A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells
Frank,Ines; Stoessel,Hella; Gettie,Agegnehu; Turville,Stuart G.; Bess Jr.,Julian W.; Lifson,Jeffrey D.; Sivin,Irving; Romani,Nikolaus; Robbiani,Melissa
Journal of Virology 82(11): 5329-5339
Publication date: 2008
Dendritic cells (DCs) play a key role in innate immune responses,and their interactions with T cells are critical for the inductionof adaptive immunity. However, immunodeficiency viruses areefficiently captured by DCs and can be transmitted to and amplifiedin CD4 T cells, with potentially deleterious effects on theinduction of immune responses. In DC-T cell co-cultures, contactwith CD4, not CD8, T cells preferentially facilitated virusmovement to and release at immature and mature DC-T cell contactsites. This occurred within 5 minutes of DC-T cell contact.While the fusion inhibitor T-1249 did not prevent virus captureby DCs nor the release of viruses at the DC-T cell contact points,it readily blocked virus transfer to and amplification in CD4T cells. Higher doses of T-1249 were needed to block the morerobust replication driven by mature DCs. Virus accumulated inDCs within T-1249-treated co-cultures but they were actuallyless infectious than DCs isolated from untreated co-cultures.Importantly, T-1249 did not interfere with the stimulation ofvirus-specific CD4 and CD8 T cell responses when present duringvirus-loading of DCs or for the time of the DC-T cell co-culture.These results provide clues to identifying strategies to preventDC-driven virus amplification in CD4 T cells, whilst maintainingvirus-specific immunity, an objective critical in the developmentof microbicides and therapeutic vaccines.