Induction of immune responses and break of tolerance by DNA against the HIV-1 coreceptor CCR5 but no protection from SIVsm challenge

An inactivating mutation in the human CCR5 gene reduces the risk of HIV-1 i nfection in individuals with homozygous alleles. We explored whether geneti c immunization would induce an immune response directed to CCR5 structures and if immunological tolerance toward endogenous CCR5 could be broken. We a lso studied whether this immunization approach could protect cynomolgus mon keys from an infection, with SIVsm, which primarily uses CCR5 as a corecept or. Epidermal but not intramuscular delivery of the CCR5 gene to mice elici ted strong IgG antibody binding responses to CCR5. Intramucosal immunizatio n of cynomolgus macaques with CCR5 DNA followed by boosts with CCR5 peptide s induced prominent IgG and IgA antibody responses in serum and vaginal was hings. The CCR5-specific antibodies neutralized the infectivity of primary human R5 HIV-1 strains, and the macaque SIVsm but not that of a tissue cult ure-adapted X4 HIV-1 strain. The consecutive CCR5 gene and CCR5 peptide imm unizations induced B- and T-cell responses to peptides representing both hu man and macaque amino acid sequences of the respective CCR5 proteins. This indicates that tolerance was broken against endogenous macaque CCR5, which has a 98% homology to the human CCR5 gene. After the final boost, the vacci nated monkeys together with two control monkeys were challenged with SIVsm. Neither protection against nor enhancement of SIVsm infection was achieved . (C) 2000 Academic Press.