T. Lehner et al., Immunogenicity of the extracellular domains of C-C chemokine receptor 5 and the in vitro effects on simian immunodeficiency virus or HIV infectivity, J IMMUNOL, 166(12), 2001, pp. 7446-7455
The C-C chemokine receptor CCR5 serves an important function in chemotaxis
of lymphocytes, monocytes, and dendritic cells. CCR5 is also the major core
ceptor in most macrophage-tropic HIV-1 infections. Immunization of rhesus m
acaques with a baculovirus-generated CCR5 construct or peptides derived fro
m the sequences of the four extracellular domains of CCR5 elicited IgG and
IgA Abs, inhibition of SIV replication, and CD4(+) T cell proliferative res
ponses to three of the extracellular domains of CCR5. The immune sera react
ed with cell surface CCR5 expressed on HEK 293 cells. T and B cell epitope
mapping revealed major and minor T and B cell epitopes in the N-terminal, f
irst, and second loops of CCR5. The three C-C chemokines, RANTES, macrophag
e-inflammatory protein-lee, and macrophage-inflammatory protein-1 beta, wer
e up-regulated by immunization with the CCR5-derived peptides, and the cell
surface expression of CCR5 was decreased. The CCR5 Abs were complementary
to the C-C chemokines in inhibiting HIV replication in vitro. Immunization
with the four extracellular domains of CCR5 suggests that three of them are
immunogenic, with maximal T cell responses being elicited by the second lo
op peptide. However, maximal Abs to the cell surface CCR5 or viral inhibito
ry Abs in vitro were induced by the N-terminal peptide. Up-regulation of th
e three C-C chemokines and down-modulation of cell surface CCR5 were elicit
ed by the second loop, N-terminal, and first loop peptides. The data sugges
t that a dual mechanism of C-C chemokines and specific Abs may engage and d
own-modulate the CCR5 coreceptors and prevent in vitro HIV or SIV replicati
on.