We previously demonstrated that mucosal immunization with SHIV virus-like particles (VLPs) was able to induce strong humoral and cellular immune responses against HIV envelope protein (Env). To understand the mechanism for such enhanced immune responses, we studied the interaction between VLPs and dendritic cells (DCs) in initiating immune responses. We found that about 50% of DCs were bound by octadecyle rhodamine B (R18) labeled SHIV VLPs. The bound SHIV VLPs were internalized by DCs when cultured at 37 degrees C. Incubation of immature human PBMC-derived DCs with SHIV VLPs for 48 h resulted in the significant up-regulation of CD40, CD80, CD83, CD54, CD86, HLA-A, B, C and HLA-DR, DP, DQ molecules on activated DC CD11c+ subpopulations. SHIV VLPs efficiently stimulated DCs to release IL-12, IFN-gamma and TNF-alpha. Furthermore, SHIV VLPs-activated DCs were fully functional in inducing allogeneic T cell proliferation. We conclude that DCs can interact and process SHIV VLPs efficiently and may be critical in initiation of SHIV VLPs-induced immune responses. Thus, interaction between VLPs and DCs may play an important role in the enhancement of immune responses in VLPs-based vaccination.