Journal Article

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 co-cultures, 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 minutes of DC–T-cell contact. While the fusion inhibitor T-1249 did not prevent virus capture by DCs nor 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 co-cultures but they were actually less infectious than DCs isolated from untreated co-cultures. 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 co-culture. These results provide clues to identifying strategies to prevent DC-driven virus amplification in CD4+ T cells, whilst maintaining virus-specific immunity, an objective critical in the development of microbicides and therapeutic vaccines.