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To develop a novel SIV-CCR5 receptor vaccine strategy that will protect macaques from SHIV infection by the vaginal mucosal route.The rationale for this strategy is that humans who express the homozygous Δ32 CCR5 mutation and the associated upregulation of CC chemokines, the downmodulation of cell-surface expression of CCR5 and antibodies to CCR5 are protected against HIV infection.A vaccine was prepared consisting of three extracellular peptides of CCR5, an N-terminal HIV gp120 fragment generated in transgenic plants and recombinant SIV p27. These were linked to the 70 000 Mr microbial heat shock protein (HSP70) carrier. The vaccine was administered (×3) either by the vaginal mucosal route or by targeting the proximity of the draining iliac lymph nodes.Serum and vaginal fluid IgG and IgA antibodies, IL-2 and IFN-γ-producing cells, and macrophage-inflammatory protein (MIP) 1β and MIP-1α (CCL4 and CCL3) were significantly raised in immunized macaques (P = 0.01–0.05). Vaginal challenge with SHIV89.6P infected all macaques, but sequential analysis over 24 weeks showed a significant variation in viral loads between the animals (P = 0.05). Whereas SHIV89.6P persisted in the four unimmunized macaques, in five of the eight immunized macaques the virus was cleared or became undetectable by reverse transcriptase–polymerase chain reaction. The CD4 cell counts in the immunized macaques were significantly higher than those in unimmunized animals (P < 0.05).An immunization strategy that targets both the virus and its CCR5 receptor has significantly inhibited SHIV89.6P infection and may serve as a novel strategy in the prevention of HIV transmission.