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 infection in individuals with homozygous alleles. We explored whether genetic immunization would induce an immune response directed to CCR5 structures and if immunological tolerance toward endogenous CCR5 could be broken. We also studied whether this immunization approach could protect cynomolgus monkeys from an infection, with SIVsm, which primarily uses CCR5 as a coreceptor. Epidermal but not intramuscular delivery of the CCR5 gene to mice elicited strong IgG antibody binding responses to CCR5. Intramucosal immunization of cynomolgus macaques with CCR5 DNA followed by boosts with CCR5 peptides induced prominent IgG and IgA antibody responses in serum and vaginal washings. The CCR5-specific antibodies neutralized the infectivity of primary human R5 HIV-1 strains, and the macaque SIVsm but not that of a tissue culture-adapted X4 HIV-1 strain. The consecutive CCR5 gene and CCR5 peptide immunizations induced B- and T-cell responses to peptides representing both human 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 vaccinated monkeys together with two control monkeys were challenged with SIVsm. Neither protection against nor enhancement of SIVsm infection was achieved.
Zuber
B
B
Swedish Institute for Infectious Disease Control, Solna, Sweden. bartek.zuber@smi.ki.se
Hinkula
J
J
Vödrös
D
D
Lundholm
P
P
Nilsson
C
C
Mörner
A
A
Levi
M
M
Benthin
R
R
Wahren
B
B
D000595:Amino Acid Sequence; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D000917:Antibody Formation; D001483:Base Sequence; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA
D000910:Antibodies, Heterophile; D007074:Immunoglobulin G; D019713:Receptors, CCR5; D019444:Vaccines, DNA