Most HIV infections occur by transmission across mucosal surfaces, where dendritic cells (DCs) are the first cells to encounter the virus. Dendritic cells are specialized antigen-presenting cells critical for eliciting T cell-mediated immune responses. Delayed-type hypersensitivity (DTH) is a cellular immune response in some viral infections and it is mediated by CD4+ and/or CD8+ T cells. We hypothesized that a DTH response to HIV induced by antigen-pulsed DCs would protect against a mucosal exposure to the virus. In a small pilot experiment, six rhesus monkeys were immunized with autologous, antigen-pulsed DCs by the intradermal route and five of the monkeys were boosted with a second dose of DCs at 3 months. Antibody responses to SIV were detected in two of six vaccinated monkeys, lymphocyte-proliferative responses were detected in five of the six monkeys and cytotoxic T lymphocyte (CTL) responses were detected in four of the six monkeys. Using a novel in vitro assay of SIV replication in DCs cocultured with autologous CD4+ T cells and monocytes, suppression of viral replication was detected from five of the six monkeys at multiple time points before and after SIV challenge. Macaques were orally challenged with SIVmac239 at 1-3 months after the booster inoculation. Peak viral loads were similar to those of four naive animals but, compared with naive monkeys, declined at 6 months to levels 1 log(10) or more lower in monkeys that had been vaccinated and that had > or = 50% suppression of SIV replication in DCs. Optimizing this immunization strategy may result in a strong antiviral DTH response that could better control a mucosal lentiviral infection.