Dendritic cells (DCs), the immune system?s most effective antigen presenting cells, have been (i) implicated, along with T cells, as one of the first cells targeted by HIV after mucosal exposure and (ii) shown to promote virus replication in concert with CD4+ T cells. Paralleling the human system, macaque DC-T cell mixtures have been defined as a distinctive niche in which SIV can propogate in vitro and in vivo. Different subsets of DCs and T cells and the virus itself can influence the level of virus growth. Furthermore, DCs express several molecules that are used by the virus for binding and entry, including CD4, chemokine receptors, and DC-SIGN. Therefore, having the capacity to interfere with DC-virus interactions and impede virus replication when DCs encounter T cells would be advantageous for microbicide strategies. This proposal will focus on defining how carrageenan-derived compounds impact DC-virus interactions and their ability to drive virus spread between cells in vitro and in vivo. The net negative charge of carrageenans likely repels virus interactions with the target cell and, thus, impairs interactions with all potential virus receptors on the DC surface. Four pertinent questions will be considered to evaluate this strategy. 1. Do carrageenans influence DC function? 2. 2. Can carrageenan-based reagents block the binding, uptake or transmission of SIV by DCs using a novel inactivated virus model? 3. Are modified carrageenan-derived formulations more effective at impeding virus replication in the DC- T cell milieu? 4. Will carrageenan-based products prevent vaginal transmission in macaques? This work will uncover how carrageenan-based compounds oppose DC-driven virus spread, one of the critical steps in establishing infection upon mucosal exposure. Defining optimal conditions, under which this natural compound can be exploited in this way, will create a solid basis to advance carrageenan-derived microbicide formulations to prevent HIV transmission.
