A novel HIV-CCR5 receptor vaccine strategy in the control of mucosal SIV/HIV infection

Objective: To develop a novel SIV-CCR5 receptor vaccine strategy that will protect macaques from SHIV infection by the vaginal mucosal route. Design: The rationale for this strategy is that humans who express the homozygous Delta32 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. Methods: 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 M-r microbial heat shock protein (HSP70) carrier. The vaccine was administered (X3) either by the vaginal mucosal route or by targeting the proximity of the draining iliac lymph nodes. Results: Serum and vaginal fluid IgG and IgA antibodies, IL-2 and IFN-gamma-producing cells, and macrophage-inflammatory protein (MIP) 1beta and MIP-1alpha (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). Conclusion: 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. (C) 2004 Lippincott Williams & Wilkins.