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.


METHODS
The rationale for this strategy is that humans who express the homozygous delta32 CCR5 mutation and the associated upregulation of CC chemokines, the down-modulation 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 Mr 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 SHIV(89.6P) infected all macaques, but sequential analysis over 24 weeks showed a significant variation in viral loads between the animals (P = 0.05). Whereas SHIV(89.6P) 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).


CONCLUSIONS
An immunization strategy that targets both the virus and its CCR5 receptor has significantly inhibited SHIV(89.6P) infection and may serve as a novel strategy in the prevention of HIV transmission.
Bogers
Willy M J M
WM
Department of Virology, Biomedical Research Primate Centre, Rijswijk, the Netherlands.
Bergmeier
Lesley A
LA
Ma
Julian
J
Oostermeijer
Herman
H
Wang
Yufei
Y
Kelly
Charles G
CG
Ten Haaft
Peter
P
Singh
Mahavir
M
Heeney
Jonathan L
JL
Lehner
Thomas
T
D016915:AIDS Vaccines / Q000627:therapeutic use*; D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D018791:CD4 Lymphocyte Count; D018946:Chemokine CCL5 / Q000032:analysis; D005260:Female; D015658:HIV Infections / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008253:Macaca mulatta; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D009092:Mucous Membrane / Q000276:immunology; D019713:Receptors, CCR5 / Q000032:analysis / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology; D014621:Vagina / Q000276:immunology; D019562:Viral Load
D016915:AIDS Vaccines; D000914:Antibodies, Viral; D015415:Biomarkers; D018946:Chemokine CCL5; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D007371:Interferon-gamma