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Journal of Virology, June 2008, p. 5329-5339, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.01987-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Fusion Inhibitor Prevents Spread of Immunodeficiency Viruses, but Not Activation of Virus-Specific T Cells, by Dendritic Cells

I. Frank,¹ H. Stössel,² A. Gettie,³ S. G. Turville,^1, J. W. Bess Jr.,⁴ J. D. Lifson,⁴ I. Sivin,¹ N. Romani,² and M. Robbiani^1*

Center for Biomedical Research, Population Council, New York, New York 10065,¹ Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria,² Aaron Diamond AIDS Research Center, 455 First Avenue New York, New York 10016,³ AIDS Vaccine Program, SAIC Frederick, National Cancer Institute at Frederick, Building 535, Frederick, Maryland 21702⁴

Received 10 September 2007/ Accepted 14 March 2008

Dendritic cells (DCs) play a key role in innate immune responses, and their interactions with T cells are critical for the induction of adaptive immunity. However, immunodeficiency viruses are efficiently captured by DCs and can be transmitted to and amplified in CD4⁺ T cells, with potentially deleterious effects on the induction of immune responses. In DC-T-cell cocultures, contact with CD4⁺, not CD8⁺, T cells preferentially facilitated virus movement to and release at immature and mature DC-T-cell contact sites. This occurred within 5 min of DC-T-cell contact. While the fusion inhibitor T-1249 did not prevent virus capture by DCs or the release of viruses at the DC-T-cell contact points, it readily blocked virus transfer to and amplification in CD4⁺ T cells. Higher doses of T-1249 were needed to block the more robust replication driven by mature DCs. Virus accumulated in DCs within T-1249-treated cocultures but these DCs were actually less infectious than DCs isolated from untreated cocultures. Importantly, T-1249 did not interfere with the stimulation of virus-specific CD4⁺ and CD8⁺ T-cell responses when present during virus-loading of DCs or for the time of the DC-T-cell coculture. These results provide clues to identifying strategies to prevent DC-driven virus amplification in CD4⁺ T cells while maintaining virus-specific immunity, an objective critical in the development of microbicides and therapeutic vaccines.

Published ahead of print on 26 March 2008.

Present address: Center for Virus Research, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia.