ T cell lines recognizing multiple distinct epitopes were expanded by coculture of transfected dendritic cells with peripheral blood mononuclear cells from viremic and aviremic HIV-infected subjects. Importantly, lysosome-targeted antigen drove a significantly greater expansion of Nef-specific CD4+ T cells than cytoplasmic antigen. The frequency of recognition of CD8 but not CD4 epitopes by mRNA-expanded T cells was inversely proportional to sequence entropy and was similar to ex vivo responses from a large chronic cohort. Thus human dendritic cells transfected with mRNA encoding lysosome-targeted HIV antigen can expand a broad, polyclonal repertoire of antiviral T cells, offering a promising approach to HIV immunotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Minkis, D. G. Kavanagh, G. Alter, D. Bogunovic, D. O'Neill, S. Adams, A. Pavlick, B. D. Walker, M. A. Brockman, R. T. Gandhi, et al. Type 2 Bias of T Cells Expanded from the Blood of Melanoma Patients Switched to Type 1 by IL-12p70 mRNA-Transfected Dendritic Cells Cancer Res., November 15, 2008; 68(22): 9441 - 9450. [Abstract] [Full Text] [PDF] N. M. Melhem, S. M. Gleason, X. D. Liu, and S. M. Barratt-Boyes High-Level Antigen Expression and Sustained Antigen Presentation in Dendritic Cells Nucleofected with Wild-Type Viral mRNA but Not DNA Clin. Vaccine Immunol., September 1, 2008; 15(9): 1337 - 1344. [Abstract] [Full Text] [PDF] E. R. Van Gulck, G. Vanham, L. Heyndrickx, S. Coppens, K. Vereecken, D. Atkinson, E. Florence, I. Kint, Z. N. Berneman, and V. V. Tendeloo Efficient In Vitro Expansion of Human Immunodeficiency Virus (HIV)-Specific T-Cell Responses by gag mRNA-Electroporated Dendritic Cells from Treated and Untreated HIV Type 1-Infected Individuals J. Virol., April 1, 2008; 82(7): 3561 - 3573. [Abstract] [Full Text] [PDF] M. Lichterfeld, D. G. Kavanagh, K. L. Williams, B. Moza, S. K. Mui, T. Miura, R. Sivamurthy, R. Allgaier, F. Pereyra, A. Trocha, et al. A viral CTL escape mutation leading to immunoglobulin-like transcript 4 mediated functional inhibition of myelomonocytic cells J. Exp. Med., November 26, 2007; 204(12): 2813 - 2824. [Abstract] [Full Text] [PDF] L. B. Arruda, D. Sim, P. R. Chikhlikar, M. Maciel Jr, K. Akasaki, J. T. August, and E. T. A. Marques Dendritic Cell-Lysosomal-Associated Membrane Protein (LAMP) and LAMP-1-HIV-1 Gag Chimeras Have Distinct Cellular Trafficking Pathways and Prime T and B Cell Responses to a Diverse Repertoire of Epitopes J. Immunol., August 15, 2006; 177(4): 2265 - 2275. [Abstract] [Full Text] [PDF]

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