A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells
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.
Frank, Ines, Hella Stoessel, Agegnehu Gettie, Stuart G. Turville, Julian W. Bess Jr., Jeffrey D. Lifson, Irving Sivin, Nikolaus Romani, and Melissa Robbiani. 2008. "A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells," Journal of Virology 82(11): 5329–5339.